Page 1 of 85 Diabetes

Heparanase overexpression induces glucagon resistance and

protects animals from chemically-induced diabetes

Dahai Zhang1, Fulong Wang1, Nathaniel Lal1, Amy Pei-Ling Chiu1, Andrea Wan1, Jocelyn

Jia1, Denise Bierende1, Stephane Flibotte1, Sunita Sinha1, Ali Asadi2, Xiaoke Hu2, Farnaz

Taghizadeh2, Thomas Pulinilkunnil3, Corey Nislow1, Israel Vlodavsky4, James D.

Johnson2, Timothy J. Kieffer2, Bahira Hussein1 and Brian Rodrigues1

1Faculty of Pharmaceutical Sciences, UBC, 2405 Wesbrook Mall, Vancouver, BC, Canada V6T

1Z3; 2Department of Cellular & Physiological Sciences, Life Sciences Institute, UBC, 2350

Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3; 3Department of Biochemistry and

Molecular Biology, Faculty of Medicine, Dalhousie University, 100 Tucker Park Road, Saint

John, NB, Canada E2L 4L5; 4Cancer and Vascular Biology Research Center, Rappaport

Faculty of Medicine, Technion, Haifa, Israel 31096

Running Title: Heparanase overexpression and the pancreatic islet

Corresponding author:

Dr. Brian Rodrigues

Faculty of Pharmaceutical Sciences

University of British Columbia, 2405 Wesbrook Mall, Vancouver, B.C., Canada V6T 1Z3

TEL: (604) 8224758; FAX: (604) 8223035

Email: [email protected]

Key Words: Heparanase, heparan sulfate proteoglycan, glucose homeostasis, glucagon

resistance, pancreatic islet, STZ

Word Count: 4761

Total Number of DiabetesFigures: Publish 6 Ahead of Print, published online October 7, 2016 Diabetes Page 2 of 85

Abstract

Heparanase, a protein with enzymatic and nonenzymatic properties, contributes towards disease progression and prevention. In the current study, a fortuitous observation in transgenic mice globally overexpressing heparanase (heptg) was the discovery of improved glucose homeostasis. We examined the mechanisms that contribute towards this improved glucose metabolism. Heparanase overexpression was associated with enhanced GSIS and hyperglucagonemia, in addition to changes in islet composition and structure. Strikingly, the pancreatic islet transcriptome was greatly altered in heptg mice with over 2000 genes differentially expressed versus control. The upregulated genes were enriched for diverse functions including cell death regulation, extracellular matrix component synthesis, and pancreatic hormone production. The downregulated genes were tightly linked to regulation of the cell cycle. In response to multiple lowdose STZ, heptg animals developed less severe hyperglycemia compared to WT, an effect likely related to their beta cells being more functionally efficient. In animals given a single, high dose of STZ, causing severe and rapid development of hyperglycemia related to the catastrophic loss of insulin, heptg mice continued to have significantly lower blood glucose. In these mice, protective pathways were uncovered for managing hyperglycemia and include augmentation of FGF21 and GLP1. This study uncovers the opportunity to utilize properties of heparanase in management of diabetes.

Page 3 of 85 Diabetes

Introduction

Heparan sulfate proteoglycans (HSPG), located mainly on the cell surface and in the

extracellular matrix, are composed of a core protein to which one or more heparan sulfate (HS)

side chains are attached (1). HSPGs function, not only as structural proteins, but also as

anchors for bioactive molecules, as HS is negatively charged. Highly expressed in pancreatic

islets, HS binds and guides the signalling and distribution of fibroblast growth factor (FGF)

family members, which regulate pancreatic endocrine cell differentiation, clustering and

development (2). It has been suggested that the presence of HSPG in the nucleus has a

suppressive effect on histone acetyltransferase activity and may therefore modulate gene

expression (3).

Heparanase is an endoβDglucuronidase that is ubiquitously expressed in many organs,

with blood and endothelial cells having the highest expression. Heparanase is encoded as a

65kDa latent precursor (HepL) that requires proteolytic cleavage to form an active enzyme

(HepA) (4). Functionally, HepA cleaves HS at Dglucuronic acid residues, an action associated

with extracellular matrix disruption (5) and release of cell surfacebound molecules such as

FGF (2). Aside from the function of HepA in cleaving HS, HepL can also activate numerous

signalling elements including Erk1/2, PI3KAKT, RhoA and Src (69). These signalling events,

in addition to the entry of HepA into the nucleus to regulate histone acetylation by cleaving HS,

have been suggested as mechanisms for modulating gene expression (3).

Heparanase has physiological functions in wound healing and hair growth (10). However,

intensive research has also hinted towards an additional role of heparanase in both disease

progression and prevention. Thus, in cancer, degradation of HS chains by the increased

expression of heparanase is associated with extracellular matrix and basement membrane

(BM) disruption; loss of this physical barrier facilitates tumour cell invasion (11). In the

pancreas, isletenriched HS blocks immune cell infiltration, reduces Tcell mediated Diabetes Page 4 of 85

inflammation (12), and supports beta cell survival and function (13). Thus, removal of HS by heparanase is critical for the initiation and progression of autoimmune (Type 1) diabetes (12).

Additionally, heparanase expression is induced in many organs during diabetes. In the heart, such inappropriate expression may amplify fatty acid delivery and utilization. These events, if sustained, can lead to lipotoxicity and cardiovascular disease (14). In contrast to these observations, heparanase has also been shown to have beneficial effects in some diseases.

For instance, overexpression of this protein is protective against adriamycininduced kidney injury (15). In the brain, fragmentation of HS as a result of heparanase cleavage reduced amyloid deposition in Alzheimer’s disease (16). Similarly, amyloid formation in the islets, a hallmark of Type 2 diabetes, could be ameliorated by heparanaseinduced matrix metalloproteinase9 (MMP9) expression (17; 18). MMP9 constitutes an endogenous islet protease that limits islet amyloid deposition and its concomitant toxic effects via degradation of the amyloid polypeptide (19). Thus, precise temporal and spatial control of heparanase may be essential for normal cell physiology.

In the current study, when monitoring the metabolism of transgenic mice that globally overexpress heparanase (heptg), we made the fortuitous observation that glucose homeostasis was improved in these animals. Compared to wild type (WT) controls, these mice had lower plasma insulin and blood glucose levels; however, they exhibited higher glucagon concentrations, suggesting the presence of glucagon resistance. Given that glucagon receptor knockout (GRKO) mice exhibited increased insulin sensitivity and resistance to diabetes (20; 21), we followed up these preliminary observations by examining whether heparanase overexpression could contribute towards improving glucose metabolism as well as resistance to chemicallyinduced diabetes. Our data indicate that heparanase overexpression is associated with dramatic shifts in hormones secreted from the pancreas, reorganization of islet composition and structure, significant changes in islet gene expression, and protection from streptozotocin (STZ)induced diabetes. Page 5 of 85 Diabetes

Research Design and Methods

Experimental Animals

Wild type (WT) C57BL/6J mice aged 10 to 12 weeks were purchased from Charles River

Laboratories. Heparanase transgenic mice (heptg), in which a constitutive βactin promoter

drives the expression of human heparanase gene in a C57BL/6J genetic background, were a

kind gift from Dr. Israel Vlodavsky. All animals were housed in 12h light/dark cycle, and

pathogenfree conditions. Heptg mice were previously crossed for 10 generations with

C57BL/6J mice to produce a stable homozygous background. Male homozygous heptg mice

aged 12 to 15 weeks were used for all experiments. For confirmation of genotype, genomic

DNA was prepared from 21 dayold animal ear punched tissue, and analyzed by PCR (Fig. 1

A) as previously detailed (10). All experiments were approved by the University of British

Columbia Animal Care Committee, and were performed in accordance with the Canadian

Council on Animal Care Guidelines.

Metabolic Assessments and Treatment of Animals

For measurement of basal blood glucose and plasma hormones, animals were fasted for 6 or

16 h and blood sampled from the tail vein. Blood glucose was measured using an ACCU-

CHEK glucose monitor (Roche, Basel, Switzerland). Blood was also collected using a

heparinized microtube (Fisher Scientific, Waltham, MA, USA), and centrifuged immediately

for separation of plasma. Circulating hormones in the plasma were measured using the

following kits: mouse insulin (ALPCO, Salem, NH, USA), glucagon and GLP1 (Meso Scale

Discovery, Rockville, MD, USA), FGF21 (R&D Systems, Minneapolis, MN, USA). For the oral

glucose tolerance test (OGTT) or intraperitoneal (i.p.) glucose tolerance test (IPGTT), animals

were fasted overnight (16 h), 2 g/kg glucose administered orally or i.p., and blood glucose

measured at the indicated times. A different cohort of animals was treated in the same

manner for the assessment of insulin following the OGTT. To perform the glucagon challenge, Diabetes Page 6 of 85

glucagon (1 µg/kg body weight) was administered i.p. into 6 or 16 h fasted mice, and blood glucose measured at the indicated times. The insulin (0.75 U/kg body weight) and Larginine

(2 g/kg, i.p.) challenge were performed the same way in 6 h fasted mice. In addition to glucose measurement following injection of Larginine, plasma insulin and glucagon were also measured at the indicated times. For evaluation of skeletal muscle sensitivity to insulin, mice were fasted for 6 h prior to an i.p. injection of 2 µg/kg insulin. 10 min post insulin injection, skeletal muscle (soleus and gastrocnemius) was isolated for Western Blot determination of phospho and total Akt (Cell Signalling, Danvers, MA, USA), with beta actin (Santa Cruz,

Dallas, TX, USA) used as an internal control.

Diabetes Induction

Streptozotocin (STZ) is a betacell selective toxin. Using STZ, we employed two different strategies to induce diabetes. With the first protocol, we injected multiple low doses of STZ

(MLDSTZ, 50 mg/kg i.p.) for 5 consecutive days. This procedure induces gradual beta cell death, followed by an immune system response (22). Body weight and plasma glucose levels were monitored daily after the first STZ injection. Metabolic assessment and organ isolation were performed 1 week after the last STZ injection, following confirmation of hyperglycemia.

We also used a single high dose of STZ (SHDSTZ, 200 mg/kg i.p.), which is directly cytotoxic to beta cells, resulting in robust hyperglycemia within 2448 h (23).

Staining and Quantification

The pancreas from normal or MLDSTZ mice was perfused with PBS, harvested, fixed in 4% paraformaldehyde, and stored in 70% ethanol before paraffin embedding. All paraffin sections

(5m thickness) were processed by Waxit Histology laboratories (Vancouver, BC, Canada).

Immunofluorescence staining and quantification of insulin (Cell Signalling Technology, Beverly,

MA, USA), glucagon (SigmaAldrich, St. Louis, MO, USA), GLUT2 (Chemicon International

Inc, Temecula, CA) and synaptophysin (Novus Biologicals, Littleton, CO, USA) were Page 7 of 85 Diabetes

performed as previously described (24). Alcian blue (0.65 M MgCl2, pH 5.8; SigmaAldrich, St.

Louis, MO, USA) staining and imaging was used to visualize HS.

Western Blot

Western blot was done as described previously (25). Heparanase (Abcam, Cambridge, UK)

and heparan sulfate (Santa Cruz, Dallas, TX, USA) expression in the pancreas were

determined using the appropriate antibodies.

Islet Isolation

Pancreatic islets were isolated using collagenase as described previously (13; 26). Briefly, the

pancreas was perfused with collagenase through the pancreatic duct. Additional collagenase

digestion was performed in a water bath. Following digestion, the tube containing the tissue

sample was shaken vigorously. Individual islets were handpicked under a brightfield

microscope. Islets were cultured for 3 h (37 °C, 5% CO2) in RPMI1640 medium (Invitrogen,

Carlsbad, CA, USA) with 5 mM glucose (Sigma, St. Louis, MO, USA), 100 units/mL penicillin,

100 g/mL streptomycin (Invitrogen), and 10% FBS (Invitrogen). For RNA sequencing, 100

islets were selected, rinsed with PBS and snap frozen for later isolation of RNA. For glucose

induced insulin secretion, 10 islets were rinsed three times with PBS to remove glucose and

insulin, and then transferred to RPMI1640 medium with either 3 mM or 16.7 mM glucose for

15 mins, followed by medium collection and insulin determination using ELISA. The total

insulin content in islets was determined following acidethanol extraction.

RNA Sequencing and Analysis

RNA from 5 heptg and 5 WT mice was isolated using an RNeasy purification kit (Qiagen,

Hilden, Germany). Sequencing libraries were prepared from 400 ng total RNA using the

TruSeq Stranded mRNA Sample Preparation kit according to the manufacturer’s instructions

(Illumina, San Diego, USA). Samples were checked for quality using a Bioanalyzer (Agilent,

CA, USA) and quantified using Qubit fluorometer (Thermo Fisher, MA, USA). Libraries were Diabetes Page 8 of 85

then multiplexed and sequenced over one rapid run lane on the HiSeq2500 (Illumina), collecting 89 million 100 bp pairedend reads. Kallisto version 0.42.4 was first used to build an index file for the mouse reference transcriptome GRCm38 as downloaded from the Ensembl web site (www.ensembl.org). The sequence reads for each sample were then quantified with the quant function of Kallisto. In house Perl scripts were used to sum the read counts at the transcript level for each gene and to create a matrix comprising the read counts for all the genes for all the samples. Differential expression analysis was then performed on the data from that matrix using the R package DESeq2 (27). Each sample was assessed using the quality control software RSeQC version 2.6.3 (28) and the PtR script from the trinity suite (29).

One potential outlier was detected when clustering the samples and was therefore removed for the differential expression analysis. RNA sequencing transcriptomic data were analyzed using Panther and DAVID. Network analysis was conducted using STRING.

Statistical Analysis

Statistics were performed using Sigma Plot (Systat Software Inc., Chicago, IL, USA). For all analysis, student ttest or oneway ANOVA was used to determine differences between group mean values. Values are presented as means ± SEM with individual data points. p<0.05 was considered statistically significant.

Page 9 of 85 Diabetes

Results

Heparanase Transgenic Mice Have Improved Glucose Homeostasis

At 3 months of age, heptg mice had similar body weights compared to WT (heptg,

22.03±1.11 g; WT 22.11±1.08 g). However, the determination of circulating plasma insulin in

heptg animals after a 6 h fast revealed lower levels compared to WT (Fig. 1B). Interestingly,

the transgenic animals also demonstrated reduced basal blood glucose (Fig. 1C), suggesting

higher insulin efficiency in these mice. This was tested by administering a bolus dose of

insulin and measuring Akt activation in skeletal muscle. Samples of skeletal muscle from hep

tg mice showed an enhanced insulin response (Fig. 1D). To pursue this observation, we

performed an OGTT after an overnight fast. Unlike in the case of an acute fast, prolonged

fasting eliminated the difference in blood glucose between the two genotypes (Fig. 1E). In

addition, although heptg mice tended to clear glucose faster, this improvement was not

statistically significant (Fig. 1E), suggesting that the improvement in insulin sensitivity

observed under basal conditions is not readily apparent during an OGTT. Following an insulin

tolerance test, we were also unable to detect any difference in blood glucose lowering

between the two groups, up to 30 min after insulin injection. Interestingly, after 30 min of

insulin, we start to see a separation (recovery of glucose levels) between the WT and heptg

mice (Supplementary Fig. 1). Unexpectedly, in response to the glucose challenge, insulin

secretion in heptg animals was almost 2fold higher than in WT (Fig. 1F). In addition, when

islets from WT and heptg mice were isolated and exposed to high glucose, heptg islets were

capable of releasing greater amounts of insulin compared to WT (Fig. 1G). Although heptg

islets appeared to contain slightly more insulin compared to WT, this difference was not

statistically significant (Supplementary Fig. 2). Similarly, as neither Ins 1 nor Ins 2 expression

demonstrated any significant difference between the two strains (data not shown), our data Diabetes Page 10 of 85

suggest that heparanase overexpression influences the secretory process of insulin rather than its synthesis.

Heparanase Overexpression Induces Glucagon Resistance And Changes In Pancreatic

Islet Structure

Intriguingly, heptg mice showed an augmentation in circulating basal glucagon levels (Fig. 2A and Supplementary Fig. 3). However, these mice demonstrated resistance when given a glucagon challenge after 6 (Supplementary Fig. 3) or 16 h (Fig. 2B) of fasting. The glucagon resistance in heptg mice was evident in the absence of any change in the glucagon receptor in the liver (Supplementary Fig. 4). In response to Larginine, which drives islet hormone secretion independent of glucose sensing, heptg mice showed higher glucagon and lower insulin secretion, effects that were reflected in a higher glucose excursion in these animals

(Fig. 2C). To determine the basis for this observed hyperglucagonemia, we quantified pancreatic alpha cells, and their ratio to beta cells, using fluorescent staining. Expressed as glucagon positive (WT, 0.000465 ± 0.00026; heptg, 0.000764 ± 0.000318; p=0.433) and insulin positive (WT, 0.004056 ± 0.000991; heptg, 0.004608 ± 0.001674; p=0.056) area individually (signal positive area versus total area of the section to represent the alpha and beta cell number in the pancreas), there was no statistical difference between WT and heptg animals in the number of insulin or glucagon positive cells. However, when the data was expressed as a ratio of alpha/beta cells, the heptg islets demonstrated alpha cells that were more abundant. Additionally, unlike WT islets, wherein alpha cells are mostly found in the periphery and beta cells in the core, heptg islets contained alpha cells that were randomly distributed (Fig. 2D). Islets in heptg mice exhibit similar average size and size distribution (Fig.

2E), and no difference in their number compared to WT (Supplementary Fig. 5). Overall, heparanase overexpression was associated with dramatic shifts in hormones secreted from the pancreas, in addition to changes in islet composition and structure. Page 11 of 85 Diabetes

Heparanase Overexpression Greatly Alters The Pancreatic Islet Transcriptome

Entry of heparanase into the nucleus to regulate histone acetylation has been put forth as a

mechanism to modulate transcription (3). Given the impact of heparanase overexpression on

insulin and glucagon, we sought to characterize the heptg islet transcriptome using RNA

sequencing (Supplementary Table 1). As expected, heparanase was the most profoundly

altered mRNA in the islet transcriptome, exhibiting a >100 fold change (Fig. 3B). This was

mirrored by an equally robust increase in heparanase protein expression (Fig. 3B, inset).

Strikingly, after correction for multiple testing, over 2000 genes were significantly differentially

expressed with p<0.05. Of these, 1176 were upregulated and 985 were downregulated (Fig.

3A, inset). From the mRNAs that increased above a cutoff (>2fold, p<0.001), we identified

350 genes enriched in multiple cellular processes including in development (e.g. Crlf1, Ifrd1)

(30), metabolism (e.g. Acacb, Ppargc1a) (31), and cell death regulation (e.g., Npas4, Igf1,

P2rx1) (Fig. 3A) (32; 33). Of note, glucagon (Gcg) expression increased (Fig. 3B), and

corresponded to the high plasma glucagon observed in heptg mice. Among the 112 genes

that decreased (>2fold, p<0.001), the most compelling effect was observed for genes related

to the cell cycle (e.g., Cdc20, Ccnb) (Fig. 3A). In addition, glucagon receptor (Gcgr)

expression was also decreased (p=0.0004) (Fig. 3B). Combining these data with a protein

protein interaction network model, we identified two functional networks that were upregulated

relevant to the current study (Fig. 4, circles): one associated with hormone secretion (e.g. Ppy,

Pyy), and the other with extracellular structure [e.g. Sdc1 (that encodes for syndecan 1),

Hs3st3b1 (that encodes for heparan sulfateglucosamine 3sulfotransferase 3B1)] (Fig. 3B

and Fig. 4). The amplification of pancreatic heparan sulfate that was observed in heptg mice

(Fig. 3C) could be attributed, at least in part, to the increase in Sdc1 and Hs3st3b1. Among

the downregulated genes, a highly connected network of genes related to the cell cycle

function was recognized (Fig. 4, box). Altogether, these data suggest that its ability to Diabetes Page 12 of 85

modulate gene expression is consistent with the role of heparanase as a potent regulator of islet structure and function.

Heparanase Transgenic Mice Exhibit Resistance To Multiple Low-Dose Streptozotocin-

Induced Hyperglycemia

As heptg islets are enriched in heparan sulfate, which is important for beta cell survival (13), we attempted to chemically induce diabetes in these mice. Interestingly, although WT animals showed robust hyperglycemia within one week of STZ injection, heptg mice failed to present with plasma glucose levels comparable to WT (Fig. 5A). Measurement of plasma insulin provided one explanation for this observation. STZ caused a precipitous drop of plasma insulin in WT animals, an effect that was absent in heptg mice (Fig. 5B). Prolonging the duration of the study did not change the results heptg mice remained resistant to STZ induced hyperglycemia for up to 8 weeks following injection (Supplementary Fig. 6). This resistance to STZ was likely not due to any difference in expression of pancreatic GLUT2

(Supplementary Fig. 7), the transporter required for STZ uptake. To establish whether the failure to develop STZinduced hyperglycemia was a consequence of beta cell preservation, we quantified beta cell mass. Surprisingly, upon injection of STZ, both the WT and heptg mice displayed an identical loss of insulinpositive cells (Fig. 5C). This implies that the resistance to experimental diabetes in heptg mice is not a consequence of beta cell survival, consistent with observations seen in GRKO mice, which do not develop Type 1 diabetes when injected with STZ (20). Given our observation that heptg mice secrete more insulin in response to an OGTT (Fig. 1F), it is possible that the islets, which survived STZ toxicity in heptg diabetic mice, have a greater insulin secretory capacity. In this regard, heptg mice injected with STZ were still, albeit in limited capacity, able to secrete insulin in response to an

IPGTT (Fig. 5D). Taken together, our data suggest that the protective effects of heparanase against STZinduced diabetes is unlikely to be a consequence of HSmediated beta cell Page 13 of 85 Diabetes

survival, but could be related to the ability of any residual beta cells in these animals to

continue their secretion of insulin.

Severity Of Diabetes Remains Disparate Between WT and Hep-tg Mice Injected With

Single High Dose Streptozotocin

Multiple lowdose STZ induces beta cell death by activating immune mechanisms (22). Hence,

we also tested the response of heptg mice to a single high dose of STZ, which produces

severe diabetes by direct beta cell toxicity via DNA alkylation (23). In contrast to our

observation with multiple lowdose STZ, both WT and heptg mice injected with 200 mg/kg

STZ (single high dose) exhibited a significant reduction in plasma insulin levels (Fig. 6B). In

agreement with the loss of insulin, WT diabetic mice demonstrated sustained hyperglycemia

(Fig. 6A). Significantly, the values from day 3 onwards for these mice were beyond the upper

limit of detection (33.3 mmol/L) of the glucometer, suggesting that the actual blood glucose

concentrations were likely higher. Although high dose STZ was competent to lower insulin and

induce diabetes in heptg mice, the magnitude of hyperglycemia was lower than that seen in

WT animals (Fig. 6A), suggesting the contribution of an insulin mimetic factor. Fibroblast

growth factor21 (FGF21) has significant beneficial effects on glucose homeostasis (34).

Measurement of FGF21 plasma concentration indicated that heptg mice had higher

concentrations compared to WT (Fig. 6C). Moreover, although STZinduced diabetes caused

a significant drop in FGF21 levels in WT mice, its levels in heptg mice was strikingly amplified

by threefold (Fig. 6C), and was likely related to its increased hepatic production

(Supplementary Fig. 8). Another hormone that has glucoselowering effects independent of

insulin is glucagonlike peptide 1 (GLP1) (35). In response to high dose STZ, GLP1 trended

in the opposite direction between these two strains (Fig. 6D). Thus, in heptg mice, driving

circulating insulin concentrations down to very low levels uncovers novel protective pathways

for the management of hyperglycemia. Diabetes Page 14 of 85

Discussion

Homozygous transgenic mice overexpressing human heparanase globally are fertile and have a normal life span (10). In addition, physiological functions associated with heparanase in these mice include roles in embryonic implantation, food consumption, tissue remodeling, and vascularization (10). In the current study, an unexpected feature of these animals was our discovery of improved glucose homeostasis, but resistance to glucagon. Strikingly, compared to controls, heptg mice manifested significant changes in islet gene expression of over 2000 genes. These mice also demonstrated resistance to chemicallyinduced diabetes. Our data suggest a novel role for heparanase in mechanisms that serve to correct hyperglycemia.

In heptg mice, both basal insulin and glucose levels were lower than in WT following a 6 h fast, suggesting superior insulin sensitivity in these animals. This idea was reinforced by an enhanced insulin response to activation of skeletal muscle Akt in this study. Supporting these observations is that, in myeloma cells, insulin receptor is the predominant receptor tyrosine kinase activated by heparanase (6). The lower glucose concentration was evident in the presence of high glucagon levels, suggesting a deficit in glucagon action. Interestingly, an insulin tolerance test used to evaluate insulin efficiency was unable to detect any difference in blood glucose lowering between the two groups. Moreover, the traditional oral glucose challenge test was also unable to confirm a higher rate of glucose disposal in heptg mice. We reasoned that the overnight fast prior to performing the OGTT could explain this inconsistency.

Following fasting, hypersensitivity of the liver to glucagon accounts for a multifold increase in hepatic glucose production (35). Should this happen, even marginally, in heptg mice that have higher basal glucagon levels, the advantage of augmented insulin sensitivity in these animals would be dampened, resulting in a similar glucose clearance compared to WT.

Remarkably, in heptg mice, the OGTT elicited higher insulin release, whereas isolated islets from these animals had a more robust secretion of insulin in response to glucose, even with Page 15 of 85 Diabetes

islet insulin content and gene expression remaining unchanged. Our data suggest that

although heparanase appears to enhance insulin signalling, whole body tests to determine

insulin sensitivity were unable to confirm this, likely as a consequence of the overriding

influence of an insulin counterregulatory hormone such as glucagon in the heptg mice.

In GRKO mice, a prolonged deficiency in glucagon receptor signalling activates alpha cell

proliferation, and leads to a compensatory elevation in glucagon production (36). We were

surprised to observe that these characteristics in GRKO mice were strikingly similar to

features seen in heptg animals, which did not respond to a glucagon challenge as well as WT

mice. More importantly, heptg islets presented an architecture that is conducive to

hypersecretion of glucagon, under basal conditions and also subsequent to injection of

arginine. In these mice, alpha cells lost their peripheral mantlelike localization and were

distributed randomly throughout the islets. In addition, the alpha/beta cell ratio was higher in

heptg mice. These changes in alpha cells were evident even though islet size and size

distribution remained unaffected. Currently, it is unclear whether these alterations in alpha cell

morphology are consequences of glucagon resistance, or of disrupted pancreatic islet

development through the action of heparanase on HS.

Measurement of HS in the pancreas produced an unanticipated result; rather than depleting

HS, the heptg pancreas displayed the opposing phenotype, with increased expression of HS,

and the gene (Hs3st3b1) that encodes for its biosynthetic enzyme, 3Osulfotransferase,

being dominant features. A similar observation has also been made in the heptg liver, where

the authors described the accumulation of “heparinlike” HS degradation products, both within

and between cells, resulting in an accelerated biosynthesis of HS (37). It follows that like in

the liver, pancreatic heparanase processes HS into smaller heparinlike oligosaccharides.

Regardless of whether a result of its enzymatic activities, or its nontraditional signalling

activities, overexpression of heparanase produced a dramatic alteration in the islet Diabetes Page 16 of 85

transcriptome. Among the clusters of genes that were increased, of particular interest were genes that regulate cell death, synthesize extracellular matrix components, and produce pancreatic hormones. Related to cell death, this was not unusual as cancer cells use the properties of heparanase to induce gene expression and cell survival (38). The impact on the extracellular matrix is especially meaningful, as components like collagen and laminin have roles in islet cell differentiation, proliferation, and hormone secretion (39). Finally, peptide hormones like somatostatin and pancreatic polypeptide hormone are known to influence pancreatic islet function in a paracrine manner (40; 41). Unlike the upregulated genes that were enriched for diverse functions, the downregulated genes formed a coherent functional group including those tightly linked to the cell cycle. Whether these changes in expression creates an energysparing environment that would be conducive to a higher level of hormone production, as recently reported (42), is certainly consistent with our observations and deserving of further investigation. Collectively, our data provide support for the notion that heparanase in the pancreas is particularly beneficial, reinforcing it against the effects of exogenous stress.

Multiple lowdose STZ mimics Type 1 diabetes by stimulating beta cell apoptosis through the recruitment of immune cells (22). Given the role that HS plays in modulating the innate immune response by effecting immune cell adhesion, cytokine and chemokine binding, and providing a physical barrier against leukocytes infiltration (43), an increase in HS as seen in heptg mice could be potentially beneficial. This, when added to the genomic signature in these mice that is protective against cell death, one would anticipate a resistance to MLDSTZ beta cell cytotoxicity. Indeed, our results, for the first time, demonstrate that heptg animals developed less severe hyperglycemia compared to WT, and that this was associated with an almost unchanged circulating insulin concentration. Inexplicably, the preserved plasma insulin in these animals was not a consequence of higher beta cell mass, as quantification of these cells using immunostaining indicated that heptg beta cells were destroyed to an equal extent Page 17 of 85 Diabetes

compared to WT. It is possible that, of the beta cells that survived STZ toxicity in both groups,

an enhanced insulin secretory capacity in heptg animals could explain this anomaly. In

support, heptg diabetic animals can still increase insulin secretion in response to a glucose

challenge, an effect that is lost in WT diabetic mice. Our data suggest that heparanase

produces beta cells that are more functionally efficient, an effect likely related to an elevation

of 3Osulfotransferases and accumulation of HS in these islets.

STZ in high doses induces diabetes by a mechanism different from MLDSTZ; it directly

destroys beta cells by alkylating DNA (23). Additionally, as there is a comparatively more

severe and rapid development of hyperglycemia related to a catastrophic loss of insulin, we

tested whether heparanase would continue to correct hyperglycemia in this model. Despite

the identical low levels of residual circulating insulin in both diabetic groups, heptg mice

continued to have significantly lower blood glucose. In GRKO mice, FGF21 and GLP1 have

been suggested to be the hormones responsible for glucose clearance in the absence of

insulin (44). This was also true in the heptg diabetic mouse. In these animals, regardless of

their basal concentrations, SHDSTZ caused an augmentation of both FGF21 and GLP1,

effects that can contribute to their lower glucose levels. Altogether, the results indicate that,

with the onset of hyperglycemia, additional glucose lowering mechanisms are triggered in

heptg mice.

It has been proposed that HS in pancreatic islet BM functions as an obstruction against

leukocyte infiltration, in addition to protecting the beta cell against ROS induced cell death

(45). Thus, in the nonobese diabetic (NOD) mouse, augmented production of active

heparanase by immune cells permits destruction of islet BM HS, entry of leukocytes, and

degradation of intracellular HS. As the heparanase inhibitor PI88 preserved intraislet HS and

protected NOD mice from T1D, the authors concluded that heparanase inhibition is useful

against T1D progression (13). Contrasting results were observed in NOD mice injected with Diabetes Page 18 of 85

exogenous heparanase, which ameliorated the occurrence of diabetes (46). Unlike the NOD mice or metastatic cancer cells (47) where the overproduction of active heparanase is responsible for disease development, our model is one in which, in a disease free background, latent heparanase is overexpressed, with an associated amplification of islet HS. Thus, although active heparanase has been considered a pathogenic marker, our study has discovered multiple novel properties of latent heparanase related to the control of glycaemia.

Overexpression of this protein caused glucose lowering, potentiation of insulin secretion, HS induction, prodigious changes in islet gene expression, and protection against chemically induced diabetes. This study unlocks the possibility of utilizing these properties of heparanase in the management of diabetes.

Page 19 of 85 Diabetes

Article Information

Supplementary Material. This article contains Supplementary Data online at

http://diabetes.diabetesjournals.org.

Funding. This work was supported by an operating grant from the Canadian Institutes of

Health Research to BR (CIHRMOP133547). Amy PeiLing Chiu and Dahai Zhang are the

recipients of Doctoral Student Research Awards from the Canadian Diabetes Association.

Duality of Interest. None declared.

Author Contributions. D.Z. performed most of the experiments and with B.R., generated the

hypothesis, designed the study, performed the data analysis and wrote the manuscript. F.W.,

N.L., A.P.C., A.W., J.J., D.B., F.T., A.A., B.H., and B.H. contributed in part, to some of the

experiments performed. S.F., S.S., and C.N did RNA Sequencing and its analysis. T.P., I.V.,

J.D.J., and T.J.K. contributed to the discussion and manuscript editing. B.R. is the guarantor

of this work.

Diabetes Page 20 of 85

Figure Legends

Fig. 1. Heparanase overexpression improves glucose homeostasis. A. PCR amplification of DNA extracted from WT and heptg mice ear tissue. L19 is used as an internal control. B-C.

Following a 6 h fast, plasma insulin and blood glucose levels were measured in WT and TG mice. n=910, *p<0.05 vs. WT. D. Intraperitoneal administration of insulin (2 µg/kg body weight) to 6 h fasted mice, followed by skeletal muscle isolation for Western Blot. n=3,

*p<0.05 vs. control, #p<0.05 vs. WT insulin. E-F. Following an overnight fast (16 h), WT and

TG mice were administered an oral glucose (2 g/kg) gavage. At the indicated times, blood glucose and insulin were measured. n=45, *p<0.05 vs. WT. G. Isolated islets (10) from the different groups were used to extract insulin with AcidEthanol, and the insulin content was measured with ELISA (WT, 2.38±0.23 ng/mL; heptg, 3.08±1.04 ng/mL, p=0.218). Different islets (10) from the same animals were exposed to 3 mM and 16.7 mM glucose respectively, and insulin secretion determined. n=3, *p<0.05.

Fig. 2. Glucagon resistance and altered islet cytoarchitecture in heparanase overexpressing mice. A. Plasma glucagon levels in the two groups of mice were determined after a 16 h fast. n=45, *p<0.05 vs. WT. B. For the glucagon challenge, 16 h fasted mice were administered glucagon (1 µg/kg), and blood glucose measured at the indicated times. n=5, *p<0.05 vs. WT. C. In 6 h fasted mice, 2 g/kg Larginine was administered i.p. and plasma glucagon, insulin, and blood glucose (fold change in glucose was calculated by normalizing to the corresponding value at t=0) measured at the indicated times. n=5, *p<0.05 vs. WT. D. Higher magnification of insulin and glucagon positive cells in pancreas isolated from the two groups of animals using immunofluorescence staining, together with quantification of the alpha/beta cell ratio, n=3, *p<0.05 vs. WT. E. Whole pancreas sections were stained for insulin (red) and glucagon (green), scanned, and islets counted and quantified by size. Page 21 of 85 Diabetes

Figure 3. Islet transcriptome changes dramatically in hep-tg mice. A. Islet RNA from WT

and heptg mice was sequenced and the (p<0.001) upregulated (red) and downregulated

(green) genes were categorized based on the functions. Bar represents the enrichment of the

genes in particular category over the total genes of input. B. Representative genes in

extracellular matrix, signaling and cell cycle were shown. Heparanase gene was used as

positive control of the entire RNA sequencing, together with islet protein detection as inset. C.

Pancreas staining for heparan sulfate using alcian blue (pH 5.8, 0.65 M MgCl2) and its

quantification using Western blot. n=3, *p<0.05 vs. WT.

Fig. 4. Association network of genes that were significantly different between WT and

hep-tg mice. Analysis of a proteinprotein interaction network assembled from RNAseq data.

The blue square depicts the entire downregulated network that is related to cell cycle. The red

circles encompass both the hormoneassociated network and the extracellular elements

network. Lines represent associations based on differential expression evidence.

Fig. 5. Hep-tg mice are resistant to multiple low-dose streptozotocin induced diabetes.

A-B. To induce Type 1 diabetes, WT and heptg mice were administered 50 mg/kg STZ for 5

consecutive days. 7 days after the last STZ injection and following a 6 h fast, tail vein blood

was used for glucose and plasma insulin determination, n=510, *p<0.05. C. Pancreas from

STZ injected mice was isolated and immunestained for insulin (red) and glucagon (green),

and insulin positive cells were quantified in the different groups. n=3, *p<0.05. vs con. D.

Following an IPGTT, plasma insulin in STZ injected WT and heptg mice were measured over

the indicated times. The data is expressed as a fold change normalized to the corresponding

values at t=0 min for each animal within the two groups. n=35, *p<0.05 vs WT.

Fig. 6. Single high dose streptozotocin in hep-tg mice uncovers protective responses

to manage hyperglycemia. A. A single high dose (200 mg/kg) STZ (SHDSTZ) was

administered i.p., and glucose levels monitored daily over 5 days. n=48, *p<0.05. B-D. One Diabetes Page 22 of 85

week after injection of SHDSTZ, insulin, FGF21 and GLP1 levels from WT and heptg mice were determined. n=48, *p<0.05.

References

1. Sarrazin S, Lamanna WC, Esko JD: Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol 2011;3 2. Gittes GK: Developmental biology of the pancreas: a comprehensive review. Dev Biol 2009;326:4-35 3. Purushothaman A, Hurst DR, Pisano C, Mizumoto S, Sugahara K, Sanderson RD: Heparanase-mediated loss of nuclear syndecan-1 enhances histone acetyltransferase (HAT) activity to promote expression of genes that drive an aggressive tumor phenotype. J Biol Chem 2011;286:30377-30383 4. Wu L, Viola CM, Brzozowski AM, Davies GJ: Structural characterization of human heparanase reveals insights into substrate recognition. Nat Struct Mol Biol 2015;22:1016-1022 5. Vlodavsky I, Ilan N, Naggi A, Casu B: Heparanase: Structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des 2007;13:2057-2073 6. Purushothaman A, Babitz SK, Sanderson RD: Heparanase Enhances the Insulin Receptor Signaling Pathway to Activate Extracellular Signal-regulated Kinase in Multiple Myeloma. J Biol Chem 2012;287:41288-41296 7. Riaz A, Ilan N, Vlodavsky I, Li JP, Johansson S: Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence. J Biol Chem 2013;288:12366- 12375 8. Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N: Heparanase induces vascular endothelial growth factor expression: Correlation with p38 phosphorylation levels and Src activation. Cancer Res 2006;66:1455-1463 9. Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N: Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res 2006;66:1455-1463 10. Zcharia E, Metzger S, Chajek-Shaul T, Aingorn H, Elkin M, Friedmann Y, Weinstein T, Li JP, Lindahl U, Vlodavsky I: Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior. FASEB J 2004;18:252-263 11. Arvatz G, Weissmann M, Ilan N, Vlodavsky I: Heparanase and cancer progression: New directions, new promises. Hum Vaccin Immunother 2016:1-4 12. Bogdani M, Korpos E, Simeonovic CJ, Parish CR, Sorokin L, Wight TN: Extracellular matrix components in the pathogenesis of type 1 diabetes. Curr Diab Rep 2014;14:552 13. Ziolkowski AF, Popp SK, Freeman C, Parish CR, Simeonovic CJ: Heparan sulfate and heparanase play key roles in mouse beta cell survival and autoimmune diabetes. J Clin Invest 2012;122:132-141 14. Wan A, Rodrigues B: Endothelial Cell-Cardiomyocyte Crosstalk in Diabetic Cardiomyopathy. Cardiovasc Res 2016; 15. Assady S, Alter J, Axelman E, Zohar Y, Sabo E, Litvak M, Kaplan M, Ilan N, Vlodavsky I, Abassi Z: Nephroprotective effect of heparanase in experimental nephrotic syndrome. PLoS One 2015;10:e0119610 16. Jendresen CB, Cui H, Zhang X, Vlodavsky I, Nilsson LN, Li JP: Overexpression of heparanase lowers the amyloid burden in amyloid-beta precursor protein transgenic mice. J Biol Chem 2015;290:5053-5064 17. Purushothaman A, Chen LG, Yang Y, Sanderson RD: Heparanase Stimulation of Protease Expression Implicates It as a Master Regulator of the Aggressive Tumor Phenotype in Myeloma. J Biol Chem 2008;283:32628-32636 18. Aston-Mourney K, Zraika S, Udayasankar J, Subramanian SL, Green PS, Kahn SE, Hull RL: Matrix metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide. J Biol Chem 2013;288:3553-3559 19. Meier DT, Tu LH, Zraika S, Hogan MF, Templin AT, Hull RL, Raleigh DP, Kahn SE: Matrix Metalloproteinase-9 Protects Islets from Amyloid-induced Toxicity. J Biol Chem 2015;290:30475-30485 20. Sorensen H, Winzell MS, Brand CL, Fosgerau K, Gelling RW, Nishimura E, Ahren B: Glucagon receptor knockout mice display increased insulin sensitivity and impaired beta-cell function. Diabetes 2006;55:3463-3469 Page 23 of 85 Diabetes

21. Conarello SL, Jiang G, Mu J, Li Z, Woods J, Zycband E, Ronan J, Liu F, Roy RS, Zhu L, Charron MJ, Zhang BB: Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 2007;50:142-150 22. McEvoy RC, Andersson J, Sandler S, Hellerstrom C: Multiple low-dose streptozotocin-induced diabetes in the mouse. Evidence for stimulation of a cytotoxic cellular immune response against an insulin- producing beta cell line. J Clin Invest 1984;74:715-722 23. Deeds MC, Anderson JM, Armstrong AS, Gastineau DA, Hiddinga HJ, Jahangir A, Eberhardt NL, Kudva YC: Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim 2011;45:131-140 24. Asadi A, Bruin JE, Kieffer TJ: Characterization of Antibodies to Products of Proinsulin Processing Using Immunofluorescence Staining of Pancreas in Multiple Species. J Histochem Cytochem 2015;63:646-662 25. An D, Pulinilkunnil T, Qi D, Ghosh S, Abrahani A, Rodrigues B: The metabolic "switch" AMPK regulates cardiac heparin-releasable lipoprotein lipase. Am J Physiol Endocrinol Metab 2005;288:E246-253 26. Alejandro EU, Kalynyak TB, Taghizadeh F, Gwiazda KS, Rawstron EK, Jacob KJ, Johnson JD: Acute Insulin Signaling in Pancreatic Beta-Cells Is Mediated by Multiple Raf-1 Dependent Pathways. Endocrinology 2010;151:502-512 27. Love MI, Huber W, Anders S: Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014;15:550 28. Wang L, Wang S, Li W: RSeQC: quality control of RNA-seq experiments. Bioinformatics 2012;28:2184- 2185 29. Grabherr MG, Haas BJ, Yassour M, Levin JZ, Thompson DA, Amit I, Adiconis X, Fan L, Raychowdhury R, Zeng QD, Chen ZH, Mauceli E, Hacohen N, Gnirke A, Rhind N, di Palma F, Birren BW, Nusbaum C, Lindblad- Toh K, Friedman N, Regev A: Full-length transcriptome assembly from RNA-Seq data without a reference genome. Nat Biotechnol 2011;29:644-U130 30. Zimmer Y, Milo-Landesman D, Svetlanov A, Efrat S: Genes induced by growth arrest in a pancreatic beta cell line: identification by analysis of cDNA arrays. FEBS Lett 1999;457:65-70 31. Oropeza D, Jouvet N, Bouyakdan K, Perron G, Ringuette LJ, Philipson LH, Kiss RS, Poitout V, Alquier T, Estall JL: PGC-1 coactivators in beta-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids. Mol Metab 2015;4:811-822 32. Sabatini PV, Krentz NAJ, Zarrouki B, Westwell-Roper CY, Nian CL, Uy RA, Shapiro AMJ, Poitout V, Lynn FC: Npas4 Is a Novel Activity-Regulated Cytoprotective Factor in Pancreatic beta-Cells. Diabetes 2013;62:2808-2820 33. Lingohr MK, Buettner R, Rhodes CJ: Pancreatic beta-cell growth and survival - a role in obesity-linked type 2 diabetes? Trends Mol Med 2002;8:375-384 34. Kwon MM, O'Dwyer SM, Baker RK, Covey SD, Kieffer TJ: FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1. Cell Rep 2015;13:1521-1527 35. Dardevet D, Moore MC, Neal D, DiCostanzo CA, Snead W, Cherrington AD: Insulin-independent effects of GLP-1 on canine liver glucose metabolism: duration of infusion and involvement of hepatoportal region. Am J Physiol Endocrinol Metab 2004;287:E75-81 36. Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ: Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 2003;100:1438-1443 37. Escobar Galvis ML, Jia J, Zhang X, Jastrebova N, Spillmann D, Gottfridsson E, van Kuppevelt TH, Zcharia E, Vlodavsky I, Lindahl U, Li JP: Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat Chem Biol 2007;3:773-778 38. Nadir Y, Brenner B: Heparanase procoagulant activity in cancer progression. Thromb Res 2016;140 Suppl 1:S44-48 39. Meda P: Protein-mediated interactions of pancreatic islet cells. Scientifica (Cairo) 2013;2013:621249 40. Hauge-Evans AC, King AJ, Carmignac D, Richardson CC, Robinson ICAF, Low MJ, Christie MR, Persaud SJ, Jones PM: Somatostatin Secreted by Islet delta-Cells Fulfills Multiple Roles as a Paracrine Regulator of Islet Function. Diabetes 2009;58:403-411 41. Kahleova H, Mari A, Nofrate V, Matoulek M, Kazdova L, Hill M, Pelikanova T: Improvement in beta-cell function after diet-induced weight loss is associated with decrease in pancreatic polypeptide in subjects with type 2 diabetes. J Diabetes Complications 2012;26:442-449 Diabetes Page 24 of 85

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Page 25 of 85 Diabetes

A B C

1.2 12 L19 Hep L19+Hep 1.0 10

WT TG WT TG TG 0.8 8 * * 0.6 6

L19 0.4 4 Blood Glucose (mmol/L) Plasma Insulin (ng/mL) 0.2 2 Hep 0.0 0 WT TG WT TG

D Skeletal Muscle E

WT TG Insulin _ + _ + 20 pAKT Ser473

total AKT 16

beta-Actin 12 # 14 * - Insulin 8 OGTT Glucose (mmol/L) 12 + Insulin WT 10 4 TG 8 6 * 0 4 (min) pAKT/AKT (fold increase) 0 30 60 90 120 2 0 WT TG

F G * 2.0 * * 2.5 3 mM 16.7mM 1.6 WT 2.0 TG 1.2 1.5 *

0.8 1.0 OGTT Insulin (ng/mL) Insulin (ng/mL) 0.4 0.5

0.0 0.0 0 30 60 90 120 (min) WT TG

Fig. 1 Diabetes Page 26 of 85

A B 8.0 400 * 300 6.0 * 200 * *

100 Blood Glucose (mmol/L) * WT 4.0 TG 0 Plasma glucagon (pg/mL) WT TG Glucagon 0 20 40 60 80 100 120 (min) C 0.55 2500

Arginine * WT * 2000 1.2 0.50 TG Arginine 1500 * * 0.45 0.9 1000 * Arginine Insulin (ng/mL) 0.40 * Glucagon (pg/mL) 500 * 0.6 Glucose (fold change)

0 0.35 0 15 60 90 (min) 0 15 60 90 (min) 0 15 60 90 (min) D Glucagon Insulin 0.20 *

0.15

0.10

0.05 Alpha/beta Alpha/beta Cells Ratio 0.00 WT TG WT TG 50 m E

Glucagon ) Insulin 2 8000 m  6000

4000

2000 Average IsletAverage Size ( 0 WT WT TG 0.6

0.5 WT TG 0.4

0.3

0.2

Frequency (%) Frequency 0.1

0.0 <300 300-5000 >5000 (m2) Islet Sizes TG 250 m m 40 Fig. 2 Page 27 of 85 Diabetes A single-organism process single-organism cellular process tissue development regulation of cell death regulation of apoptotic process regulation of programmed cell death digestion positive regulation of biological process organ development regulation of biological quality Cellular process response to stress Development cell communication 1176 chemical homeostasis Cell Death biological regulation Homeostasis response to stimulus small molecule metabolic process 985 positive regulation of cellular process organic hydroxy compound metabolic process homeostatic process organic acid metabolic process spindle organization spindle assembly upregulated regulation of microtubule cytoskeleton organization downregulated regulation of chromosome segregation regulation of attachment of spindle microtubules to kinetochore regulation of cell cycle process Cell cycle regulation of mitotic cell cycle Cellular Structure mitotic nuclear division microtubule cytoskeleton organization chromosome segregation microtubule cytoskeleton organization involved in mitosis sister chromatid segregation nuclear chromosome segregation organelle fission mitotic cell cycle process single-organism organelle organization cell cycle process nuclear division mitotic sister chromatid segregation cell cycle cell division

-60 -40 -20 0 20 40 60 80 Enrichment (% of input) B 6 WT TG 75 kDa Latent Heparanase

Signaling Enzymes 4 50 kDa Active Heparanase Structural molecule Cell Cycle

2 Log2 fold change Gcgr Nek2 Ccna2Ccnb1Nusap1Cdk1 Pbk AspmCkap2l Espl1 0 Cdc20Top2a Cenpf

Igf1 Gal Gcg Ppy Pyy Ngfr Sdc1 Rgs4 Apoe Hpse Acacb Npas4 Myo5cHspb1 Col7a1 Lama2Lamb3 Tubb1Tuba1c Hs3st3b1 -2 C WT TG 4

3 * HS 2

Beta- 1 Actin 0 HS/beta-actin (fold change) (fold HS/beta-actin WT TG 5 m WT TG Fig. 3 Diabetes Page 28 of 85

Fig. 4 Page 29of85 C D A

Insulin (fold change) Plasma glucose (mmol/L) 400 400 10 15 20 25 0 5 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0  M WT-MLD-STZ i 5mn90 min 15 min 0 min WT * WT-STZ * * TG TG-MLD-STZ WT-MLD-STZ TG-STZ Con Diabetes B MLD-STZ Plasma Insulin (ng/mL) Insulin positive/total area 0.0 0.4 0.8 1.2 0.000 0.001 0.002 0.003 0.004 0.005 0.006 * WT WT * * * Fig. 5 TG TG-MLD-STZ TG * Diabetes Page 30 of 85

B A * Control 35 * 1.2 SHD-STZ

30 * * 1.0 25 * 0.8 * 20 0.6 15 WT 0.4 10 * TG Plasma Insulin (ng/mL) Insulin Plasma

Blood Glucose (mmol/L) Blood Glucose 5 0.2

0 0.0 0 1 2 3 4 5 (Day) WT TG

C D

120 * * * * 1600 * *

1200 80

800 40 GLP-1 (pg/mL) FGF21 (pg/mL) 400

0 0 WT TG WT TG

Fig. 6 Page 31 of 85 Diabetes

Supplementary Figure 1. Intraperitoneal administration of insulin (2 g/kg body weight) to 6 h fasted mice,

followed by measurement of glucose at the indicated times. n=7-8

1.2

WT TG 1.0

0.8

0.6 ITT (Normalized) Glucose

0.4 0 20 40 60 80 100 (min)

Supplementary Figure 2. 10 islets from WT and hep-tg mice were pooled respectively and insulin extracted

with Acid-Ethanol. The insulin content was measured with ELISA.

4

3

2

1 Total Insulin (ng/mL)

0 WT TG Supplementary Figure 3. Plasma glucagon levels from the two groups of mice were measured after 6 h fast.

Additionally, 6 h fasted mice were administered glucagon (1 ug/kg), and blood glucose measured at the indicated

times. n=5 *p<0.05

9

WT 8 * * 1600 * TG

* 7 1200 * 6 * 800 5 * 400 Plasma Glucagon (pg/mL) 4

0 (mmol/L) Glucose Blood WT TG 3 Glucagon 2 0 20 40 60 80 100 (min) Diabetes Page 32 of 85 Page 33 of 85 Diabetes Diabetes Page 34 of 85

ensembl_id mgi_symbolbaseMean log2FoldChangelfcSE stat pvalue padj ENSMUSG00000035273 Hpse 4765.279 6.9233033 0.26 26.751 1.19E-157 1.74E-153 ENSMUSG00000080242 Gm15487 200.7755 6.508209 0.27 24.351 5.63E-131 4.11E-127 ENSMUSG00000091957 Rps2-ps10 440.0678 5.4497956 0.24 22.913 3.43E-116 1.67E-112 ENSMUSG00000096403 Gm9825 66.83042 4.8644966 0.27 17.965 3.69E-72 1.35E-68 ENSMUSG00000026535 Ifi202b 22.28876 3.8741858 0.34 11.362 6.50E-30 1.90E-26 ENSMUSG00000020051 Pah 29.04714 3.037607 0.35 8.6255 6.38E-18 5.49E-15 ENSMUSG00000004821 Tmed11 20.43397 3.0324925 0.35 8.5982 8.09E-18 6.29E-15 ENSMUSG00000095427 Rps2-ps6 28.61607 3.0101958 0.35 8.6736 4.19E-18 4.08E-15 ENSMUSG00000010064 Slc38a3 34.99768 2.9458911 0.35 8.3626 6.13E-17 4.19E-14 ENSMUSG00000047797 Gjb1 24.13871 2.8723854 0.36 8.0469 8.49E-16 4.43E-13 ENSMUSG00000056978 Hamp2 29.08734 2.8112841 0.36 7.9099 2.58E-15 1.22E-12 ENSMUSG00000042010 Acacb 39.35242 2.6993787 0.34 7.8246 5.09E-15 2.33E-12 ENSMUSG00000031919 Tmed6 210.7557 2.6874545 0.3 8.8147 1.20E-18 1.25E-15 ENSMUSG00000009614 Sardh 23.17182 2.6733202 0.35 7.5503 4.34E-14 1.67E-11 ENSMUSG00000034528 Hsd17b13 76.73386 2.6152792 0.33 7.991 1.34E-15 6.75E-13 ENSMUSG00000044734 Serpinb1a 71.63215 2.5597117 0.31 8.1749 2.96E-16 1.88E-13 ENSMUSG00000033590 Myo5c 39.57776 2.51477 0.34 7.2894 3.11E-13 9.90E-11 ENSMUSG00000020150 Gamt 50.98365 2.4941177 0.35 7.1008 1.24E-12 3.68E-10 ENSMUSG00000068220 Lgals1 44.51471 2.4781844 0.31 7.9175 2.42E-15 1.18E-12 ENSMUSG00000070532 1700084C01Rik96.55147 2.4739888 0.36 6.9094 4.87E-12 1.13E-09 ENSMUSG00000024857 Cabp2 22.0531 2.4701603 0.36 6.9061 4.98E-12 1.14E-09 ENSMUSG00000021953 Tdh 11.37391 2.4650348 0.36 6.8858 5.75E-12 1.29E-09 ENSMUSG00000044485 Klk1b11 11.93188 2.4151793 0.36 6.7472 1.51E-11 3.10E-09 ENSMUSG00000004951 Hspb1 110.8648 2.4051569 0.32 7.607 2.80E-14 1.17E-11 ENSMUSG00000030717 Nupr1 2456.907 2.4023909 0.35 6.7883 1.13E-11 2.37E-09 ENSMUSG00000074264 Amy1 57.17337 2.398449 0.33 7.1915 6.41E-13 1.95E-10 ENSMUSG00000030796 Tead2 31.23567 2.3742525 0.35 6.8007 1.04E-11 2.21E-09 ENSMUSG00000001249 Hpn 20.10529 2.3703763 0.34 6.9826 2.90E-12 7.43E-10 ENSMUSG00000031170 Slc38a5 171.0122 2.3607112 0.25 9.5209 1.72E-21 2.79E-18 ENSMUSG00000062478 Ctrc 108.0745 2.3523856 0.36 6.5692 5.06E-11 9.73E-09 ENSMUSG00000020758 Itgb4 58.91103 2.2776839 0.34 6.6286 3.39E-11 6.70E-09 ENSMUSG00000046352 Gjb2 50.94667 2.2618565 0.35 6.4309 1.27E-10 2.26E-08 ENSMUSG00000006345 Ggt1 110.4002 2.246247 0.36 6.2826 3.33E-10 5.23E-08 ENSMUSG00000044005 Gls2 36.5468 2.2292838 0.32 7.0305 2.06E-12 5.37E-10 ENSMUSG00000030762 Aqp8 10.12043 2.2167742 0.36 6.1915 5.96E-10 8.80E-08 ENSMUSG00000025075 Habp2 10.79815 2.2014554 0.36 6.1481 7.84E-10 1.11E-07 ENSMUSG00000090015 Gm15446 27.86541 2.1945111 0.29 7.5825 3.39E-14 1.34E-11 ENSMUSG00000021944 Gata4 19.97253 2.1840539 0.35 6.1684 6.90E-10 9.89E-08 ENSMUSG00000036136 Fam110c 23.53705 2.1741149 0.34 6.3161 2.68E-10 4.41E-08 ENSMUSG00000024114 Prss41 32.09469 2.1576354 0.25 8.5972 8.17E-18 6.29E-15 ENSMUSG00000066513 Klk1b4 10.42898 2.1425866 0.36 6.0042 1.92E-09 2.47E-07 Page 35 of 85 Diabetes

ENSMUSG00000029369 Afm 5.279569 2.1254293 0.36 5.9356 2.93E-09 3.60E-07 ENSMUSG00000066515 Klk1b3 11.24368 2.122429 0.36 5.9273 3.08E-09 3.72E-07 ENSMUSG00000101088 1810018F18Rik13.42959 2.1105067 0.36 5.9208 3.20E-09 3.84E-07 ENSMUSG00000071517 Gm10334 214.3345 2.1034326 0.35 5.9754 2.30E-09 2.89E-07 ENSMUSG00000030219 Erp27 213.8521 2.0534777 0.35 5.7998 6.64E-09 7.09E-07 ENSMUSG00000050359 Sprr1a 34.66777 2.0437685 0.34 6.0908 1.12E-09 1.52E-07 ENSMUSG00000022037 Clu 2854.64 2.0368645 0.29 7.0711 1.54E-12 4.24E-10 ENSMUSG00000061808 Ttr 15491.26 2.0301091 0.22 9.2691 1.88E-20 2.29E-17 ENSMUSG00000034957 Cebpa 22.96678 2.0175128 0.35 5.7748 7.70E-09 8.10E-07 ENSMUSG00000000567 Sox9 20.19604 1.9888271 0.34 5.8893 3.88E-09 4.43E-07 ENSMUSG00000061959 Ces1e 7.921635 1.9427693 0.36 5.4616 4.72E-08 4.01E-06 ENSMUSG00000078520 Cela3a 12.44291 1.9200953 0.35 5.4456 5.16E-08 4.31E-06 ENSMUSG00000074272 Ceacam1 373.9786 1.9146575 0.26 7.2897 3.11E-13 9.90E-11 ENSMUSG00000072674 Plac9b 4.036935 1.8995332 0.36 5.3288 9.89E-08 7.39E-06 ENSMUSG00000024184 Pdia2 1515.392 1.8897672 0.35 5.3945 6.87E-08 5.48E-06 ENSMUSG00000015134 Aldh1a3 23.51831 1.8752325 0.32 5.7961 6.79E-09 7.19E-07 ENSMUSG00000061897 Gm14292 8.28307 1.8422838 0.35 5.233 1.67E-07 1.11E-05 ENSMUSG00000020053 Igf1 18.92652 1.8385535 0.36 5.1417 2.72E-07 1.66E-05 ENSMUSG00000022132 Cldn10 8.053754 1.8186918 0.35 5.1354 2.82E-07 1.69E-05 ENSMUSG00000062751 Prss1 64.66028 1.8181306 0.35 5.2524 1.50E-07 1.03E-05 ENSMUSG00000006649 Nphs1 24.40752 1.8168851 0.32 5.6284 1.82E-08 1.73E-06 ENSMUSG00000026628 Atf3 429.198 1.8131269 0.36 5.0642 4.10E-07 2.27E-05 ENSMUSG00000061878 Sphk1 23.83501 1.8120575 0.33 5.5237 3.32E-08 2.92E-06 ENSMUSG00000025650 Col7a1 51.35868 1.8096588 0.32 5.7235 1.04E-08 1.04E-06 ENSMUSG00000049382 Krt8 7170.888 1.8059996 0.24 7.4137 1.23E-13 4.49E-11 ENSMUSG00000058056 Palld 158.2963 1.7945521 0.31 5.757 8.56E-09 8.76E-07 ENSMUSG00000071553 Cpa2 8332.965 1.7814254 0.35 5.1235 3.00E-07 1.78E-05 ENSMUSG00000024907 Gal 69.85601 1.7797969 0.35 5.0446 4.54E-07 2.45E-05 ENSMUSG00000000394 Gcg 218128.9 1.7690939 0.19 9.2159 3.09E-20 3.47E-17 ENSMUSG00000032060 Cryab 36.48865 1.7637411 0.3 5.82 5.88E-09 6.52E-07 ENSMUSG00000020303 Stc2 21.60924 1.7478285 0.36 4.8816 1.05E-06 4.98E-05 ENSMUSG00000027376 Prom2 19.03592 1.7394261 0.33 5.1978 2.02E-07 1.30E-05 ENSMUSG00000047407 Tgif1 86.69673 1.738088 0.3 5.7147 1.10E-08 1.09E-06 ENSMUSG00000026735 Ptf1a 12.52448 1.7343343 0.35 4.9255 8.41E-07 4.16E-05 ENSMUSG00000006777 Krt23 8.587353 1.7312762 0.36 4.8492 1.24E-06 5.65E-05 ENSMUSG00000096525 Gm2663 8.315835 1.7310631 0.35 4.914 8.92E-07 4.38E-05 ENSMUSG00000073987 Ggh 178.7768 1.725233 0.24 7.0499 1.79E-12 4.76E-10 ENSMUSG00000074800 Gm4149 74.41023 1.7103981 0.33 5.2209 1.78E-07 1.17E-05 ENSMUSG00000039878 Slc39a5 110.0689 1.704707 0.34 4.9442 7.64E-07 3.81E-05 ENSMUSG00000024225 Clps 16267.75 1.7031498 0.34 4.9502 7.41E-07 3.75E-05 ENSMUSG00000043003 Rasef 5.991975 1.7020032 0.36 4.7623 1.91E-06 8.03E-05 ENSMUSG00000032643 Fhl3 26.11149 1.698229 0.32 5.2295 1.70E-07 1.12E-05 Diabetes Page 36 of 85

ENSMUSG00000019539 Rcn3 105.1405 1.6980164 0.18 9.3597 8.00E-21 1.09E-17 ENSMUSG00000021573 Tppp 11.7055 1.6973468 0.33 5.0994 3.41E-07 1.95E-05 ENSMUSG00000045091 Aqp12 112.098 1.6870424 0.34 4.9005 9.56E-07 4.64E-05 ENSMUSG00000017344 Vtn 36.56962 1.6748207 0.32 5.2194 1.80E-07 1.17E-05 ENSMUSG00000001604 Tcea3 12.39545 1.6738483 0.35 4.8034 1.56E-06 6.75E-05 ENSMUSG00000027082 Tfpi 27.85738 1.6659186 0.26 6.3509 2.14E-10 3.64E-08 ENSMUSG00000030800 Prss8 114.5446 1.6625763 0.3 5.4656 4.61E-08 3.97E-06 ENSMUSG00000006731 B4galnt1 20.86159 1.6601179 0.34 4.8834 1.04E-06 4.95E-05 ENSMUSG00000027954 Efna1 104.3973 1.6534676 0.23 7.0665 1.59E-12 4.30E-10 ENSMUSG00000029868 Trpv6 7.568776 1.6421238 0.36 4.5862 4.51E-06 0.000158 ENSMUSG00000023433 Cela3b 19405.11 1.6393734 0.34 4.7805 1.75E-06 7.43E-05 ENSMUSG00000027533 Fabp5 67.65256 1.636238 0.31 5.2643 1.41E-07 9.75E-06 ENSMUSG00000024747 Aldh1a7 8.495103 1.6204545 0.35 4.6844 2.81E-06 0.000108 ENSMUSG00000040562 Gstm2 150.2994 1.6178476 0.25 6.5521 5.67E-11 1.06E-08 ENSMUSG00000083365 Gm12895 39.69675 1.613462 0.3 5.3251 1.01E-07 7.39E-06 ENSMUSG00000083558 Gm12896 39.69675 1.613462 0.3 5.3251 1.01E-07 7.39E-06 ENSMUSG00000063713 Klk1b24 3.080368 1.608784 0.35 4.653 3.27E-06 0.000122 ENSMUSG00000018339 Gpx3 4621.558 1.6040039 0.15 10.471 1.17E-25 2.45E-22 ENSMUSG00000037095 Lrg1 11.84994 1.6038859 0.36 4.4825 7.38E-06 0.000233 ENSMUSG00000002769 Gnmt 53.04554 1.5952697 0.31 5.1595 2.48E-07 1.56E-05 ENSMUSG00000024503 Spink1 685.8984 1.5915949 0.34 4.6656 3.08E-06 0.000117 ENSMUSG00000017316 Ppy 25300.93 1.5847461 0.2 8.0873 6.10E-16 3.57E-13 ENSMUSG00000068874 Selenbp1 19.55201 1.5822212 0.31 5.0465 4.50E-07 2.44E-05 ENSMUSG00000034112 Atp2c2 4.676237 1.5810173 0.35 4.558 5.16E-06 0.000174 ENSMUSG00000029522 Pla2g1b 1087.762 1.5775771 0.34 4.6349 3.57E-06 0.00013 ENSMUSG00000023031 Cela1 52522.05 1.5767782 0.34 4.6289 3.68E-06 0.000133 ENSMUSG00000058579 Cela2a 52437.26 1.5726594 0.34 4.6204 3.83E-06 0.000137 ENSMUSG00000001627 Ifrd1 908.9643 1.5719391 0.23 6.8806 5.96E-12 1.32E-09 ENSMUSG00000100801 Gm15459 18.17632 1.5697281 0.32 4.9443 7.64E-07 3.81E-05 ENSMUSG00000020766 Galk1 8.469105 1.5587528 0.36 4.363 1.28E-05 0.000358 ENSMUSG00000094808 1810009J06Rik8.668229 1.5577496 0.34 4.5374 5.70E-06 0.000188 ENSMUSG00000063229 Ldha 181.7854 1.5557086 0.32 4.8191 1.44E-06 6.41E-05 ENSMUSG00000084174 Sycn 6109.863 1.5463125 0.34 4.5584 5.15E-06 0.000174 ENSMUSG00000038412 Higd1a 99.27258 1.5453014 0.23 6.8039 1.02E-11 2.19E-09 ENSMUSG00000101111 Gm28437 2602.038 1.5419913 0.28 5.6036 2.10E-08 1.93E-06 ENSMUSG00000024538 Ppic 28.8697 1.539303 0.33 4.627 3.71E-06 0.000134 ENSMUSG00000023074 Mospd1 13.99996 1.5324176 0.33 4.702 2.58E-06 0.000101 ENSMUSG00000031957 Ctrb1 87795.34 1.5324081 0.34 4.5314 5.86E-06 0.000192 ENSMUSG00000042436 Mfap4 3.453064 1.5261842 0.35 4.3068 1.66E-05 0.000434 ENSMUSG00000024028 Tff2 861.9843 1.5258272 0.34 4.4909 7.09E-06 0.000226 ENSMUSG00000083087 Gm11249 7.537008 1.5179132 0.36 4.2447 2.19E-05 0.000536 ENSMUSG00000027359 Slc27a2 6.23084 1.5149263 0.35 4.2934 1.76E-05 0.000453 Page 37 of 85 Diabetes

ENSMUSG00000054446 Cpa1 42666.86 1.5146293 0.34 4.4798 7.47E-06 0.000236 ENSMUSG00000099980 Gm5619 7.973046 1.5141406 0.34 4.479 7.50E-06 0.000236 ENSMUSG00000053279 Aldh1a1 8.345901 1.5111454 0.36 4.2411 2.22E-05 0.000543 ENSMUSG00000049521 Cdc42ep1 46.33983 1.5102846 0.31 4.8448 1.27E-06 5.74E-05 ENSMUSG00000024774 Ankrd22 4.909881 1.5081551 0.35 4.3014 1.70E-05 0.000441 ENSMUSG00000024215 Spdef 7.429239 1.5077744 0.36 4.2398 2.24E-05 0.000544 ENSMUSG00000024526 Cidea 29.58283 1.5054783 0.24 6.3276 2.49E-10 4.14E-08 ENSMUSG00000074268 Amy2a5 189275.7 1.5029941 0.33 4.4878 7.20E-06 0.000229 ENSMUSG00000024043 Arhgap28 21.12833 1.5013751 0.34 4.4575 8.29E-06 0.000254 ENSMUSG00000019899 Lama2 49.02117 1.4915295 0.29 5.1517 2.58E-07 1.61E-05 ENSMUSG00000008136 Fhl2 131.9103 1.4898605 0.25 5.918 3.26E-09 3.87E-07 ENSMUSG00000026994 Galnt3 11.68881 1.4890486 0.35 4.2281 2.36E-05 0.000569 ENSMUSG00000022408 Fam83f 18.7272 1.4872012 0.27 5.4346 5.49E-08 4.54E-06 ENSMUSG00000025481 Urah 9.932399 1.4817985 0.36 4.1466 3.37E-05 0.000764 ENSMUSG00000026639 Lamb3 22.67239 1.4800703 0.35 4.2044 2.62E-05 0.00062 ENSMUSG00000039960 Rhou 272.8252 1.4767619 0.26 5.7222 1.05E-08 1.05E-06 ENSMUSG00000054106 Try4 32624.27 1.4759172 0.34 4.3943 1.11E-05 0.000319 ENSMUSG00000021922 Itih4 13.8747 1.4744298 0.36 4.1178 3.83E-05 0.000846 ENSMUSG00000021999 Cpb2 24.77247 1.471992 0.26 5.6073 2.06E-08 1.91E-06 ENSMUSG00000015970 Chdh 37.94209 1.4699779 0.34 4.3056 1.67E-05 0.000435 ENSMUSG00000092035 Peg10 131.0608 1.4689353 0.29 5.001 5.70E-07 2.99E-05 ENSMUSG00000044786 Zfp36 453.2368 1.4636733 0.29 5.0711 3.96E-07 2.20E-05 ENSMUSG00000042784 Muc1 106.3349 1.4607689 0.32 4.5175 6.26E-06 0.000203 ENSMUSG00000080058 Gm11175 156.6346 1.459047 0.29 4.9973 5.81E-07 3.01E-05 ENSMUSG00000028179 Cth 26.46792 1.4585768 0.35 4.1649 3.12E-05 0.000714 ENSMUSG00000000120 Ngfr 6.821386 1.4571994 0.34 4.2494 2.14E-05 0.000528 ENSMUSG00000034936 Arl4d 57.93919 1.4558998 0.24 6.1411 8.20E-10 1.15E-07 ENSMUSG00000046008 Pnlip 63345.82 1.4555826 0.34 4.3305 1.49E-05 0.000403 ENSMUSG00000030088 Aldh1l1 51.01006 1.4525182 0.32 4.5337 5.79E-06 0.000191 ENSMUSG00000036570 Fxyd1 8.362617 1.4511854 0.35 4.1007 4.12E-05 0.000899 ENSMUSG00000032436 Cmtm7 21.05447 1.4508691 0.29 4.9792 6.38E-07 3.26E-05 ENSMUSG00000049350 Zg16 8739.249 1.450337 0.34 4.3227 1.54E-05 0.000413 ENSMUSG00000007888 Crlf1 21.53454 1.4429484 0.34 4.3008 1.70E-05 0.000441 ENSMUSG00000051727 Kctd14 18.35291 1.4418165 0.36 4.0395 5.36E-05 0.001107 ENSMUSG00000023043 Krt18 2995.46 1.4414756 0.22 6.6003 4.10E-11 8.00E-09 ENSMUSG00000026421 Csrp1 643.289 1.4350375 0.23 6.2518 4.06E-10 6.31E-08 ENSMUSG00000030263 Lrmp 10.37252 1.4315226 0.36 3.9977 6.40E-05 0.001288 ENSMUSG00000047139 Cd24a 489.4102 1.4289166 0.18 7.7853 6.96E-15 3.08E-12 ENSMUSG00000089855 Gm15662 12175.79 1.4234904 0.23 6.3069 2.85E-10 4.62E-08 ENSMUSG00000036106 Prr5 5.462912 1.4201534 0.36 3.9693 7.21E-05 0.001416 ENSMUSG00000024818 Slc25a45 8.91972 1.4199458 0.36 3.9658 7.31E-05 0.001429 ENSMUSG00000020911 Krt19 95.44592 1.4192896 0.36 3.9677 7.26E-05 0.001422 Diabetes Page 38 of 85

ENSMUSG00000034226 Rhov 22.25909 1.4122897 0.31 4.5594 5.13E-06 0.000173 ENSMUSG00000031740 Mmp2 5.566009 1.4094644 0.36 3.9361 8.28E-05 0.001581 ENSMUSG00000028420 Tmem38b 102.4174 1.4006388 0.26 5.325 1.01E-07 7.39E-06 ENSMUSG00000049241 Hcar1 32.81987 1.3983646 0.29 4.7596 1.94E-06 8.09E-05 ENSMUSG00000025289 Prdx4 183.5675 1.3977789 0.23 5.9817 2.21E-09 2.81E-07 ENSMUSG00000000078 Klf6 299.4318 1.3906601 0.28 4.8928 9.94E-07 4.78E-05 ENSMUSG00000037254 Itih2 19.31705 1.389949 0.32 4.2929 1.76E-05 0.000453 ENSMUSG00000026398 Nr5a2 17.04554 1.3819919 0.32 4.2548 2.09E-05 0.00052 ENSMUSG00000047501 Cldn4 3210.367 1.3781751 0.22 6.3426 2.26E-10 3.80E-08 ENSMUSG00000047281 Sfn 61.55049 1.3773603 0.29 4.8081 1.52E-06 6.66E-05 ENSMUSG00000017311 Pyy 6743.633 1.3762981 0.15 9.3574 8.17E-21 1.09E-17 ENSMUSG00000017007 Rbpjl 79.26759 1.362338 0.34 4.0461 5.21E-05 0.001088 ENSMUSG00000036422 Pcdh8 7.605706 1.3600907 0.35 3.8477 0.000119 0.002129 ENSMUSG00000020592 Sdc1 54.23833 1.3566377 0.3 4.4509 8.55E-06 0.000258 ENSMUSG00000020787 P2rx1 23.09964 1.3544794 0.34 3.9964 6.43E-05 0.001293 ENSMUSG00000038530 Rgs4 2198.917 1.3467948 0.29 4.7219 2.34E-06 9.28E-05 ENSMUSG00000027875 Hmgcs2 4.302825 1.3462373 0.35 3.8107 0.000139 0.002406 ENSMUSG00000034227 Foxj1 4.432621 1.3444166 0.36 3.7555 0.000173 0.002884 ENSMUSG00000040498 Igsf23 3.394946 1.3423231 0.34 3.969 7.22E-05 0.001416 ENSMUSG00000052305 Hbb-b1 99.68226 1.3393726 0.23 5.7683 8.01E-09 8.36E-07 ENSMUSG00000021411 Pxdc1 24.93318 1.3326088 0.29 4.6497 3.32E-06 0.000123 ENSMUSG00000029167 Ppargc1a 28.80801 1.3308559 0.35 3.8368 0.000125 0.002206 ENSMUSG00000029860 Zyx 286.9708 1.3292371 0.24 5.6178 1.93E-08 1.82E-06 ENSMUSG00000028836 Slc30a2 6.900694 1.3270558 0.33 3.9714 7.15E-05 0.001408 ENSMUSG00000030650 Tmc5 8.260406 1.3237575 0.36 3.6987 0.000217 0.003417 ENSMUSG00000023905 Tnfrsf12a 452.4397 1.3234932 0.16 8.3855 5.05E-17 3.69E-14 ENSMUSG00000063903 Klk1 5053.21 1.3200881 0.33 4.0047 6.21E-05 0.001255 ENSMUSG00000030310 Slc6a1 5.721014 1.319628 0.36 3.6853 0.000228 0.003534 ENSMUSG00000024175 Tekt4 4.271253 1.3193689 0.35 3.7286 0.000193 0.003138 ENSMUSG00000036492 Rnf39 7.064114 1.3146476 0.36 3.6806 0.000233 0.003596 ENSMUSG00000042622 Maff 301.8896 1.3105937 0.28 4.6806 2.86E-06 0.00011 ENSMUSG00000016255 Tubb1 26.60371 1.3081502 0.29 4.4616 8.13E-06 0.00025 ENSMUSG00000007097 Atp1a2 13.77983 1.3053637 0.33 3.9218 8.79E-05 0.001654 ENSMUSG00000029193 Cckar 45.25189 1.2969986 0.33 3.9262 8.63E-05 0.001631 ENSMUSG00000056569 Mpz 26.40229 1.293106 0.27 4.8071 1.53E-06 6.66E-05 ENSMUSG00000016995 Matn4 6.704099 1.2922778 0.36 3.6091 0.000307 0.004408 ENSMUSG00000039330 Tsga10ip 3.58129 1.291158 0.35 3.6558 0.000256 0.003896 ENSMUSG00000043091 Tuba1c 297.8212 1.2874816 0.16 8.1093 5.09E-16 3.10E-13 ENSMUSG00000053388 Trim50 4.836469 1.2828674 0.33 3.9305 8.48E-05 0.001607 ENSMUSG00000029656 C8b 343.7349 1.2818488 0.15 8.642 5.52E-18 5.05E-15 ENSMUSG00000035314 Gdpd5 10.5219 1.2768725 0.35 3.6196 0.000295 0.004314 ENSMUSG00000024922 Ovol1 23.50108 1.2711374 0.36 3.5623 0.000368 0.005072 Page 39 of 85 Diabetes

ENSMUSG00000045201 Lrrc3b 3.393821 1.2706624 0.34 3.701 0.000215 0.003391 ENSMUSG00000002985 Apoe 383.0498 1.2698219 0.18 7.0984 1.26E-12 3.68E-10 ENSMUSG00000036938 Try5 19337.81 1.2659933 0.32 3.9033 9.49E-05 0.001762 ENSMUSG00000032724 Abtb2 85.03568 1.262578 0.3 4.2488 2.15E-05 0.000528 ENSMUSG00000070407 Hs3st3b1 9.503842 1.2615284 0.35 3.5761 0.000349 0.004888 ENSMUSG00000026432 Avpr1b 64.46239 1.2589812 0.3 4.2197 2.45E-05 0.000587 ENSMUSG00000037428 Vgf 695.5835 1.2584701 0.18 7.0723 1.52E-12 4.24E-10 ENSMUSG00000048489 8430408G22Rik113.2271 1.2562388 0.3 4.1941 2.74E-05 0.000641 ENSMUSG00000056313 1810011O10Rik91.98855 1.2557952 0.24 5.2485 1.53E-07 1.04E-05 ENSMUSG00000024197 Plin3 56.66857 1.2525665 0.3 4.2305 2.33E-05 0.000564 ENSMUSG00000031896 Ctrl 19807.63 1.2508823 0.33 3.8402 0.000123 0.002184 ENSMUSG00000045903 Npas4 226.0721 1.2465351 0.3 4.0993 4.14E-05 0.0009 ENSMUSG00000004366 Sst 15383.55 1.2459766 0.15 8.3592 6.31E-17 4.19E-14 ENSMUSG00000016349 Eef1a2 206.2231 1.2448755 0.15 8.0732 6.85E-16 3.81E-13 ENSMUSG00000060429 Sntb1 6.812538 1.2311833 0.36 3.4428 0.000576 0.007212 ENSMUSG00000031762 Mt2 4780.974 1.2304697 0.35 3.496 0.000472 0.006214 ENSMUSG00000036885 Arhgef26 10.36536 1.2293242 0.36 3.4371 0.000588 0.007342 ENSMUSG00000066720 Cldn9 12.45173 1.2271432 0.35 3.475 0.000511 0.006627 ENSMUSG00000045319 Proser2 26.15422 1.226588 0.32 3.8695 0.000109 0.001973 ENSMUSG00000024912 Fosl1 52.59145 1.2250251 0.23 5.3345 9.58E-08 7.26E-06 ENSMUSG00000028063 Lmna 1399.244 1.2243186 0.23 5.2343 1.66E-07 1.11E-05 ENSMUSG00000075012 Fjx1 17.44507 1.2241721 0.34 3.5585 0.000373 0.005135 ENSMUSG00000040969 Arhgef38 11.33478 1.2238704 0.35 3.5466 0.00039 0.005323 ENSMUSG00000010080 Epn3 11.1882 1.223565 0.36 3.4344 0.000594 0.00737 ENSMUSG00000031765 Mt1 6244.202 1.2232548 0.35 3.5249 0.000424 0.005692 ENSMUSG00000039942 Ptger4 14.62262 1.2227907 0.31 3.9943 6.49E-05 0.001302 ENSMUSG00000055044 Pdlim1 72.04165 1.2069272 0.28 4.3234 1.54E-05 0.000412 ENSMUSG00000027358 Bmp2 13.94045 1.206287 0.33 3.6279 0.000286 0.004232 ENSMUSG00000026773 Pfkfb3 299.1789 1.1978619 0.31 3.8776 0.000105 0.001917 ENSMUSG00000050854 Tmem125 25.32805 1.1964152 0.33 3.6531 0.000259 0.003934 ENSMUSG00000001827 Folr1 117.0868 1.1943233 0.2 6.0253 1.69E-09 2.22E-07 ENSMUSG00000041119 Pde9a 7.079686 1.1938167 0.34 3.4881 0.000486 0.006354 ENSMUSG00000025091 Pnliprp2 3429.342 1.1871012 0.32 3.6881 0.000226 0.003513 ENSMUSG00000074034 Gm5921 4.243333 1.1849871 0.35 3.4332 0.000597 0.007397 ENSMUSG00000040957 Cables1 22.58605 1.1829002 0.31 3.781 0.000156 0.002637 ENSMUSG00000073102 Drc1 40.16224 1.1821636 0.25 4.6638 3.10E-06 0.000118 ENSMUSG00000007379 Dennd2c 31.03255 1.1783603 0.27 4.3145 1.60E-05 0.000423 ENSMUSG00000028927 Padi2 16.35867 1.1754407 0.34 3.4363 0.00059 0.007351 ENSMUSG00000045775 Slc16a5 25.58216 1.1707622 0.32 3.6142 0.000301 0.004353 ENSMUSG00000024778 Fas 28.76758 1.1700288 0.34 3.4092 0.000652 0.007944 ENSMUSG00000035896 Rnase1 8703.577 1.1678688 0.32 3.632 0.000281 0.004182 ENSMUSG00000030790 Adm 8.7328 1.1673789 0.36 3.2634 0.001101 0.01201 Diabetes Page 40 of 85

ENSMUSG00000018849 Wwc1 50.62111 1.1667361 0.25 4.7393 2.14E-06 8.73E-05 ENSMUSG00000032011 Thy1 15.29038 1.1664084 0.33 3.5309 0.000414 0.005581 ENSMUSG00000022602 Arc 131.1642 1.1655292 0.35 3.2889 0.001006 0.011202 ENSMUSG00000020186 Csrp2 35.88674 1.1643435 0.25 4.6005 4.21E-06 0.000148 ENSMUSG00000049265 Kcnk3 122.0477 1.1620143 0.27 4.3202 1.56E-05 0.000415 ENSMUSG00000025089 Gfra1 74.38611 1.1613162 0.22 5.3248 1.01E-07 7.39E-06 ENSMUSG00000069919 Hba-a1 35.40495 1.1604002 0.32 3.6255 0.000288 0.004255 ENSMUSG00000037280 Galnt6 6.062659 1.1589308 0.36 3.2392 0.001199 0.012838 ENSMUSG00000064177 Ghrl 40.86063 1.1561979 0.32 3.5733 0.000353 0.004922 ENSMUSG00000020806 Rhbdf2 77.46863 1.155774 0.19 5.9275 3.08E-09 3.72E-07 ENSMUSG00000067279 Ppp1r3c 11.71844 1.1557406 0.31 3.7516 0.000176 0.002922 ENSMUSG00000038775 Vill 15.16722 1.1532658 0.33 3.4721 0.000516 0.00667 ENSMUSG00000045954 Sdpr 11.19062 1.1502529 0.34 3.4005 0.000673 0.008121 ENSMUSG00000027257 Pacsin3 14.62812 1.1488767 0.34 3.3973 0.000681 0.008195 ENSMUSG00000010136 Pifo 5.909892 1.1484051 0.36 3.2288 0.001243 0.013215 ENSMUSG00000072680 Tmem254c 61.72064 1.1476076 0.22 5.2622 1.42E-07 9.78E-06 ENSMUSG00000029882 2210010C04Rik24243.79 1.1442342 0.32 3.5822 0.000341 0.004816 ENSMUSG00000074872 Ctxn2 11.78275 1.1429019 0.33 3.4571 0.000546 0.006954 ENSMUSG00000022270 Fam134b 300.4299 1.1424134 0.19 6.004 1.93E-09 2.47E-07 ENSMUSG00000056306 Sertm1 23.47386 1.1419372 0.29 3.9155 9.02E-05 0.001686 ENSMUSG00000071076 Jund 1231.771 1.1409667 0.25 4.5642 5.01E-06 0.000171 ENSMUSG00000040447 Spns2 35.06233 1.1399133 0.29 3.9767 6.99E-05 0.001386 ENSMUSG00000100862 Gm10925 3490.175 1.1382961 0.24 4.7288 2.26E-06 9.08E-05 ENSMUSG00000023328 Ache 93.92868 1.1368882 0.16 6.9173 4.60E-12 1.09E-09 ENSMUSG00000021453 Gadd45g 400.6295 1.1367078 0.2 5.5694 2.56E-08 2.32E-06 ENSMUSG00000028699 Tspan1 20.33627 1.1362056 0.35 3.2028 0.001361 0.014193 ENSMUSG00000057163 Prss2 31045.63 1.1357241 0.32 3.5617 0.000368 0.005076 ENSMUSG00000020644 Id2 406.4805 1.1282409 0.22 5.1691 2.35E-07 1.50E-05 ENSMUSG00000029314 Agpat9 12.81559 1.127322 0.31 3.618 0.000297 0.004324 ENSMUSG00000053886 Sh2d4a 13.96091 1.1235497 0.35 3.244 0.001179 0.012698 ENSMUSG00000022665 Ccdc80 10.95787 1.1219659 0.33 3.3534 0.000798 0.009288 ENSMUSG00000020080 Hkdc1 4.508772 1.1213708 0.35 3.2403 0.001194 0.012823 ENSMUSG00000072789 Gm10420 3.174414 1.1196432 0.35 3.1547 0.001607 0.016253 ENSMUSG00000026604 Ptpn14 69.90528 1.118817 0.27 4.1295 3.63E-05 0.000811 ENSMUSG00000007872 Id3 153.5176 1.1182013 0.22 5.1443 2.68E-07 1.65E-05 ENSMUSG00000061983 Rps12 773.5877 1.1176915 0.25 4.4787 7.51E-06 0.000236 ENSMUSG00000037621 Atoh8 25.8092 1.1170985 0.31 3.5739 0.000352 0.004919 ENSMUSG00000040205 Cuzd1 785.7815 1.1153925 0.32 3.4957 0.000473 0.006216 ENSMUSG00000028645 Slc2a1 293.9072 1.1123694 0.26 4.3548 1.33E-05 0.000368 ENSMUSG00000001473 Tubb6 256.5953 1.1102253 0.27 4.0618 4.87E-05 0.001023 ENSMUSG00000031714 Gab1 47.12 1.1100448 0.27 4.1868 2.83E-05 0.000656 ENSMUSG00000075705 Msrb1 95.34302 1.1090835 0.26 4.2722 1.94E-05 0.00049 Page 41 of 85 Diabetes

ENSMUSG00000055675 Kbtbd11 16.44792 1.1084788 0.3 3.6888 0.000225 0.003508 ENSMUSG00000073867 AA474408 5737.487 1.1079501 0.17 6.5632 5.27E-11 1.00E-08 ENSMUSG00000034686 Prr7 22.00665 1.1067733 0.28 3.9901 6.60E-05 0.001321 ENSMUSG00000043165 Lor 11.2392 1.1064612 0.33 3.3799 0.000725 0.008611 ENSMUSG00000034463 Scara3 37.81269 1.1063243 0.25 4.5071 6.57E-06 0.000212 ENSMUSG00000041548 Hspb8 107.7148 1.1025492 0.21 5.1366 2.80E-07 1.68E-05 ENSMUSG00000010601 Apol7a 3.427643 1.1024867 0.34 3.2739 0.001061 0.011624 ENSMUSG00000033350 Chst2 39.13027 1.1023732 0.31 3.592 0.000328 0.004662 ENSMUSG00000038415 Foxq1 3.128085 1.1011512 0.34 3.2345 0.001219 0.013012 ENSMUSG00000009114 2610028H24Rik4.083146 1.0983034 0.36 3.0695 0.002144 0.020053 ENSMUSG00000035226 Rims4 5.482705 1.0964554 0.36 3.0701 0.00214 0.020038 ENSMUSG00000004891 Nes 152.9285 1.0960457 0.27 4.0132 5.99E-05 0.001219 ENSMUSG00000015312 Gadd45b 269.9721 1.093962 0.32 3.4268 0.000611 0.007533 ENSMUSG00000030701 Plekhb1 104.0769 1.0924317 0.21 5.3052 1.13E-07 8.02E-06 ENSMUSG00000035451 Foxa1 3.111386 1.0918226 0.35 3.0779 0.002085 0.019687 ENSMUSG00000051243 Islr2 5.849014 1.0917232 0.35 3.107 0.00189 0.018381 ENSMUSG00000000782 Tcf7 3.874269 1.0907924 0.36 3.0588 0.002222 0.020543 ENSMUSG00000035506 Slc12a8 20.28265 1.0904332 0.33 3.2891 0.001005 0.011202 ENSMUSG00000091476 Gm16432 21.90811 1.0884232 0.32 3.3706 0.00075 0.008844 ENSMUSG00000053007 Creb5 15.50719 1.0871469 0.34 3.2359 0.001213 0.012967 ENSMUSG00000004035 Gstm7 16.91797 1.086077 0.28 3.8178 0.000135 0.002351 ENSMUSG00000042179 Pnliprp1 16983.04 1.0843437 0.32 3.4312 0.000601 0.007437 ENSMUSG00000060969 Irx1 67.55322 1.0841875 0.21 5.2742 1.33E-07 9.28E-06 ENSMUSG00000036872 Abcc12 12.91859 1.0838864 0.34 3.1607 0.001574 0.015979 ENSMUSG00000029657 Hsph1 545.044 1.0827029 0.28 3.9185 8.91E-05 0.00167 ENSMUSG00000069516 Lyz2 46.37643 1.0806618 0.23 4.7285 2.26E-06 9.08E-05 ENSMUSG00000066687 Zbtb16 5.295887 1.0804552 0.36 3.0351 0.002405 0.021646 ENSMUSG00000060548 Tnfrsf19 3.3245 1.0796186 0.35 3.054 0.002258 0.020739 ENSMUSG00000001506 Col1a1 22.90424 1.0795295 0.33 3.2273 0.00125 0.013258 ENSMUSG00000035960 Apex1 187.8793 1.0788834 0.18 6.1122 9.83E-10 1.34E-07 ENSMUSG00000028464 Tpm2 15.47735 1.0781991 0.3 3.6265 0.000287 0.004242 ENSMUSG00000034139 Serpini2 181.8648 1.0753647 0.32 3.3796 0.000726 0.008614 ENSMUSG00000028937 Acot7 17.20407 1.0702264 0.33 3.289 0.001005 0.011202 ENSMUSG00000078193 Gm2000 390.6134 1.0697519 0.21 5.118 3.09E-07 1.81E-05 ENSMUSG00000022951 Rcan1 226.9193 1.0693321 0.2 5.4727 4.43E-08 3.83E-06 ENSMUSG00000074457 S100a16 63.03085 1.0690816 0.25 4.328 1.50E-05 0.000406 ENSMUSG00000026840 Lamc3 3.022557 1.0680605 0.35 3.0333 0.002419 0.02172 ENSMUSG00000006529 Itih1 8.350033 1.0674574 0.34 3.1095 0.001874 0.018274 ENSMUSG00000034758 Tle6 60.38726 1.0669285 0.2 5.3938 6.90E-08 5.48E-06 ENSMUSG00000011179 Odc1 1804.176 1.0660181 0.23 4.6878 2.76E-06 0.000107 ENSMUSG00000025911 Adhfe1 5.090943 1.0659672 0.35 3.052 0.002273 0.020822 ENSMUSG00000032902 Slc16a1 11.49775 1.065853 0.32 3.3789 0.000728 0.008622 Diabetes Page 42 of 85

ENSMUSG00000029580 Actb 4088.034 1.0628188 0.19 5.7331 9.86E-09 1.00E-06 ENSMUSG00000005125 Ndrg1 1713.885 1.0594264 0.23 4.5305 5.89E-06 0.000192 ENSMUSG00000041959 S100a10 490.7055 1.0592806 0.17 6.202 5.58E-10 8.32E-08 ENSMUSG00000029661 Col1a2 48.24641 1.0568376 0.29 3.7042 0.000212 0.003359 ENSMUSG00000073530 Pappa2 2130.648 1.055709 0.27 3.9426 8.06E-05 0.001543 ENSMUSG00000019762 Iyd 3.433959 1.0553421 0.35 2.9861 0.002826 0.024559 ENSMUSG00000042035 Igsf3 20.61165 1.0538377 0.27 3.8959 9.78E-05 0.001806 ENSMUSG00000015605 Srf 634.7484 1.0519603 0.27 3.9573 7.58E-05 0.001478 ENSMUSG00000035964 Tmem59l 327.557 1.0512854 0.14 7.3735 1.66E-13 5.92E-11 ENSMUSG00000031880 Rrad 15.66715 1.0507108 0.31 3.4181 0.000631 0.007715 ENSMUSG00000000982 Ccl3 19.80381 1.0503159 0.35 3.044 0.002334 0.021183 ENSMUSG00000008384 Sertad1 160.9136 1.0481594 0.18 5.7259 1.03E-08 1.04E-06 ENSMUSG00000043259 Fam13c 12.67881 1.0481179 0.31 3.4009 0.000672 0.008116 ENSMUSG00000042745 Id1 51.46005 1.0466516 0.29 3.6721 0.000241 0.003695 ENSMUSG00000059991 Nptx2 76.74174 1.0459295 0.22 4.6581 3.19E-06 0.00012 ENSMUSG00000079679 Vwde 170.0092 1.045334 0.21 4.9223 8.55E-07 4.21E-05 ENSMUSG00000030954 Gp2 3407.502 1.0449462 0.31 3.339 0.000841 0.009693 ENSMUSG00000035237 Lcat 8.123503 1.0448777 0.36 2.9382 0.003302 0.027417 ENSMUSG00000041920 Slc16a6 132.925 1.0422583 0.27 3.8746 0.000107 0.001935 ENSMUSG00000027597 Ahcy 373.6195 1.0409309 0.25 4.1333 3.58E-05 0.000804 ENSMUSG00000024990 Rbp4 910.4939 1.039591 0.14 7.5834 3.37E-14 1.34E-11 ENSMUSG00000022548 Apod 41.94259 1.0392325 0.23 4.5495 5.38E-06 0.000179 ENSMUSG00000034765 Dusp5 547.8901 1.0365124 0.28 3.6976 0.000218 0.003418 ENSMUSG00000026259 Ngef 23.5296 1.0351437 0.27 3.7845 0.000154 0.002612 ENSMUSG00000029727 Cyp3a13 14.62993 1.0319385 0.32 3.2163 0.001299 0.013679 ENSMUSG00000047904 Sstr2 44.65628 1.0308982 0.28 3.6911 0.000223 0.003487 ENSMUSG00000033174 Mgll 47.69594 1.0301692 0.3 3.3804 0.000724 0.008611 ENSMUSG00000015405 Ace2 385.4461 1.0292196 0.2 5.2429 1.58E-07 1.06E-05 ENSMUSG00000069833 Ahnak 306.2063 1.0268798 0.29 3.55 0.000385 0.005268 ENSMUSG00000005540 Fcer2a 21.10592 1.0260003 0.26 3.9182 8.92E-05 0.00167 ENSMUSG00000078252 Krtap17-1 5.174176 1.024659 0.36 2.8632 0.004194 0.032892 ENSMUSG00000053560 Ier2 147.7501 1.0240591 0.33 3.083 0.00205 0.019473 ENSMUSG00000003752 Itpkc 225.7721 1.0236335 0.2 5.1083 3.25E-07 1.87E-05 ENSMUSG00000006720 Zfp184 31.08768 1.0229269 0.29 3.5207 0.00043 0.005758 ENSMUSG00000040511 Pvr 118.8528 1.0221994 0.18 5.763 8.26E-09 8.57E-07 ENSMUSG00000062825 Actg1 12704.1 1.0221224 0.19 5.3624 8.21E-08 6.39E-06 ENSMUSG00000020297 Nsg2 21.02605 1.0212309 0.31 3.2915 0.000997 0.011165 ENSMUSG00000003032 Klf4 184.1572 1.0169581 0.29 3.5352 0.000407 0.005511 ENSMUSG00000020205 Phlda1 60.02227 1.0169023 0.24 4.1898 2.79E-05 0.000649 ENSMUSG00000031790 Mmp15 38.14715 1.0126007 0.3 3.4212 0.000623 0.007652 ENSMUSG00000066278 Vps37b 221.1254 1.0117754 0.22 4.6164 3.90E-06 0.000139 ENSMUSG00000027400 Pdyn 760.2567 1.010428 0.21 4.8923 9.97E-07 4.78E-05 Page 43 of 85 Diabetes

ENSMUSG00000037278 Tmem97 223.6154 1.0103352 0.28 3.557 0.000375 0.005149 ENSMUSG00000066512 Klk1b5 112.9553 1.0100183 0.31 3.2869 0.001013 0.011226 ENSMUSG00000023911 Flywch2 23.78316 1.0095931 0.25 4.1026 4.09E-05 0.000894 ENSMUSG00000064220 Hist2h2aa1 204.9174 1.0058998 0.28 3.5388 0.000402 0.00546 ENSMUSG00000067203 H2-K2 131.7236 1.0056296 0.32 3.1882 0.001432 0.014751 ENSMUSG00000085893 Gm12091 4.633888 1.0050788 0.36 2.8197 0.004807 0.036541 ENSMUSG00000037012 Hk1 120.5823 1.0040275 0.18 5.6683 1.44E-08 1.39E-06 ENSMUSG00000020653 Klf11 128.3742 1.0039606 0.26 3.8629 0.000112 0.002017 ENSMUSG00000049866 Arl4c 96.46453 1.0037496 0.25 4.0915 4.29E-05 0.000922 ENSMUSG00000010660 Plcd1 12.26322 1.0037084 0.31 3.2782 0.001045 0.011492 ENSMUSG00000040016 Ptger3 22.55598 1.0034776 0.35 2.8682 0.004128 0.032536 ENSMUSG00000033578 Tmem35 10.35772 1.0033418 0.32 3.1205 0.001805 0.017771 ENSMUSG00000021795 Sftpd 11.48949 1.0019941 0.35 2.8547 0.004308 0.033591 ENSMUSG00000006356 Crip2 69.30172 1.0007939 0.22 4.4654 7.99E-06 0.000248 ENSMUSG00000016559 H3f3b 2542.948 1.0007195 0.18 5.6872 1.29E-08 1.26E-06 ENSMUSG00000050440 Hamp 27.04047 1.0005306 0.35 2.8817 0.003955 0.031472 ENSMUSG00000027895 Kcnc4 4.594084 1.0005088 0.36 2.8105 0.004946 0.037354 ENSMUSG00000057969 Sema3b 5.674349 1.0000975 0.36 2.7957 0.005178 0.038523 ENSMUSG00000090946 Ccdc71l 44.58789 0.9991449 0.22 4.4469 8.71E-06 0.000262 ENSMUSG00000032269 Htr3a 4.467444 0.9971487 0.36 2.7987 0.005131 0.038343 ENSMUSG00000037157 Il22ra1 2.9447 0.996833 0.33 2.9841 0.002844 0.024649 ENSMUSG00000070822 Zscan18 72.06976 0.9959552 0.31 3.2259 0.001256 0.013312 ENSMUSG00000008999 Bmp7 15.42773 0.9942081 0.31 3.2001 0.001374 0.014272 ENSMUSG00000096569 Amy2a2 35093.48 0.9934482 0.32 3.1471 0.001649 0.016577 ENSMUSG00000096770 Amy2a4 35093.48 0.9934482 0.32 3.1471 0.001649 0.016577 ENSMUSG00000093931 Amy2a3 35093.48 0.9934482 0.32 3.1471 0.001649 0.016577 ENSMUSG00000072676 Tmem254a 21.96422 0.9932865 0.27 3.7385 0.000185 0.003051 ENSMUSG00000021867 Tmem254b 21.96422 0.9932865 0.27 3.7385 0.000185 0.003051 ENSMUSG00000027463 Slc52a3 4.928853 0.9859142 0.36 2.7659 0.005677 0.041045 ENSMUSG00000049734 Trex1 200.3655 0.9824833 0.32 3.0473 0.002309 0.02105 ENSMUSG00000020227 Irak3 49.58107 0.9818002 0.28 3.4518 0.000557 0.007048 ENSMUSG00000069917 Hba-a2 60.38562 0.9812525 0.29 3.4143 0.00064 0.007811 ENSMUSG00000068699 Flnc 15.34689 0.9808999 0.33 2.9569 0.003108 0.026262 ENSMUSG00000053110 Yap1 57.59726 0.9798093 0.24 4.099 4.15E-05 0.0009 ENSMUSG00000022054 Nefm 183.3686 0.977914 0.18 5.4232 5.85E-08 4.73E-06 ENSMUSG00000039057 Myo16 5.960508 0.976707 0.35 2.7721 0.00557 0.040604 ENSMUSG00000057286 St6galnac2 20.78715 0.9763473 0.33 2.9422 0.003258 0.027173 ENSMUSG00000044986 Tst 16.18232 0.9762856 0.35 2.7938 0.005209 0.038716 ENSMUSG00000024558 Mapk4 108.2616 0.9744811 0.31 3.1098 0.001872 0.018272 ENSMUSG00000013089 Etv5 195.44 0.9739567 0.32 3.0255 0.002483 0.022211 ENSMUSG00000026969 Fam166a 5.521264 0.9733389 0.36 2.7413 0.00612 0.043429 ENSMUSG00000022346 Myc 83.17998 0.9730076 0.26 3.7126 0.000205 0.00326 Diabetes Page 44 of 85

ENSMUSG00000090862 Rps13 942.1491 0.9727844 0.2 4.7833 1.72E-06 7.35E-05 ENSMUSG00000031980 Agt 147.1948 0.9703142 0.18 5.4564 4.86E-08 4.11E-06 ENSMUSG00000026303 Mlph 113.6903 0.9697106 0.16 6.233 4.58E-10 6.97E-08 ENSMUSG00000028766 Alpl 13.96629 0.9694982 0.31 3.1691 0.001529 0.015579 ENSMUSG00000048905 4930539E08Rik598.4463 0.9694728 0.36 2.7232 0.006465 0.045288 ENSMUSG00000028389 Zfp37 110.2786 0.9681102 0.2 4.7592 1.94E-06 8.09E-05 ENSMUSG00000054364 Rhob 344.4973 0.9668489 0.25 3.8663 0.00011 0.001993 ENSMUSG00000024885 Aldh3b1 26.6005 0.9659634 0.27 3.6189 0.000296 0.00432 ENSMUSG00000005360 Slc1a3 3.235159 0.9648476 0.36 2.7147 0.006634 0.046224 ENSMUSG00000024732 Ccdc86 254.3166 0.9634051 0.15 6.4674 9.97E-11 1.82E-08 ENSMUSG00000083079 Amy2b 477.0109 0.9633244 0.31 3.0914 0.001992 0.019108 ENSMUSG00000002980 Bcam 102.7978 0.9631845 0.15 6.2935 3.10E-10 4.99E-08 ENSMUSG00000045128 Rpl18a 1578.711 0.9605256 0.23 4.2489 2.15E-05 0.000528 ENSMUSG00000045502 Hcar2 132.7558 0.9602815 0.28 3.4389 0.000584 0.007299 ENSMUSG00000019889 Ptprk 115.8371 0.9601948 0.22 4.39 1.13E-05 0.000324 ENSMUSG00000059654 Reg1 6342.153 0.9600565 0.31 3.1358 0.001714 0.017092 ENSMUSG00000050271 D8Ertd82e 38.11239 0.9591485 0.25 3.8158 0.000136 0.002365 ENSMUSG00000004631 Sgce 59.84827 0.9571413 0.21 4.6599 3.16E-06 0.000119 ENSMUSG00000068240 Gm11808 1241.395 0.9571123 0.19 5.1576 2.50E-07 1.57E-05 ENSMUSG00000035694 Caps2 18.95287 0.9568105 0.31 3.0384 0.002378 0.021489 ENSMUSG00000035277 Arx 62.56579 0.956329 0.22 4.3144 1.60E-05 0.000423 ENSMUSG00000015085 Entpd2 38.60939 0.9559106 0.25 3.7858 0.000153 0.002605 ENSMUSG00000069682 Gm10275 1717.094 0.9548446 0.18 5.3345 9.58E-08 7.26E-06 ENSMUSG00000024366 Gfra3 28.51742 0.9547382 0.26 3.7147 0.000203 0.003243 ENSMUSG00000031530 Dusp4 208.85 0.9534823 0.31 3.0899 0.002002 0.01917 ENSMUSG00000026360 Rgs2 294.3962 0.9528237 0.28 3.3815 0.000721 0.008595 ENSMUSG00000044197 Gpr146 117.6057 0.9525971 0.24 4.0113 6.04E-05 0.001226 ENSMUSG00000035357 Pdzrn3 11.56638 0.9519053 0.31 3.0524 0.00227 0.020809 ENSMUSG00000017144 Rnd3 107.8385 0.9515159 0.24 3.8875 0.000101 0.001855 ENSMUSG00000031016 Wee1 80.25396 0.9501257 0.29 3.2925 0.000993 0.011157 ENSMUSG00000061477 Rps7 1390.9 0.9473403 0.16 5.8707 4.34E-09 4.84E-07 ENSMUSG00000072675 Duxbl1 3.045054 0.9467324 0.34 2.8115 0.004931 0.03729 ENSMUSG00000026655 Fam107b 111.6279 0.9457583 0.33 2.8476 0.004405 0.034146 ENSMUSG00000026818 Cel 31371.99 0.9444819 0.3 3.1037 0.001911 0.018493 ENSMUSG00000014846 Tppp3 251.0304 0.9442145 0.25 3.7717 0.000162 0.002724 ENSMUSG00000047517 Dmbt1 3421.943 0.9440161 0.31 3.0733 0.002117 0.019951 ENSMUSG00000024803 Ankrd1 5.593313 0.9438535 0.35 2.6814 0.007331 0.049752 ENSMUSG00000049517 Rps23 1276.078 0.9426053 0.17 5.4314 5.59E-08 4.56E-06 ENSMUSG00000105388 Rpl36a-ps2 114.4972 0.9415711 0.28 3.3438 0.000826 0.009565 ENSMUSG00000030157 Clec2d 88.74849 0.9403093 0.32 2.9131 0.003579 0.029167 ENSMUSG00000064080 Fbln2 13.92183 0.9395766 0.32 2.9043 0.00368 0.029692 ENSMUSG00000062328 Rpl17 2189.023 0.9391845 0.16 5.7996 6.65E-09 7.09E-07 Page 45 of 85 Diabetes

ENSMUSG00000029864 Gstk1 28.12629 0.9383486 0.27 3.485 0.000492 0.006412 ENSMUSG00000058952 Cfi 15.07437 0.9379599 0.33 2.8011 0.005093 0.038144 ENSMUSG00000028840 Zfp593 54.51257 0.9377145 0.2 4.6349 3.57E-06 0.00013 ENSMUSG00000054162 Spock3 20.34669 0.9374383 0.28 3.4009 0.000672 0.008116 ENSMUSG00000074607 Tox2 21.74337 0.9338275 0.31 3.0462 0.002318 0.021097 ENSMUSG00000018387 Shroom1 9.694779 0.9337974 0.32 2.9082 0.003635 0.029439 ENSMUSG00000031266 Gla 136.5859 0.9318806 0.18 5.1086 3.25E-07 1.87E-05 ENSMUSG00000011463 Cpb1 30408.53 0.9304676 0.3 3.0669 0.002163 0.02019 ENSMUSG00000061848 Gm5805 10.92361 0.9294874 0.33 2.7784 0.005462 0.040105 ENSMUSG00000019577 Pdk4 80.5036 0.9293553 0.28 3.2736 0.001062 0.01163 ENSMUSG00000041841 Rpl37 894.9177 0.9290526 0.2 4.5984 4.26E-06 0.000149 ENSMUSG00000071415 Rpl23 1799.107 0.9289833 0.17 5.3139 1.07E-07 7.73E-06 ENSMUSG00000035202 Lars2 26070.47 0.9277988 0.19 4.8567 1.19E-06 5.49E-05 ENSMUSG00000063838 Cdc42ep5 18.49263 0.9268426 0.32 2.8686 0.004123 0.032524 ENSMUSG00000036040 Adamtsl2 19.45445 0.9255491 0.32 2.9247 0.003448 0.028318 ENSMUSG00000057841 Rpl32 1695.518 0.9254561 0.21 4.3674 1.26E-05 0.000353 ENSMUSG00000001504 Irx2 109.07 0.9225179 0.21 4.3209 1.55E-05 0.000415 ENSMUSG00000030222 Rerg 30.76709 0.9220776 0.26 3.5067 0.000454 0.006003 ENSMUSG00000009545 Kcnq1 26.78088 0.9212405 0.3 3.0938 0.001976 0.018994 ENSMUSG00000067288 Rps28 749.9954 0.9208317 0.19 4.8525 1.22E-06 5.57E-05 ENSMUSG00000071532 Gm10335 8.301365 0.9192228 0.34 2.7267 0.006396 0.044884 ENSMUSG00000107176 Gm9794 75.41425 0.9172184 0.28 3.3035 0.000955 0.010797 ENSMUSG00000003153 Slc2a3 42.66335 0.9167116 0.3 3.0985 0.001945 0.018733 ENSMUSG00000041605 5730559C18Rik168.0996 0.9164935 0.19 4.937 7.93E-07 3.94E-05 ENSMUSG00000033061 Resp18 6754.948 0.9153757 0.12 7.693 1.44E-14 6.18E-12 ENSMUSG00000024486 Hbegf 136.9635 0.9153034 0.24 3.8057 0.000141 0.002446 ENSMUSG00000031451 Gas6 54.86847 0.9150361 0.22 4.0934 4.25E-05 0.000915 ENSMUSG00000024048 Myl12a 485.0421 0.9131187 0.12 7.3255 2.38E-13 8.09E-11 ENSMUSG00000053399 Adamts18 15.94297 0.9123913 0.31 2.9051 0.003671 0.029641 ENSMUSG00000079435 Rpl36a 387.0348 0.9095979 0.2 4.5092 6.51E-06 0.00021 ENSMUSG00000015656 Hspa8 5219.983 0.9092001 0.21 4.4197 9.88E-06 0.000291 ENSMUSG00000018932 Map2k3 337.2381 0.9086224 0.21 4.3247 1.53E-05 0.000411 ENSMUSG00000039081 Zfp503 26.00833 0.9080436 0.32 2.8825 0.003945 0.031411 ENSMUSG00000071519 Prss3 1756.227 0.9049297 0.3 3.0475 0.002307 0.02105 ENSMUSG00000020889 Nr1d1 786.1613 0.9044208 0.27 3.3547 0.000795 0.009278 ENSMUSG00000053113 Socs3 523.1403 0.9040757 0.29 3.081 0.002063 0.019536 ENSMUSG00000085795 Zfp703 82.47689 0.9032366 0.23 3.9261 8.63E-05 0.001631 ENSMUSG00000028982 Slc25a33 14.86031 0.8998366 0.29 3.0711 0.002132 0.020035 ENSMUSG00000025813 Homer2 40.61314 0.8996299 0.26 3.4462 0.000568 0.007152 ENSMUSG00000032523 Hhatl 24.41531 0.8989094 0.3 2.9495 0.003182 0.026723 ENSMUSG00000054855 Rnd1 43.86119 0.8988079 0.31 2.8861 0.003901 0.031128 ENSMUSG00000000409 Lck 29.77697 0.894855 0.31 2.8936 0.003808 0.030537 Diabetes Page 46 of 85

ENSMUSG00000060803 Gstp1 247.8404 0.8940415 0.26 3.4665 0.000527 0.006761 ENSMUSG00000072940 Gm10443 127.7942 0.8907374 0.3 2.9853 0.002833 0.02458 ENSMUSG00000030228 Pik3c2g 29.7967 0.8901167 0.27 3.3583 0.000784 0.009173 ENSMUSG00000009246 Trpm5 505.0825 0.8897568 0.2 4.4675 7.91E-06 0.000247 ENSMUSG00000062157 Ifnlr1 34.26414 0.8878291 0.3 2.9857 0.00283 0.024563 ENSMUSG00000030342 Cd9 91.86165 0.8873098 0.22 3.9538 7.69E-05 0.001494 ENSMUSG00000043421 Hilpda 88.36807 0.8872459 0.33 2.7096 0.006737 0.046767 ENSMUSG00000008668 Rps18 1999.29 0.8859042 0.17 5.0942 3.50E-07 1.99E-05 ENSMUSG00000032051 Fdx1 77.2622 0.8852242 0.18 4.8192 1.44E-06 6.41E-05 ENSMUSG00000007892 Rplp1 1819.192 0.8851448 0.2 4.452 8.51E-06 0.000258 ENSMUSG00000015133 Lrrk1 33.23427 0.8843281 0.27 3.3322 0.000862 0.009904 ENSMUSG00000021493 Pdlim7 278.6327 0.883365 0.2 4.3329 1.47E-05 0.0004 ENSMUSG00000062997 Rpl35 603.6595 0.8831453 0.22 4.0166 5.90E-05 0.001204 ENSMUSG00000034930 Rtkn 68.33099 0.8819965 0.2 4.4393 9.03E-06 0.000269 ENSMUSG00000027298 Tyro3 14.26292 0.8772088 0.32 2.73 0.006334 0.044585 ENSMUSG00000030847 Bag3 379.9315 0.8771324 0.23 3.7984 0.000146 0.002496 ENSMUSG00000052146 Rps10 1272.769 0.8770925 0.16 5.4169 6.07E-08 4.87E-06 ENSMUSG00000029093 Sorcs2 145.8889 0.8763125 0.16 5.5372 3.07E-08 2.73E-06 ENSMUSG00000024052 Lpin2 390.1894 0.8753221 0.19 4.6201 3.84E-06 0.000137 ENSMUSG00000018822 Sfrp5 153.4772 0.8733469 0.22 3.9887 6.64E-05 0.001327 ENSMUSG00000053644 Aldh7a1 231.9692 0.8727671 0.19 4.6996 2.61E-06 0.000102 ENSMUSG00000078963 Hsbp1l1 40.2845 0.8708183 0.22 3.9523 7.74E-05 0.001499 ENSMUSG00000036826 Igflr1 4.10072 0.8693416 0.31 2.8099 0.004956 0.037401 ENSMUSG00000025362 Rps26 642.4316 0.8685699 0.2 4.3321 1.48E-05 0.0004 ENSMUSG00000031668 Eif2ak3 918.6027 0.8683171 0.21 4.1417 3.45E-05 0.000779 ENSMUSG00000046733 Gprc5a 24.07817 0.8658547 0.26 3.2814 0.001033 0.011388 ENSMUSG00000030432 Rpl28 1039.217 0.8649255 0.22 3.9433 8.04E-05 0.001543 ENSMUSG00000028195 Cyr61 93.60598 0.8648416 0.3 2.8468 0.004417 0.034216 ENSMUSG00000022474 Pmm1 77.73139 0.8647509 0.28 3.0845 0.002039 0.019419 ENSMUSG00000024827 Gldc 28.34506 0.8633032 0.24 3.6153 0.0003 0.004353 ENSMUSG00000027447 Cst3 1835.203 0.8630122 0.12 7.269 3.62E-13 1.13E-10 ENSMUSG00000058119 Gm5771 547.4884 0.8630086 0.29 2.9505 0.003172 0.026668 ENSMUSG00000024608 Rps14 2143.262 0.862525 0.18 4.8697 1.12E-06 5.20E-05 ENSMUSG00000075327 Zbtb2 88.42097 0.8608152 0.22 3.8687 0.000109 0.001977 ENSMUSG00000071604 Fam189a2 35.9612 0.8608108 0.26 3.3603 0.000779 0.009128 ENSMUSG00000017009 Sdc4 917.9793 0.8596178 0.24 3.5579 0.000374 0.005137 ENSMUSG00000082474 Gm8213 14.54666 0.8595027 0.31 2.8176 0.004839 0.036703 ENSMUSG00000019851 Perp 105.2214 0.8588046 0.24 3.6137 0.000302 0.004353 ENSMUSG00000026824 Kcnj3 14.32194 0.8561207 0.3 2.8587 0.004254 0.033256 ENSMUSG00000003955 Fam162a 58.09456 0.8560718 0.28 3.067 0.002162 0.02019 ENSMUSG00000000214 Th 157.778 0.8556214 0.18 4.7486 2.05E-06 8.44E-05 ENSMUSG00000058546 Rpl23a 1484.504 0.8556003 0.18 4.8698 1.12E-06 5.20E-05 Page 47 of 85 Diabetes

ENSMUSG00000052253 Zfp622 242.4685 0.8554486 0.21 4.0086 6.11E-05 0.001239 ENSMUSG00000063457 Rps15 1691.986 0.8544511 0.19 4.51 6.48E-06 0.00021 ENSMUSG00000073433 Arhgdig 151.676 0.8541413 0.27 3.2115 0.001321 0.013859 ENSMUSG00000025290 Rps24 2247.698 0.8539912 0.18 4.7843 1.72E-06 7.35E-05 ENSMUSG00000026249 Serpine2 70.89828 0.8528734 0.18 4.7663 1.88E-06 7.91E-05 ENSMUSG00000047115 Fam221a 50.33904 0.8518076 0.25 3.4059 0.000659 0.00802 ENSMUSG00000024621 Csf1r 62.87139 0.8515605 0.21 3.9659 7.31E-05 0.001429 ENSMUSG00000031375 Bgn 59.3561 0.851519 0.27 3.1989 0.001379 0.014311 ENSMUSG00000068341 Reg3d 172.2589 0.8513493 0.3 2.859 0.004249 0.033245 ENSMUSG00000022895 Ets2 1368.45 0.8503191 0.23 3.6716 0.000241 0.003698 ENSMUSG00000046364 Rpl27a 793.8596 0.8501758 0.16 5.4533 4.95E-08 4.15E-06 ENSMUSG00000057863 Rpl36 658.1457 0.8500131 0.17 4.8714 1.11E-06 5.19E-05 ENSMUSG00000005836 Gata6 82.74602 0.8498056 0.17 5.0853 3.67E-07 2.07E-05 ENSMUSG00000046727 Cystm1 332.5761 0.8490725 0.12 7.3029 2.82E-13 9.35E-11 ENSMUSG00000035673 Sbno2 384.7088 0.8485586 0.18 4.627 3.71E-06 0.000134 ENSMUSG00000060938 Rpl26 1872.035 0.8482765 0.17 5.0608 4.17E-07 2.30E-05 ENSMUSG00000031488 Rab11fip1 233.9572 0.8474847 0.23 3.7587 0.000171 0.002857 ENSMUSG00000024039 Cbs 443.6779 0.8456523 0.24 3.5625 0.000367 0.005072 ENSMUSG00000066443 Gm10163 114.9201 0.844803 0.31 2.7024 0.006884 0.047516 ENSMUSG00000061353 Cxcl12 24.38944 0.8436651 0.28 2.9833 0.002852 0.024699 ENSMUSG00000000740 Rpl13 1715.769 0.8423891 0.18 4.6844 2.81E-06 0.000108 ENSMUSG00000095098 Ccdc85b 60.71761 0.8422417 0.19 4.4466 8.72E-06 0.000262 ENSMUSG00000017493 Igfbp4 34.06222 0.8419815 0.25 3.3217 0.000895 0.010243 ENSMUSG00000047821 Trim16 25.20524 0.8418532 0.3 2.7664 0.005668 0.041035 ENSMUSG00000036598 Ccdc113 24.27241 0.8417543 0.3 2.8348 0.004586 0.035284 ENSMUSG00000045314 Sowahb 122.3471 0.8414469 0.27 3.1535 0.001613 0.01631 ENSMUSG00000039001 Rps21 1129.393 0.8409495 0.14 5.9684 2.40E-09 2.97E-07 ENSMUSG00000045763 Basp1 90.19634 0.8405811 0.26 3.2548 0.001135 0.012295 ENSMUSG00000031563 Wwc2 38.61666 0.8392971 0.27 3.1117 0.00186 0.018184 ENSMUSG00000040972 Igsf21 23.09642 0.8368285 0.28 2.9364 0.003321 0.027537 ENSMUSG00000029304 Spp1 512.0833 0.8367671 0.23 3.5976 0.000321 0.004571 ENSMUSG00000074129 Rpl13a 2976.008 0.8364188 0.17 4.8565 1.19E-06 5.49E-05 ENSMUSG00000031323 Dmrtc1a 32.33765 0.8361477 0.28 3.0071 0.002638 0.023313 ENSMUSG00000027293 Ehd4 376.6126 0.8337333 0.22 3.8298 0.000128 0.002259 ENSMUSG00000009927 Rps25 1673.333 0.8329461 0.16 5.1446 2.68E-07 1.65E-05 ENSMUSG00000061576 Dpp6 211.6138 0.8329238 0.18 4.6598 3.17E-06 0.000119 ENSMUSG00000035671 Zswim4 300.6011 0.8325187 0.31 2.7001 0.006933 0.047723 ENSMUSG00000020902 Ntn1 38.85527 0.8323086 0.27 3.1176 0.001823 0.017879 ENSMUSG00000024986 Hhex 60.0492 0.8312736 0.25 3.2842 0.001023 0.011311 ENSMUSG00000001918 Slc1a5 82.93142 0.8291275 0.29 2.8993 0.00374 0.030092 ENSMUSG00000026526 Fh1 1081.659 0.8281415 0.14 5.9165 3.29E-09 3.88E-07 ENSMUSG00000054200 Ffar4 48.24376 0.8257432 0.22 3.6905 0.000224 0.003492 Diabetes Page 48 of 85

ENSMUSG00000061787 Rps17 1677.99 0.825661 0.16 5.1943 2.05E-07 1.32E-05 ENSMUSG00000030934 Oat 61.75835 0.8242663 0.19 4.2952 1.75E-05 0.00045 ENSMUSG00000073702 Rpl31 1279.287 0.8238763 0.17 4.7222 2.33E-06 9.28E-05 ENSMUSG00000006360 Crip1 124.0816 0.8237579 0.16 5.0581 4.23E-07 2.32E-05 ENSMUSG00000027249 F2 18.36624 0.8235831 0.3 2.7458 0.006036 0.042962 ENSMUSG00000053581 Zfand2a 353.5399 0.8206712 0.19 4.2135 2.51E-05 0.000602 ENSMUSG00000047675 Rps8 1859.907 0.8202315 0.19 4.3637 1.28E-05 0.000357 ENSMUSG00000020654 Adcy3 61.01869 0.8193114 0.22 3.751 0.000176 0.002926 ENSMUSG00000054499 Dedd2 132.9819 0.8187057 0.23 3.5648 0.000364 0.005046 ENSMUSG00000039278 Pcsk1n 1618.466 0.817356 0.19 4.1993 2.68E-05 0.000628 ENSMUSG00000057036 Gm7536 1197.539 0.8171687 0.16 5.1153 3.13E-07 1.83E-05 ENSMUSG00000058600 Rpl30 1279.086 0.8155944 0.14 5.6999 1.20E-08 1.18E-06 ENSMUSG00000028010 Gar1 87.67351 0.8146516 0.19 4.1812 2.90E-05 0.000672 ENSMUSG00000033318 Gstt2 53.97774 0.8146322 0.22 3.6872 0.000227 0.003518 ENSMUSG00000090137 Uba52 386.056 0.81271 0.18 4.5047 6.65E-06 0.000213 ENSMUSG00000034981 Parm1 66.70656 0.812204 0.2 4.1061 4.02E-05 0.000886 ENSMUSG00000018143 Mafk 547.7455 0.8106916 0.21 3.8352 0.000125 0.002215 ENSMUSG00000095597 Gm6472 463.7251 0.805308 0.22 3.6164 0.000299 0.004345 ENSMUSG00000030763 Lcmt1 157.069 0.8051077 0.23 3.5156 0.000439 0.005843 ENSMUSG00000084319 Tpt1-ps3 1618.555 0.8042239 0.19 4.3283 1.50E-05 0.000406 ENSMUSG00000032440 Tgfbr2 53.45412 0.8041627 0.18 4.3649 1.27E-05 0.000356 ENSMUSG00000027524 Edn3 60.00331 0.8035596 0.21 3.8943 9.85E-05 0.001811 ENSMUSG00000020905 Usp43 46.31816 0.802914 0.24 3.314 0.00092 0.010456 ENSMUSG00000052397 Ezr 358.9767 0.8023773 0.22 3.7274 0.000193 0.003142 ENSMUSG00000048612 Myof 45.38004 0.7999432 0.22 3.6914 0.000223 0.003486 ENSMUSG00000020282 Rhbdf1 53.298 0.7992989 0.2 4.0743 4.61E-05 0.000979 ENSMUSG00000041046 Ramp3 102.8921 0.7992948 0.17 4.8233 1.41E-06 6.31E-05 ENSMUSG00000034892 Rps29 1485.221 0.798385 0.17 4.8074 1.53E-06 6.66E-05 ENSMUSG00000073676 Hspe1 281.553 0.7983155 0.13 6.1266 8.98E-10 1.25E-07 ENSMUSG00000067870 Rpl31-ps8 514.423 0.7972768 0.22 3.6452 0.000267 0.004031 ENSMUSG00000031565 Fgfr1 275.5332 0.7971573 0.12 6.387 1.69E-10 2.91E-08 ENSMUSG00000025025 Mxi1 165.8465 0.7955576 0.17 4.6383 3.51E-06 0.000128 ENSMUSG00000024190 Dusp1 303.0752 0.7942173 0.28 2.8089 0.004971 0.037437 ENSMUSG00000027525 Phactr3 32.79785 0.7932947 0.25 3.2125 0.001316 0.01383 ENSMUSG00000033669 Zfp7 75.18865 0.7926726 0.19 4.2436 2.20E-05 0.000538 ENSMUSG00000030744 Rps3 2203.591 0.7905507 0.15 5.1944 2.05E-07 1.32E-05 ENSMUSG00000039985 Fam60a 138.1059 0.790091 0.25 3.1846 0.00145 0.014915 ENSMUSG00000025967 Eef1b2 1300.965 0.7896162 0.17 4.7675 1.87E-06 7.88E-05 ENSMUSG00000027199 Gatm 216.5916 0.7893609 0.2 3.8601 0.000113 0.002031 ENSMUSG00000081051 Gm15427 77.10973 0.7886106 0.24 3.3182 0.000906 0.010346 ENSMUSG00000005553 Atp4a 57.61357 0.787801 0.23 3.3649 0.000766 0.009006 ENSMUSG00000059291 Rpl11 1683.898 0.7853986 0.18 4.4526 8.48E-06 0.000258 Page 49 of 85 Diabetes

ENSMUSG00000036052 Dnajb5 157.3676 0.7852707 0.13 5.8755 4.22E-09 4.78E-07 ENSMUSG00000015745 Plekho1 58.44418 0.7845667 0.18 4.2708 1.95E-05 0.000491 ENSMUSG00000072235 Tuba1a 1767.092 0.7823625 0.22 3.51 0.000448 0.005945 ENSMUSG00000038167 Plekhg6 61.52344 0.7821062 0.25 3.0912 0.001993 0.019108 ENSMUSG00000029819 Npy 26.08318 0.7811937 0.25 3.1832 0.001457 0.014964 ENSMUSG00000020253 Ppm1m 18.27135 0.7804868 0.27 2.867 0.004143 0.032635 ENSMUSG00000036894 Rap2b 48.80871 0.7767425 0.2 3.9014 9.56E-05 0.001772 ENSMUSG00000028081 Rps3a1 3626.095 0.775099 0.13 6.0188 1.76E-09 2.29E-07 ENSMUSG00000038781 Stap2 26.06611 0.7748586 0.25 3.1219 0.001797 0.017715 ENSMUSG00000026417 Pigr 130.1517 0.7742213 0.25 3.0636 0.002187 0.020299 ENSMUSG00000025508 Rplp2 896.5991 0.7730028 0.16 4.7384 2.15E-06 8.73E-05 ENSMUSG00000040435 Ppp1r15a 871.4321 0.7727375 0.26 2.9924 0.002768 0.024198 ENSMUSG00000027360 Hdc 36.68675 0.7701518 0.25 3.0503 0.002286 0.020924 ENSMUSG00000069805 Fbp1 30.73285 0.7697278 0.27 2.8175 0.004841 0.036703 ENSMUSG00000000627 Sema4f 18.58837 0.7696225 0.29 2.6827 0.007303 0.049681 ENSMUSG00000016256 Ctsz 575.8704 0.7694083 0.19 4.1515 3.30E-05 0.00075 ENSMUSG00000086583 Gm15500 3083.917 0.7679887 0.16 4.6573 3.20E-06 0.00012 ENSMUSG00000046711 Hmga1 360.9126 0.7677288 0.14 5.4639 4.66E-08 3.98E-06 ENSMUSG00000028851 Nudc 635.8622 0.7675614 0.1 7.4255 1.12E-13 4.21E-11 ENSMUSG00000039110 Mycbpap 24.64934 0.7664198 0.26 2.9113 0.003599 0.02925 ENSMUSG00000029195 Klb 50.92187 0.7662436 0.21 3.6103 0.000306 0.004397 ENSMUSG00000098274 Rpl24 1225.975 0.7659477 0.18 4.2495 2.14E-05 0.000528 ENSMUSG00000032518 Rpsa 3252.468 0.7654456 0.17 4.5666 4.96E-06 0.000169 ENSMUSG00000031320 Rps4x 2659.211 0.7653742 0.16 4.7382 2.16E-06 8.73E-05 ENSMUSG00000031382 Asb11 38.6516 0.7653034 0.24 3.1426 0.001675 0.016781 ENSMUSG00000031075 Ano1 31.94642 0.7634357 0.25 2.9998 0.002701 0.023762 ENSMUSG00000006333 Rps9 2040.378 0.7622887 0.16 4.6424 3.44E-06 0.000126 ENSMUSG00000047215 Rpl9 2299.053 0.7612436 0.15 5.0602 4.19E-07 2.30E-05 ENSMUSG00000031995 St14 486.8725 0.761047 0.18 4.2537 2.10E-05 0.000522 ENSMUSG00000060126 Tpt1 4326.611 0.7604251 0.16 4.7389 2.15E-06 8.73E-05 ENSMUSG00000020460 Rps27a 2122.078 0.7586329 0.15 5.098 3.43E-07 1.96E-05 ENSMUSG00000012848 Rps5 1352.85 0.7584319 0.18 4.2888 1.80E-05 0.000458 ENSMUSG00000036887 C1qa 372.0104 0.7575775 0.19 3.9614 7.45E-05 0.001454 ENSMUSG00000079056 Kcnip3 68.8745 0.757389 0.23 3.2876 0.00101 0.011215 ENSMUSG00000051043 Gprc5c 314.9611 0.7573511 0.19 4.0896 4.32E-05 0.000928 ENSMUSG00000106037 Gm4332 361.9327 0.7564278 0.18 4.1648 3.12E-05 0.000714 ENSMUSG00000027800 Tm4sf1 84.35757 0.7559151 0.23 3.2549 0.001134 0.012295 ENSMUSG00000063882 Uqcrh 536.8353 0.7558103 0.14 5.5403 3.02E-08 2.71E-06 ENSMUSG00000094526 Gm21451 9.781991 0.7549946 0.28 2.6936 0.007067 0.048461 ENSMUSG00000023972 Ptk7 31.90378 0.7534627 0.22 3.4264 0.000612 0.00754 ENSMUSG00000039239 Tgfb2 19.62021 0.7508539 0.28 2.6829 0.007299 0.049677 ENSMUSG00000046330 Rpl37a 1508.538 0.7496629 0.17 4.3676 1.26E-05 0.000353 Diabetes Page 50 of 85

ENSMUSG00000083695 Rnf138rt1 58.3732 0.7481641 0.27 2.76 0.005781 0.041651 ENSMUSG00000025283 Sat1 223.7224 0.7474776 0.15 4.9457 7.59E-07 3.81E-05 ENSMUSG00000060477 Irak2 127.7991 0.7465335 0.2 3.67 0.000243 0.003716 ENSMUSG00000037805 Rpl10a 497.7961 0.745669 0.2 3.6758 0.000237 0.003649 ENSMUSG00000042961 Egflam 29.76876 0.7445039 0.27 2.8081 0.004983 0.037514 ENSMUSG00000026825 Dnm1 51.54738 0.7434833 0.24 3.0825 0.002053 0.019473 ENSMUSG00000062661 Ncs1 36.76096 0.7425287 0.22 3.3061 0.000946 0.010712 ENSMUSG00000093674 Rpl41 4124.478 0.7416694 0.2 3.7294 0.000192 0.003135 ENSMUSG00000060260 Pwwp2b 43.60318 0.741019 0.24 3.0731 0.002119 0.019951 ENSMUSG00000072115 Ang 312.2036 0.7402748 0.21 3.512 0.000445 0.005911 ENSMUSG00000021270 Hsp90aa1 3186.948 0.7392588 0.21 3.458 0.000544 0.006936 ENSMUSG00000032232 Cgnl1 64.62742 0.7391767 0.23 3.2458 0.001171 0.012666 ENSMUSG00000042659 Arrdc4 159.7242 0.7373184 0.21 3.4545 0.000551 0.006996 ENSMUSG00000038954 Supt3 35.58085 0.7356372 0.24 3.1225 0.001793 0.01769 ENSMUSG00000028495 Rps6 2638.498 0.7338339 0.18 4.1303 3.62E-05 0.000811 ENSMUSG00000025545 Clybl 27.75217 0.7335869 0.26 2.8737 0.004058 0.032133 ENSMUSG00000026278 Bok 28.77543 0.7335145 0.23 3.1336 0.001727 0.017175 ENSMUSG00000079018 Ly6c1 64.94794 0.7332589 0.21 3.5693 0.000358 0.004981 ENSMUSG00000076441 Ass1 92.76518 0.7328533 0.22 3.2938 0.000989 0.011116 ENSMUSG00000003208 Ccdc94 80.27807 0.7326543 0.18 4.083 4.45E-05 0.00095 ENSMUSG00000004151 Etv1 195.8587 0.7324894 0.21 3.4454 0.00057 0.00716 ENSMUSG00000096215 Smim22 102.997 0.7316774 0.18 4.1322 3.59E-05 0.000807 ENSMUSG00000036278 Macrod1 53.25289 0.731536 0.24 3.075 0.002105 0.019865 ENSMUSG00000046546 Fam43a 83.84398 0.7311475 0.2 3.5717 0.000355 0.004948 ENSMUSG00000022848 Dirc2 309.8054 0.7297166 0.14 5.0474 4.48E-07 2.43E-05 ENSMUSG00000020019 Ntn4 43.73625 0.7295075 0.23 3.1141 0.001845 0.018074 ENSMUSG00000070803 Cited4 31.33386 0.7291884 0.27 2.7229 0.006471 0.045303 ENSMUSG00000030787 Lyve1 46.14465 0.7289685 0.22 3.376 0.000735 0.008698 ENSMUSG00000042524 Sun2 297.4677 0.7265409 0.22 3.2362 0.001212 0.012966 ENSMUSG00000057322 Rpl38 1091.827 0.725824 0.19 3.8092 0.000139 0.002417 ENSMUSG00000012405 Rpl15 1106.092 0.7252427 0.15 4.801 1.58E-06 6.81E-05 ENSMUSG00000031538 Plat 149.5297 0.7241142 0.17 4.2914 1.78E-05 0.000454 ENSMUSG00000021477 Ctsl 1706.005 0.7240651 0.17 4.1629 3.14E-05 0.000719 ENSMUSG00000039899 Fgl2 486.2136 0.7236843 0.26 2.8127 0.004913 0.037178 ENSMUSG00000058443 Gm5621 4492.986 0.7234484 0.2 3.6251 0.000289 0.004255 ENSMUSG00000059248 Sept9 1328.289 0.721813 0.19 3.8287 0.000129 0.002264 ENSMUSG00000028841 Cnksr1 300.666 0.7210015 0.19 3.7126 0.000205 0.00326 ENSMUSG00000062006 Rpl34 843.9708 0.7209963 0.16 4.5063 6.60E-06 0.000212 ENSMUSG00000025372 Baiap2 290.7029 0.7193715 0.25 2.8661 0.004156 0.032679 ENSMUSG00000084416 Rpl10a-ps1 615.4642 0.7189753 0.2 3.6232 0.000291 0.00427 ENSMUSG00000022091 Sorbs3 39.54501 0.7183897 0.23 3.173 0.001509 0.015446 ENSMUSG00000024927 Rela 456.0023 0.7181778 0.19 3.7291 0.000192 0.003135 Page 51 of 85 Diabetes

ENSMUSG00000008683 Rps15a 983.0585 0.7159456 0.16 4.4679 7.90E-06 0.000247 ENSMUSG00000029455 Aldh2 223.09 0.7153999 0.16 4.3506 1.36E-05 0.000374 ENSMUSG00000060636 Rpl35a 1245.709 0.7131116 0.16 4.3461 1.39E-05 0.000379 ENSMUSG00000015647 Lama5 86.16265 0.7128317 0.2 3.4868 0.000489 0.006381 ENSMUSG00000001552 Jup 1246.287 0.7122337 0.14 5.1543 2.55E-07 1.59E-05 ENSMUSG00000040734 Ppp1r13l 41.94822 0.7119715 0.25 2.8432 0.004466 0.034505 ENSMUSG00000050299 Gm9843 818.6855 0.7107559 0.18 3.9389 8.19E-05 0.001564 ENSMUSG00000042289 Hsd3b7 405.1724 0.7107398 0.19 3.7573 0.000172 0.00287 ENSMUSG00000079641 Rpl39 700.518 0.7106003 0.16 4.4334 9.28E-06 0.000275 ENSMUSG00000040666 Sh3bgr 31.65979 0.7105333 0.26 2.7476 0.006002 0.042865 ENSMUSG00000036390 Gadd45a 196.8281 0.7099618 0.13 5.4386 5.37E-08 4.46E-06 ENSMUSG00000025068 Gsto1 80.18456 0.7099485 0.21 3.315 0.000917 0.010435 ENSMUSG00000015837 Sqstm1 7308.091 0.7094294 0.17 4.2638 2.01E-05 0.000504 ENSMUSG00000044080 S100a1 173.9774 0.7090569 0.14 5.0706 3.96E-07 2.20E-05 ENSMUSG00000033307 Mif 259.5578 0.7079008 0.2 3.5566 0.000376 0.005149 ENSMUSG00000020400 Tnip1 409.4092 0.7077344 0.22 3.2497 0.001155 0.012499 ENSMUSG00000090733 Rps27 1464.461 0.7076422 0.16 4.4582 8.26E-06 0.000254 ENSMUSG00000004610 Etfb 265.0565 0.7069303 0.15 4.5725 4.82E-06 0.000166 ENSMUSG00000027430 Dtd1 86.06801 0.704571 0.16 4.2923 1.77E-05 0.000454 ENSMUSG00000036752 Tubb4b 870.5391 0.6985868 0.13 5.3172 1.05E-07 7.64E-06 ENSMUSG00000034738 Nostrin 39.56875 0.697887 0.24 2.8826 0.003944 0.031411 ENSMUSG00000027583 Zbtb46 32.59303 0.697616 0.25 2.7699 0.005608 0.040745 ENSMUSG00000024063 Lbh 989.3918 0.6956795 0.23 3.0816 0.002059 0.01951 ENSMUSG00000043716 Rpl7 2298.259 0.6936043 0.15 4.5332 5.81E-06 0.000191 ENSMUSG00000072692 Rpl37rt 268.877 0.6931581 0.19 3.5641 0.000365 0.005053 ENSMUSG00000031604 Msmo1 1094.173 0.6902378 0.17 3.9709 7.16E-05 0.001409 ENSMUSG00000020723 Cacng4 42.63868 0.6893763 0.25 2.799 0.005125 0.038332 ENSMUSG00000011257 Pabpc4 719.1192 0.6892532 0.15 4.6067 4.09E-06 0.000144 ENSMUSG00000016758 Bik 24.69968 0.6863237 0.25 2.703 0.006872 0.047454 ENSMUSG00000025178 Pi4k2a 1169.483 0.6846532 0.25 2.7712 0.005585 0.040659 ENSMUSG00000040659 Efhd2 290.6054 0.6839582 0.14 4.7971 1.61E-06 6.92E-05 ENSMUSG00000058258 Idi1 378.0983 0.6829589 0.15 4.5803 4.64E-06 0.000162 ENSMUSG00000052605 Isoc2b 60.47057 0.6791121 0.25 2.7468 0.006019 0.042901 ENSMUSG00000015961 Adss 181.4556 0.6788754 0.12 5.4779 4.30E-08 3.75E-06 ENSMUSG00000030428 Ttyh1 131.2182 0.6783478 0.16 4.2406 2.23E-05 0.000543 ENSMUSG00000060036 Rpl3 2796.782 0.6778887 0.15 4.4495 8.61E-06 0.000259 ENSMUSG00000020372 Gnb2l1 2478.071 0.6759363 0.15 4.3808 1.18E-05 0.000334 ENSMUSG00000030595 Nfkbib 182.4048 0.675489 0.19 3.6148 0.000301 0.004353 ENSMUSG00000032263 Bckdhb 78.6534 0.6746734 0.18 3.7272 0.000194 0.003142 ENSMUSG00000041453 Rpl21 1405.315 0.6746267 0.2 3.4057 0.00066 0.00802 ENSMUSG00000003970 Rpl8 2294.224 0.6710077 0.17 3.8971 9.74E-05 0.001799 ENSMUSG00000022323 Hrsp12 44.704 0.6706185 0.22 3.0578 0.00223 0.020593 Diabetes Page 52 of 85

ENSMUSG00000027076 Timm10 42.48852 0.6702973 0.23 2.959 0.003086 0.026138 ENSMUSG00000067274 Rplp0 4019.45 0.6699115 0.19 3.5271 0.00042 0.005655 ENSMUSG00000085787 Gm13092 50.22456 0.6688612 0.23 2.9631 0.003046 0.025932 ENSMUSG00000028910 Mecr 74.61357 0.6674294 0.23 2.9248 0.003447 0.028318 ENSMUSG00000016528 Mapkapk2 550.4693 0.6672121 0.15 4.3847 1.16E-05 0.00033 ENSMUSG00000024206 Rfx2 134.2845 0.6664591 0.14 4.6165 3.90E-06 0.000139 ENSMUSG00000022312 Eif3h 679.4786 0.6639914 0.13 5.262 1.42E-07 9.78E-06 ENSMUSG00000070473 Cldn3 208.9848 0.6635954 0.18 3.7179 0.000201 0.003224 ENSMUSG00000001289 Pfdn5 630.1519 0.6629694 0.15 4.3577 1.31E-05 0.000365 ENSMUSG00000091956 C2cd4b 291.6336 0.6624044 0.24 2.7498 0.005963 0.042668 ENSMUSG00000020407 Upp1 365.1555 0.6607012 0.18 3.5808 0.000343 0.004835 ENSMUSG00000054065 Pkp3 112.2366 0.6597922 0.22 2.9859 0.002827 0.024559 ENSMUSG00000028032 Papss1 387.0793 0.6595818 0.13 5.2224 1.77E-07 1.16E-05 ENSMUSG00000048758 Rpl29 911.494 0.6589198 0.19 3.4697 0.000521 0.0067 ENSMUSG00000083380 Gm3244 135.7078 0.6575497 0.15 4.3168 1.58E-05 0.000421 ENSMUSG00000044258 Ctla2a 86.7127 0.6567133 0.17 3.8388 0.000124 0.002191 ENSMUSG00000032231 Anxa2 194.2487 0.6564397 0.21 3.0699 0.002142 0.020043 ENSMUSG00000050856 Atp5k 215.1401 0.6553188 0.19 3.5375 0.000404 0.005483 ENSMUSG00000060591 Ifitm2 139.233 0.6546346 0.17 3.8216 0.000133 0.002324 ENSMUSG00000021385 Ippk 177.7958 0.6530484 0.21 3.1722 0.001513 0.015469 ENSMUSG00000087006 Gm13889 48.19959 0.6526634 0.23 2.7825 0.005395 0.039771 ENSMUSG00000074622 Mafb 416.4697 0.6525317 0.17 3.8414 0.000122 0.002176 ENSMUSG00000037563 Rps16 839.4948 0.6522497 0.2 3.2048 0.001352 0.014114 ENSMUSG00000028271 Gtf2b 306.979 0.6515819 0.2 3.3131 0.000923 0.010472 ENSMUSG00000035049 Rrp12 213.4512 0.6515467 0.22 3.0061 0.002646 0.02336 ENSMUSG00000071644 Eef1g 2376.687 0.6515301 0.16 4.1566 3.23E-05 0.000737 ENSMUSG00000032359 Ctsh 40.53205 0.6509024 0.22 2.9235 0.003461 0.028381 ENSMUSG00000070697 Utp3 203.7106 0.6497012 0.12 5.6049 2.08E-08 1.93E-06 ENSMUSG00000090625 Gm20721 177.7523 0.6494942 0.2 3.2442 0.001178 0.012698 ENSMUSG00000027227 Sord 106.9283 0.6456085 0.2 3.2583 0.001121 0.012183 ENSMUSG00000063171 Rps4l 239.5579 0.6453085 0.16 4.1558 3.24E-05 0.000738 ENSMUSG00000070394 Tmem256 168.051 0.6444728 0.14 4.4651 8.00E-06 0.000248 ENSMUSG00000023122 Sult1c2 47.15761 0.6428367 0.23 2.741 0.006125 0.043447 ENSMUSG00000044948 Itprip 96.07946 0.6410432 0.2 3.2182 0.00129 0.013638 ENSMUSG00000040794 C1qtnf4 33.85456 0.6410063 0.22 2.9467 0.003211 0.026919 ENSMUSG00000027613 Eif6 746.6264 0.6400563 0.2 3.2746 0.001058 0.011612 ENSMUSG00000050428 Fbxo46 69.43029 0.6376712 0.18 3.6315 0.000282 0.004187 ENSMUSG00000028461 Ccdc107 81.91035 0.6369056 0.18 3.5977 0.000321 0.004571 ENSMUSG00000032399 Rpl4 5009.826 0.6353702 0.15 4.2486 2.15E-05 0.000528 ENSMUSG00000016252 Atp5e 531.098 0.6329172 0.17 3.6796 0.000234 0.003604 ENSMUSG00000017404 Rpl19 2746.453 0.6322949 0.16 3.9837 6.78E-05 0.001349 ENSMUSG00000040181 Fmo1 129.4743 0.6320791 0.2 3.2077 0.001338 0.014001 Page 53 of 85 Diabetes

ENSMUSG00000022508 Bcl6 59.00887 0.6311632 0.21 3.0455 0.002323 0.021131 ENSMUSG00000028234 Rps20 1043.409 0.6309452 0.17 3.6288 0.000285 0.004221 ENSMUSG00000053600 Zfp472 40.20453 0.6308241 0.23 2.6951 0.007037 0.048319 ENSMUSG00000033294 Noc4l 97.01302 0.6297875 0.21 3.0566 0.002239 0.020638 ENSMUSG00000027551 Zfp64 204.7615 0.6292341 0.17 3.6982 0.000217 0.003417 ENSMUSG00000029614 Rpl6 2562.721 0.6290866 0.16 3.8919 9.94E-05 0.001824 ENSMUSG00000020547 Bzw2 117.1936 0.6289285 0.18 3.4245 0.000616 0.007578 ENSMUSG00000034006 Pqlc1 266.846 0.6271772 0.15 4.0944 4.23E-05 0.000913 ENSMUSG00000043587 Pxylp1 154.9095 0.6261954 0.21 2.983 0.002855 0.024708 ENSMUSG00000047446 Arl4a 223.3903 0.6240699 0.18 3.5433 0.000395 0.005379 ENSMUSG00000073640 Rpl27-ps3 761.6981 0.6229455 0.15 4.1512 3.31E-05 0.00075 ENSMUSG00000006378 Galr3 304.0245 0.6223819 0.22 2.7782 0.005467 0.040107 ENSMUSG00000003429 Rps11 978.4693 0.6221616 0.21 3.0152 0.002568 0.02281 ENSMUSG00000022450 Ndufa6 354.798 0.6213789 0.15 4.0603 4.90E-05 0.001028 ENSMUSG00000038274 Fau 288.0482 0.6213405 0.17 3.6788 0.000234 0.00361 ENSMUSG00000029552 Tes 428.017 0.6210405 0.2 3.0639 0.002184 0.020288 ENSMUSG00000021281 Tnfaip2 127.8075 0.6182478 0.16 3.9505 7.80E-05 0.001507 ENSMUSG00000050708 Ftl1 8094.449 0.6179276 0.16 3.8208 0.000133 0.002326 ENSMUSG00000044147 Arf6 339.4172 0.6165054 0.17 3.6569 0.000255 0.003887 ENSMUSG00000047181 Samd14 88.79079 0.6156335 0.16 3.892 9.94E-05 0.001824 ENSMUSG00000067242 Lgi1 112.7701 0.6145473 0.18 3.4918 0.00048 0.006284 ENSMUSG00000025731 0610011F06Rik253.4664 0.6138384 0.14 4.2456 2.18E-05 0.000535 ENSMUSG00000026078 Pdcl3 158.9823 0.6130161 0.14 4.452 8.51E-06 0.000258 ENSMUSG00000022562 Oplah 34.37514 0.6119401 0.22 2.7524 0.005915 0.042389 ENSMUSG00000040952 Rps19 1112.224 0.6110771 0.2 3.1073 0.001888 0.018381 ENSMUSG00000026675 Hsd17b7 116.5232 0.6101883 0.22 2.739 0.006163 0.043597 ENSMUSG00000023067 Cdkn1a 633.2548 0.6094094 0.14 4.2233 2.41E-05 0.00058 ENSMUSG00000039568 Ubald1 266.4506 0.6092504 0.16 3.7371 0.000186 0.003061 ENSMUSG00000026659 Dusp12 72.56542 0.6089166 0.19 3.2166 0.001297 0.013676 ENSMUSG00000004032 Gstm5 109.4502 0.6078403 0.14 4.2098 2.56E-05 0.000608 ENSMUSG00000063316 Rpl27 80.66025 0.6075904 0.22 2.7096 0.006736 0.046767 ENSMUSG00000055723 Rras2 116.5544 0.6063104 0.16 3.7407 0.000183 0.003034 ENSMUSG00000061315 Naca 1061.183 0.6056213 0.16 3.7861 0.000153 0.002604 ENSMUSG00000028936 Rpl22 473.6979 0.6045102 0.15 4.13 3.63E-05 0.000811 ENSMUSG00000021273 Fdft1 1028.724 0.6038704 0.13 4.6973 2.64E-06 0.000103 ENSMUSG00000036206 Sh3bp4 312.1108 0.6029018 0.2 2.9459 0.00322 0.026972 ENSMUSG00000019987 Arg1 112.4207 0.6024914 0.18 3.3354 0.000852 0.009804 ENSMUSG00000037742 Eef1a1 22649.31 0.6013245 0.12 4.9061 9.29E-07 4.53E-05 ENSMUSG00000031706 Rfx1 114.794 0.6010629 0.19 3.2062 0.001345 0.014057 ENSMUSG00000022114 Spry2 60.8389 0.6005979 0.2 3.0088 0.002623 0.023212 ENSMUSG00000036199 Ndufa13 368.7788 0.5998837 0.15 3.9751 7.03E-05 0.00139 ENSMUSG00000061104 Gm10094 280.403 0.5997872 0.16 3.7217 0.000198 0.003196 Diabetes Page 54 of 85

ENSMUSG00000026864 Hspa5 23772.17 0.5992949 0.18 3.294 0.000988 0.011116 ENSMUSG00000042312 S100a13 61.46426 0.5983806 0.21 2.8423 0.00448 0.034557 ENSMUSG00000022972 1110004E09Rik154.4429 0.5975674 0.12 4.8373 1.32E-06 5.92E-05 ENSMUSG00000025337 Sbds 478.6722 0.5965909 0.16 3.6309 0.000282 0.004192 ENSMUSG00000021792 Fam213a 226.3873 0.5954653 0.12 4.8736 1.10E-06 5.15E-05 ENSMUSG00000041560 Gltscr2 541.7912 0.5952136 0.14 4.4054 1.06E-05 0.000307 ENSMUSG00000031103 Elf4 177.0327 0.5945722 0.19 3.1486 0.001641 0.016537 ENSMUSG00000038859 Baiap2l1 269.4098 0.5942606 0.13 4.5188 6.22E-06 0.000203 ENSMUSG00000033323 Ctdp1 201.7872 0.5931064 0.14 4.2006 2.66E-05 0.000626 ENSMUSG00000048706 Lurap1l 204.7677 0.5914251 0.14 4.3666 1.26E-05 0.000354 ENSMUSG00000032802 Srxn1 1188.384 0.5897993 0.13 4.4703 7.81E-06 0.000245 ENSMUSG00000074063 Osgin1 193.6624 0.5890872 0.2 2.9113 0.003599 0.02925 ENSMUSG00000062647 Rpl7a 1907.654 0.5878371 0.16 3.7828 0.000155 0.002624 ENSMUSG00000052033 Pfdn4 104.4229 0.5859156 0.19 3.0642 0.002183 0.020284 ENSMUSG00000036430 Tbcc 78.33085 0.5854195 0.2 2.9639 0.003038 0.025932 ENSMUSG00000019261 Map1s 232.0538 0.5851323 0.19 3.0072 0.002636 0.023313 ENSMUSG00000018166 Erbb3 46.91507 0.5847844 0.19 3.0006 0.002695 0.023719 ENSMUSG00000023089 Ndufa5 127.324 0.5845477 0.16 3.6444 0.000268 0.004034 ENSMUSG00000060586 H2-Eb1 262.2352 0.584522 0.19 3.0748 0.002106 0.019866 ENSMUSG00000035413 Tmem98 70.07989 0.5838278 0.19 3.1317 0.001738 0.017234 ENSMUSG00000034168 Irf2bpl 210.4022 0.5807326 0.21 2.7767 0.005491 0.0402 ENSMUSG00000040857 Erf 153.9111 0.5800176 0.2 2.9142 0.003566 0.02909 ENSMUSG00000028998 Tomm7 274.2664 0.5782071 0.15 3.8767 0.000106 0.001921 ENSMUSG00000029381 Shroom3 605.5803 0.578199 0.21 2.7055 0.00682 0.047185 ENSMUSG00000010067 Rassf1 162.3117 0.576787 0.19 3.0103 0.00261 0.023112 ENSMUSG00000002395 Use1 313.2935 0.5755471 0.15 3.8466 0.00012 0.002136 ENSMUSG00000020415 Pttg1 77.50734 0.5736031 0.19 2.9967 0.002729 0.023937 ENSMUSG00000023904 Hcfc1r1 327.6682 0.5735698 0.15 3.9148 9.05E-05 0.001689 ENSMUSG00000025260 Hsd17b10 102.4219 0.5734028 0.18 3.1703 0.001523 0.015525 ENSMUSG00000015202 Cnksr3 87.62563 0.5733598 0.2 2.8749 0.004042 0.032054 ENSMUSG00000028447 Dctn3 247.2653 0.5724585 0.15 3.8605 0.000113 0.002031 ENSMUSG00000059070 Rpl18 1259.156 0.5723006 0.19 3.0566 0.002239 0.020638 ENSMUSG00000038717 Atp5l 780.4242 0.5722401 0.12 4.8095 1.51E-06 6.64E-05 ENSMUSG00000033998 Kcnk1 256.6414 0.5712417 0.12 4.7252 2.30E-06 9.18E-05 ENSMUSG00000034265 Zdhhc14 103.863 0.5708195 0.16 3.5039 0.000458 0.00606 ENSMUSG00000049422 Chchd10 167.2375 0.5704605 0.19 2.993 0.002762 0.02418 ENSMUSG00000027968 Larp7 112.3762 0.5677259 0.18 3.1723 0.001512 0.015469 ENSMUSG00000017778 Cox7c 333.0523 0.5663694 0.14 4.0692 4.72E-05 0.000997 ENSMUSG00000039007 Cpq 844.0675 0.5661153 0.13 4.3009 1.70E-05 0.000441 ENSMUSG00000093930 Hmgcs1 1034.812 0.5658888 0.19 2.9091 0.003624 0.029417 ENSMUSG00000025794 Rpl14 1388.74 0.5656135 0.18 3.2318 0.00123 0.013118 ENSMUSG00000024610 Cd74 785.3425 0.564969 0.17 3.4182 0.00063 0.007715 Page 55 of 85 Diabetes

ENSMUSG00000051343 Rab11fip5 144.2688 0.5643738 0.15 3.7137 0.000204 0.003253 ENSMUSG00000046719 Nxph3 61.67742 0.5642681 0.2 2.7541 0.005886 0.042263 ENSMUSG00000002043 Trappc6a 64.64072 0.5631942 0.19 2.8981 0.003754 0.030185 ENSMUSG00000090291 Lrrc10b 741.5717 0.5617266 0.13 4.3981 1.09E-05 0.000316 ENSMUSG00000021242 Npc2 1109.839 0.5614979 0.11 4.9449 7.62E-07 3.81E-05 ENSMUSG00000018648 Dusp14 76.42176 0.5608078 0.17 3.2773 0.001048 0.01152 ENSMUSG00000023944 Hsp90ab1 6589.759 0.5603925 0.12 4.54 5.63E-06 0.000186 ENSMUSG00000019505 Ubb 10378.86 0.5593854 0.15 3.76 0.00017 0.002852 ENSMUSG00000006215 Zbtb17 166.2852 0.5583848 0.17 3.2453 0.001173 0.012676 ENSMUSG00000019810 Fuca2 216.3531 0.5573176 0.13 4.3164 1.59E-05 0.000421 ENSMUSG00000047945 Marcksl1 80.44081 0.5568746 0.18 3.0712 0.002132 0.020035 ENSMUSG00000028070 Apoa1bp 263.0307 0.5565322 0.12 4.6478 3.35E-06 0.000124 ENSMUSG00000003363 Pld3 761.3336 0.5556999 0.11 5.145 2.67E-07 1.65E-05 ENSMUSG00000021190 Lgmn 148.8339 0.5543665 0.13 4.3964 1.10E-05 0.000317 ENSMUSG00000044641 Pard6b 80.02048 0.5523037 0.17 3.2591 0.001118 0.012166 ENSMUSG00000041120 Nbl1 119.6697 0.5499732 0.16 3.4634 0.000533 0.006828 ENSMUSG00000037262 Kin 153.7556 0.5497496 0.18 2.9728 0.002951 0.025345 ENSMUSG00000100755 Rps23-ps1 806.9037 0.5494022 0.17 3.1792 0.001477 0.015149 ENSMUSG00000038650 Rnh1 1286.146 0.5493821 0.18 3.1375 0.001704 0.017016 ENSMUSG00000032497 Lrrfip2 886.2413 0.5491076 0.16 3.3696 0.000753 0.008868 ENSMUSG00000021939 Ctsb 2935.011 0.5478454 0.15 3.659 0.000253 0.003865 ENSMUSG00000004285 Atp6v1f 505.2403 0.5464114 0.13 4.0844 4.42E-05 0.000946 ENSMUSG00000062683 Atp5g2 496.3656 0.5463738 0.18 3.1044 0.001906 0.018469 ENSMUSG00000037499 Nenf 293.8066 0.5453102 0.15 3.5639 0.000365 0.005053 ENSMUSG00000049775 Tmsb4x 909.904 0.5432911 0.1 5.3344 9.58E-08 7.26E-06 ENSMUSG00000026687 Aldh9a1 405.6074 0.5424702 0.14 3.9462 7.94E-05 0.001527 ENSMUSG00000039994 Timeless 69.54678 0.5422493 0.2 2.6812 0.007336 0.049766 ENSMUSG00000032469 Dbr1 176.6188 0.5416822 0.16 3.2913 0.000997 0.011165 ENSMUSG00000036478 Btg1 593.1361 0.5415464 0.18 2.9426 0.003255 0.027173 ENSMUSG00000029198 Grpel1 357.9704 0.5412706 0.1 5.433 5.54E-08 4.55E-06 ENSMUSG00000025578 Cbx8 59.86721 0.5409438 0.2 2.7489 0.005979 0.042748 ENSMUSG00000073411 H2-D1 3105.655 0.54051 0.18 3.0786 0.00208 0.019656 ENSMUSG00000030029 Lrig1 162.5347 0.5389668 0.15 3.6003 0.000318 0.004537 ENSMUSG00000058135 Gstm1 407.9592 0.5386154 0.2 2.739 0.006163 0.043597 ENSMUSG00000026988 Wdsub1 237.6491 0.5384588 0.13 4.2153 2.49E-05 0.000598 ENSMUSG00000030060 Hmces 416.743 0.5371817 0.16 3.3148 0.000917 0.010435 ENSMUSG00000000811 Txnrd3 48.42106 0.5362783 0.2 2.722 0.006489 0.045383 ENSMUSG00000034312 Iqsec1 91.33682 0.5360229 0.17 3.1274 0.001764 0.017456 ENSMUSG00000023236 Scg5 4005.607 0.5334357 0.1 5.1393 2.76E-07 1.67E-05 ENSMUSG00000010406 Mrpl52 86.97012 0.5333592 0.2 2.6887 0.007174 0.04902 ENSMUSG00000000827 Tpd52l2 542.0131 0.5321365 0.16 3.2703 0.001074 0.011746 ENSMUSG00000016427 Ndufa1 360.33 0.5320677 0.12 4.3142 1.60E-05 0.000423 Diabetes Page 56 of 85

ENSMUSG00000020775 Mrpl38 162.0586 0.5317417 0.16 3.2578 0.001123 0.012186 ENSMUSG00000037820 Tgm2 106.5601 0.5316635 0.18 2.8939 0.003805 0.030529 ENSMUSG00000028478 Clta 553.4721 0.530552 0.14 3.7279 0.000193 0.003141 ENSMUSG00000031029 Eif3f 604.739 0.5305497 0.18 2.9522 0.003155 0.026571 ENSMUSG00000042541 Shfm1 343.1744 0.5303944 0.15 3.4551 0.00055 0.006988 ENSMUSG00000030605 Mfge8 134.003 0.530294 0.19 2.7399 0.006146 0.043554 ENSMUSG00000027602 Map1lc3a 240.1757 0.5300416 0.16 3.3407 0.000836 0.009651 ENSMUSG00000037960 1110007C09Rik141.6191 0.5295642 0.19 2.8326 0.004617 0.035465 ENSMUSG00000044337 Ackr3 79.27508 0.5279186 0.17 3.0602 0.002212 0.020494 ENSMUSG00000101249 Gm29216 8170.509 0.5277933 0.17 3.082 0.002056 0.019492 ENSMUSG00000053565 Eif3k 423.8475 0.5247875 0.18 2.8745 0.004047 0.032063 ENSMUSG00000028029 Aimp1 219.5621 0.5241623 0.14 3.7765 0.000159 0.002678 ENSMUSG00000020267 Hint1 435.3126 0.5239517 0.14 3.7204 0.000199 0.003202 ENSMUSG00000049482 Ctu2 101.1138 0.5230955 0.18 2.9296 0.003394 0.027972 ENSMUSG00000073889 Il11ra1 111.1424 0.5229517 0.15 3.4934 0.000477 0.006252 ENSMUSG00000005054 Cstb 264.8262 0.5212715 0.17 3.0914 0.001992 0.019108 ENSMUSG00000032366 Tpm1 755.985 0.5195224 0.12 4.2108 2.55E-05 0.000607 ENSMUSG00000017950 Hnf4a 342.2096 0.5193555 0.16 3.2817 0.001032 0.011386 ENSMUSG00000021731 Mrps30 99.68026 0.5184972 0.16 3.3179 0.000907 0.010351 ENSMUSG00000038607 Gng10 69.26814 0.51789 0.18 2.8958 0.003782 0.030363 ENSMUSG00000028945 Rheb 599.7891 0.516418 0.15 3.5457 0.000392 0.005336 ENSMUSG00000034566 Atp5h 527.6002 0.5154419 0.13 3.8399 0.000123 0.002184 ENSMUSG00000024661 Fth1 2202.822 0.5153248 0.11 4.5552 5.23E-06 0.000175 ENSMUSG00000006373 Pgrmc1 736.8426 0.5149341 0.1 4.9976 5.81E-07 3.01E-05 ENSMUSG00000003411 Rab3b 237.8596 0.5145993 0.17 3.0558 0.002245 0.020648 ENSMUSG00000005069 Pex5 391.984 0.5126222 0.19 2.7441 0.006067 0.0431 ENSMUSG00000018565 Elp5 234.1668 0.5112274 0.16 3.2675 0.001085 0.011856 ENSMUSG00000061167 Rpl15-ps3 478.6575 0.5112106 0.17 2.9636 0.00304 0.025932 ENSMUSG00000034994 Eef2 9858.69 0.5106886 0.12 4.2566 2.08E-05 0.000517 ENSMUSG00000026670 Uap1 341.8731 0.510254 0.15 3.4022 0.000668 0.008096 ENSMUSG00000030750 Nsmce1 121.7852 0.5099148 0.14 3.5758 0.000349 0.004888 ENSMUSG00000026223 Itm2c 2316.484 0.5096839 0.07 6.9484 3.69E-12 9.15E-10 ENSMUSG00000075706 Gpx4 639.9851 0.5073857 0.18 2.872 0.004079 0.032268 ENSMUSG00000049751 Rpl36al 1095.487 0.5064103 0.18 2.8319 0.004627 0.035525 ENSMUSG00000030161 Gabarapl1 1277.128 0.5063763 0.11 4.4634 8.07E-06 0.000249 ENSMUSG00000027342 Pcna 293.5759 0.5062158 0.12 4.1042 4.06E-05 0.00089 ENSMUSG00000015401 Tmem27 2097.573 0.5057684 0.17 2.9482 0.003196 0.026824 ENSMUSG00000020857 Nme2 916.1021 0.5052094 0.18 2.7484 0.005988 0.042784 ENSMUSG00000037966 Ninj1 607.3605 0.5047939 0.13 3.7951 0.000148 0.002523 ENSMUSG00000022009 Nufip1 101.6572 0.5041636 0.15 3.4214 0.000623 0.007652 ENSMUSG00000027397 Slc20a1 304.3949 0.5040356 0.14 3.7098 0.000207 0.003292 ENSMUSG00000000303 Cdh1 3760.181 0.50161 0.15 3.4478 0.000565 0.00713 Page 57 of 85 Diabetes

ENSMUSG00000029171 Pgm1 139.9339 0.5005844 0.15 3.4059 0.000659 0.00802 ENSMUSG00000073468 Sft2d1 71.84245 0.5004032 0.17 2.9795 0.002887 0.024962 ENSMUSG00000020224 Llph 122.6596 0.5003656 0.18 2.7707 0.005593 0.040698 ENSMUSG00000027999 Pla2g12a 180.1133 0.4994868 0.16 3.1995 0.001377 0.014294 ENSMUSG00000070493 Chchd2 792.1847 0.4961463 0.12 4.1141 3.89E-05 0.000858 ENSMUSG00000017677 Wsb1 133.1648 0.4948408 0.17 2.9967 0.00273 0.023937 ENSMUSG00000027714 Exosc9 187.8591 0.4945901 0.13 3.9105 9.21E-05 0.001715 ENSMUSG00000024528 Srfbp1 61.27819 0.4945292 0.18 2.761 0.005762 0.041575 ENSMUSG00000051146 Camk2n2 302.5563 0.4934987 0.11 4.5386 5.66E-06 0.000187 ENSMUSG00000015127 Unkl 62.39809 0.4924571 0.18 2.6888 0.007172 0.04902 ENSMUSG00000015932 Dstn 3235.296 0.4909726 0.17 2.932 0.003368 0.027849 ENSMUSG00000018347 Zkscan6 118.6365 0.4907989 0.17 2.8919 0.003829 0.03064 ENSMUSG00000028223 Decr1 86.789 0.4897646 0.17 2.8485 0.004393 0.034088 ENSMUSG00000039062 Anpep 506.2394 0.4888308 0.17 2.8339 0.004599 0.035348 ENSMUSG00000024436 Mrps18b 199.3504 0.4883343 0.14 3.4718 0.000517 0.00667 ENSMUSG00000022982 Sod1 1013.364 0.4880263 0.17 2.8766 0.004019 0.031952 ENSMUSG00000004788 Eif2b2 234.8868 0.4875532 0.13 3.7381 0.000185 0.003052 ENSMUSG00000003444 Med29 110.1331 0.4864201 0.17 2.913 0.003579 0.029167 ENSMUSG00000030649 Anapc15 86.64079 0.4863419 0.17 2.8933 0.003812 0.03055 ENSMUSG00000072772 Grcc10 205.4729 0.4851739 0.13 3.6423 0.00027 0.004059 ENSMUSG00000022337 Emc2 170.5564 0.4847219 0.13 3.5972 0.000322 0.004574 ENSMUSG00000021290 2010107E04Rik194.9603 0.48423 0.16 3.0018 0.002684 0.023635 ENSMUSG00000031521 Aga 407.214 0.4840988 0.11 4.3121 1.62E-05 0.000425 ENSMUSG00000061024 Rrs1 91.87978 0.483749 0.16 3.0889 0.002009 0.019219 ENSMUSG00000027523 Gnas 7421.456 0.4833014 0.09 5.2455 1.56E-07 1.06E-05 ENSMUSG00000034826 Nup54 120.4157 0.4826981 0.17 2.9062 0.003659 0.029601 ENSMUSG00000024970 AI846148 150.0781 0.4822994 0.13 3.6249 0.000289 0.004255 ENSMUSG00000073982 Rhog 129.119 0.480782 0.18 2.7008 0.006918 0.047682 ENSMUSG00000057666 Gapdh 3461.19 0.4803471 0.16 2.9677 0.003 0.025726 ENSMUSG00000045211 Nudt18 145.744 0.479674 0.14 3.4401 0.000581 0.007277 ENSMUSG00000041697 Cox6a1 450.3327 0.4796242 0.17 2.8615 0.004216 0.03303 ENSMUSG00000029642 Polr1d 304.8642 0.4786522 0.16 3.0846 0.002039 0.019419 ENSMUSG00000021520 Uqcrb 433.9529 0.4782568 0.12 4.0062 6.17E-05 0.001249 ENSMUSG00000079037 Prnp 3035.985 0.4780617 0.13 3.7419 0.000183 0.003023 ENSMUSG00000024580 Grpel2 225.7855 0.4773081 0.12 4.0372 5.41E-05 0.001111 ENSMUSG00000008167 Fbxw9 103.9856 0.4767281 0.15 3.1336 0.001727 0.017175 ENSMUSG00000035885 Cox8a 721.0386 0.4766829 0.1 4.6434 3.43E-06 0.000126 ENSMUSG00000014313 Cox6c 480.2049 0.4766044 0.11 4.4842 7.32E-06 0.000232 ENSMUSG00000034729 Mrps10 95.16287 0.4749608 0.18 2.7065 0.006799 0.047105 ENSMUSG00000006651 Aplp1 3667.815 0.4740276 0.07 6.5371 6.27E-11 1.16E-08 ENSMUSG00000060373 Hnrnpc 953.9616 0.4736708 0.09 5.5672 2.59E-08 2.34E-06 ENSMUSG00000021876 Rnase4 2188.205 0.4735614 0.14 3.4719 0.000517 0.00667 Diabetes Page 58 of 85

ENSMUSG00000025510 Cd151 240.5338 0.4734114 0.12 3.8024 0.000143 0.002468 ENSMUSG00000021645 Smn1 102.9521 0.4729656 0.15 3.1427 0.001674 0.016781 ENSMUSG00000045193 Cirbp 885.8584 0.4721427 0.14 3.2866 0.001014 0.011229 ENSMUSG00000039676 Capsl 220.9818 0.4712613 0.16 2.974 0.002939 0.025278 ENSMUSG00000035399 Oser1 210.5834 0.4710772 0.16 2.978 0.002902 0.02504 ENSMUSG00000073421 H2-Ab1 236.6462 0.4703497 0.15 3.1414 0.001682 0.016839 ENSMUSG00000034343 Ube2f 192.9714 0.4689369 0.14 3.3215 0.000895 0.010243 ENSMUSG00000042682 Selk 1013.927 0.4679451 0.11 4.0948 4.23E-05 0.000912 ENSMUSG00000036751 Cox6b1 486.6058 0.4674426 0.15 3.0848 0.002037 0.019419 ENSMUSG00000020397 Med7 102.3022 0.4657704 0.17 2.6886 0.007176 0.04902 ENSMUSG00000033916 Chmp2a 607.6611 0.4654371 0.14 3.3596 0.000781 0.009145 ENSMUSG00000059325 Hopx 357.0433 0.4651624 0.16 2.8278 0.004687 0.035897 ENSMUSG00000031848 Lsm4 146.9483 0.4645694 0.16 2.8439 0.004457 0.034474 ENSMUSG00000019210 Atp6v1e1 1268.789 0.4619347 0.08 6.0644 1.32E-09 1.76E-07 ENSMUSG00000032350 Gclc 316.2905 0.4614632 0.17 2.755 0.00587 0.042167 ENSMUSG00000031818 Cox4i1 799.3378 0.4599353 0.14 3.2007 0.001371 0.014267 ENSMUSG00000046675 Tmem251 124.0114 0.4594159 0.15 3.0139 0.002579 0.022878 ENSMUSG00000036504 Phpt1 144.7319 0.4592821 0.15 2.9636 0.003041 0.025932 ENSMUSG00000036315 Znrd1 101.9924 0.4585724 0.16 2.7864 0.00533 0.039434 ENSMUSG00000042613 Pbxip1 720.8532 0.4581228 0.15 3.1066 0.001893 0.018386 ENSMUSG00000090136 Gm10177 694.8011 0.4572738 0.16 2.8396 0.004516 0.034806 ENSMUSG00000061838 Suclg2 270.1447 0.455499 0.13 3.385 0.000712 0.008509 ENSMUSG00000061518 Cox5b 316.0523 0.4553849 0.15 3.0374 0.002386 0.021547 ENSMUSG00000024429 Gnl1 571.5041 0.4548788 0.14 3.2939 0.000988 0.011116 ENSMUSG00000067038 Rps12-ps3 796.9288 0.4547653 0.15 3.0835 0.002046 0.019473 ENSMUSG00000019362 D8Ertd738e 280.1155 0.4534377 0.15 3.1044 0.001906 0.018469 ENSMUSG00000041881 Ndufa7 285.1413 0.4533301 0.13 3.4715 0.000518 0.006672 ENSMUSG00000054428 Atpif1 441.9846 0.4529687 0.12 3.8775 0.000106 0.001917 ENSMUSG00000041025 Iffo2 96.36069 0.4508798 0.16 2.7668 0.00566 0.041005 ENSMUSG00000021194 Chga 76447.12 0.4487786 0.12 3.6558 0.000256 0.003896 ENSMUSG00000033475 Tomm6 329.1254 0.4485555 0.15 3.0161 0.002561 0.022756 ENSMUSG00000042043 Tbca 279.8717 0.4484457 0.16 2.8644 0.004178 0.032823 ENSMUSG00000018287 Spag7 222.4222 0.4474483 0.16 2.8214 0.004782 0.036409 ENSMUSG00000030879 Mrpl17 252.228 0.4462905 0.15 2.9121 0.003591 0.02923 ENSMUSG00000003072 Atp5d 562.8986 0.4457146 0.16 2.7903 0.005265 0.039084 ENSMUSG00000032294 Pkm 3599.026 0.4454237 0.12 3.6739 0.000239 0.003672 ENSMUSG00000027170 Eif3m 570.2919 0.4454064 0.15 3.0556 0.002246 0.020648 ENSMUSG00000033488 BC026585 118.0923 0.4447943 0.16 2.8302 0.004651 0.035655 ENSMUSG00000030970 Ctbp2 189.9569 0.4443601 0.16 2.7281 0.00637 0.04475 ENSMUSG00000001964 Emd 330.1084 0.4440274 0.15 2.9783 0.002899 0.025031 ENSMUSG00000043284 Tmem11 128.7655 0.4430631 0.16 2.7901 0.005269 0.039084 ENSMUSG00000006412 Pfdn2 271.2907 0.4404783 0.12 3.6237 0.00029 0.004267 Page 59 of 85 Diabetes

ENSMUSG00000049760 2410015M20Rik263.6356 0.440194 0.15 2.8635 0.00419 0.032878 ENSMUSG00000057113 Npm1 1074.379 0.4370888 0.13 3.3837 0.000715 0.008535 ENSMUSG00000008036 Ap2s1 299.3821 0.4367124 0.16 2.7129 0.006669 0.046399 ENSMUSG00000024248 Cox7a2l 1218.622 0.4351404 0.14 3.1341 0.001724 0.017167 ENSMUSG00000102252 Snrpn 281.0933 0.4351164 0.12 3.5236 0.000426 0.00571 ENSMUSG00000032330 Cox7a2 479.005 0.4344011 0.15 2.9918 0.002773 0.02423 ENSMUSG00000062933 Gm10123 611.7575 0.43327 0.16 2.7323 0.006289 0.044311 ENSMUSG00000036764 Dnajc12 346.968 0.430968 0.12 3.5206 0.000431 0.005758 ENSMUSG00000090258 Churc1 190.3511 0.4305965 0.15 2.8756 0.004032 0.032036 ENSMUSG00000001663 Gstt1 133.793 0.4304758 0.15 2.9433 0.003248 0.027129 ENSMUSG00000022892 App 1515.779 0.4277149 0.14 3.0148 0.002571 0.022823 ENSMUSG00000024038 Ndufv3 439.2107 0.4275028 0.14 3.1185 0.001818 0.017837 ENSMUSG00000071528 Usmg5 360.3827 0.4254621 0.13 3.2401 0.001195 0.012823 ENSMUSG00000022336 Eif3e 513.1236 0.4247423 0.11 3.7327 0.000189 0.003108 ENSMUSG00000084786 Ubl5 403.5345 0.4232501 0.12 3.4569 0.000547 0.006954 ENSMUSG00000020163 Uqcr11 299.2974 0.4216831 0.16 2.68 0.007363 0.049855 ENSMUSG00000003348 Mob3a 135.1715 0.4181274 0.15 2.7504 0.005952 0.042611 ENSMUSG00000038690 Atp5j2 438.5061 0.4178335 0.15 2.752 0.005924 0.042431 ENSMUSG00000021606 Ndufs6 198.6741 0.4170027 0.15 2.8112 0.004936 0.037313 ENSMUSG00000032527 Pccb 442.8327 0.4155078 0.13 3.2165 0.001298 0.013676 ENSMUSG00000074227 Spint2 1251.786 0.4154679 0.13 3.1185 0.001817 0.017837 ENSMUSG00000045394 Epcam 1448.219 0.4150389 0.11 3.7976 0.000146 0.002501 ENSMUSG00000005687 Bcas2 380.7157 0.4132039 0.12 3.474 0.000513 0.006647 ENSMUSG00000050608 Minos1 463.9816 0.4130342 0.12 3.4552 0.00055 0.006988 ENSMUSG00000025980 Hspd1 937.3683 0.4123083 0.11 3.7173 0.000201 0.003224 ENSMUSG00000073616 Myeov2 195.3639 0.4109582 0.14 2.9223 0.003475 0.028472 ENSMUSG00000024357 Sil1 324.8144 0.4074905 0.13 3.0704 0.002138 0.020036 ENSMUSG00000073422 H2-Ke6 223.325 0.4067435 0.14 2.9873 0.002814 0.02449 ENSMUSG00000023175 Bsg 2163.912 0.4058322 0.09 4.4341 9.25E-06 0.000275 ENSMUSG00000067148 Polr1c 161.2763 0.4057426 0.13 3.0659 0.00217 0.020219 ENSMUSG00000042608 Stk40 766.0634 0.405242 0.13 3.1504 0.00163 0.016448 ENSMUSG00000060739 Nsa2 361.4936 0.403795 0.13 3.1886 0.00143 0.014741 ENSMUSG00000026355 Mcm6 193.7993 0.4031469 0.14 2.8481 0.004398 0.034106 ENSMUSG00000026234 Ncl 2246.247 0.403059 0.09 4.5785 4.68E-06 0.000163 ENSMUSG00000029465 Arpc3 491.0158 0.4026265 0.12 3.2817 0.001032 0.011386 ENSMUSG00000001383 Zmat2 417.5954 0.4025384 0.13 3.1261 0.001772 0.017499 ENSMUSG00000032604 Qars 492.6362 0.4024648 0.12 3.4531 0.000554 0.007027 ENSMUSG00000031447 Lamp1 3516.065 0.4024155 0.11 3.7153 0.000203 0.003243 ENSMUSG00000027673 Ndufb5 274.731 0.4020707 0.13 3.0293 0.002451 0.021959 ENSMUSG00000091537 Tma7 357.1423 0.4016584 0.14 2.8464 0.004422 0.034219 ENSMUSG00000034993 Vat1 639.8352 0.4014715 0.12 3.3764 0.000734 0.008693 ENSMUSG00000050071 Bex1 192.4356 0.4008694 0.13 3.059 0.002221 0.020543 Diabetes Page 60 of 85

ENSMUSG00000041375 Ccdc9 210.9477 0.4005094 0.14 2.8699 0.004105 0.032442 ENSMUSG00000030007 Cct7 1154.215 0.3974171 0.11 3.6179 0.000297 0.004324 ENSMUSG00000090841 Myl6 1595.896 0.3958924 0.13 3.1485 0.001641 0.016537 ENSMUSG00000029922 Mkrn1 632.5654 0.3948419 0.12 3.2005 0.001372 0.014267 ENSMUSG00000020484 Xbp1 2617.391 0.3941997 0.09 4.2604 2.04E-05 0.000509 ENSMUSG00000063480 Nhp2l1 416.359 0.3933617 0.13 3.1452 0.00166 0.016675 ENSMUSG00000026672 Optn 201.9338 0.3914951 0.12 3.2292 0.001241 0.013206 ENSMUSG00000029076 Sdf4 1737.618 0.3901453 0.09 4.3399 1.43E-05 0.000389 ENSMUSG00000028798 Eif3i 451.8915 0.3899991 0.14 2.7407 0.006132 0.043472 ENSMUSG00000063931 Pepd 207.56 0.389379 0.13 3.0197 0.00253 0.022554 ENSMUSG00000022420 Dnal4 143.5352 0.3865091 0.14 2.7815 0.005411 0.039849 ENSMUSG00000027502 Rtfdc1 322.6246 0.3861216 0.13 2.9381 0.003303 0.027417 ENSMUSG00000022108 Itm2b 3592.453 0.3844881 0.07 5.5365 3.09E-08 2.73E-06 ENSMUSG00000030824 Nucb1 1630.817 0.3843074 0.09 4.263 2.02E-05 0.000505 ENSMUSG00000025580 Eif4a3 524.4441 0.3833215 0.12 3.3267 0.000879 0.010083 ENSMUSG00000071866 Ppia 1729.98 0.3830313 0.12 3.0879 0.002016 0.019262 ENSMUSG00000026171 Rnf25 306.5648 0.3821402 0.11 3.4344 0.000594 0.00737 ENSMUSG00000052139 Bre 216.6671 0.3814585 0.14 2.7689 0.005624 0.040842 ENSMUSG00000025196 Cpn1 458.13 0.3810826 0.12 3.0531 0.002265 0.020786 ENSMUSG00000021660 Btf3 745.5479 0.3803931 0.13 2.9725 0.002954 0.025359 ENSMUSG00000030942 Thumpd1 259.1739 0.3788085 0.13 3.0165 0.002557 0.022751 ENSMUSG00000021576 Pdcd6 384.5103 0.3779024 0.1 3.8226 0.000132 0.002317 ENSMUSG00000068856 Sf3b4 277.7092 0.3757346 0.14 2.7714 0.005581 0.040653 ENSMUSG00000079426 Arpc4 314.881 0.3733758 0.12 3.0706 0.002137 0.020036 ENSMUSG00000022744 Cldnd1 244.2646 0.3718082 0.13 2.7661 0.005673 0.041035 ENSMUSG00000028902 Sf3a3 253.7867 0.3693765 0.14 2.6948 0.007044 0.048345 ENSMUSG00000020755 Sap30bp 225.5675 0.3682923 0.12 3.152 0.001622 0.016384 ENSMUSG00000027350 Chgb 12556.91 0.3681831 0.09 4.1521 3.30E-05 0.000749 ENSMUSG00000022463 Srebf2 1292.052 0.3656661 0.12 2.9629 0.003047 0.025932 ENSMUSG00000031059 Ndufb11 616.0336 0.3621465 0.12 2.9627 0.003049 0.025932 ENSMUSG00000038462 Uqcrfs1 381.1311 0.3621344 0.12 2.9595 0.003081 0.026129 ENSMUSG00000031950 Gabarapl2 808.0505 0.3614095 0.1 3.7224 0.000197 0.003191 ENSMUSG00000027419 Pcsk2 24614.14 0.3609893 0.09 4.1046 4.05E-05 0.00089 ENSMUSG00000049940 Pgrmc2 618.6583 0.355817 0.09 3.8838 0.000103 0.001875 ENSMUSG00000023861 Mpc1 248.626 0.3543721 0.13 2.772 0.005571 0.040604 ENSMUSG00000006301 Tmbim1 461.3308 0.3542092 0.13 2.7196 0.006536 0.045632 ENSMUSG00000034024 Cct2 794.1416 0.3523184 0.11 3.329 0.000872 0.01001 ENSMUSG00000014226 Cacybp 237.0714 0.3517072 0.13 2.7471 0.006012 0.042897 ENSMUSG00000023048 Prr13 328.0874 0.3513 0.12 2.8175 0.004839 0.036703 ENSMUSG00000044139 Prss53 5189.219 0.3511614 0.12 2.9908 0.002782 0.024282 ENSMUSG00000028692 Akr1a1 1767.515 0.3481193 0.12 2.9598 0.003078 0.026116 ENSMUSG00000025484 f 359.9328 0.3452989 0.12 2.9559 0.003117 0.026328 Page 61 of 85 Diabetes

ENSMUSG00000054452 Aes 1972.697 0.3417477 0.11 3.0361 0.002397 0.021605 ENSMUSG00000025512 Chid1 382.3003 0.3416749 0.12 2.7676 0.005647 0.040989 ENSMUSG00000025066 Sfr1 347.5112 0.3403968 0.12 2.935 0.003336 0.027646 ENSMUSG00000042712 Wbp5 1511.942 0.338958 0.12 2.8496 0.004378 0.033989 ENSMUSG00000026796 Fam129b 710.6186 0.3354535 0.11 3.047 0.002311 0.021054 ENSMUSG00000007564 Ppp2r1a 1177.479 0.3347995 0.12 2.7383 0.006176 0.043638 ENSMUSG00000029767 Calu 402.1751 0.3345788 0.12 2.7075 0.006779 0.046991 ENSMUSG00000035242 Oaz1 1458.318 0.3332511 0.12 2.8537 0.004321 0.033655 ENSMUSG00000018574 Acadvl 359.1504 0.3329854 0.12 2.8429 0.00447 0.034505 ENSMUSG00000036580 Spg20 281.9874 0.3293218 0.12 2.7921 0.005237 0.038903 ENSMUSG00000040681 Hmgn1 539.202 0.3282263 0.12 2.7278 0.006376 0.044767 ENSMUSG00000016319 Slc25a5 976.0388 0.3276629 0.09 3.696 0.000219 0.003436 ENSMUSG00000022814 Umps 250.7197 0.3266869 0.12 2.7528 0.005909 0.042365 ENSMUSG00000032959 Pebp1 1603.84 0.3263448 0.09 3.4724 0.000516 0.00667 ENSMUSG00000024966 Stip1 478.3197 0.322288 0.11 3.0045 0.00266 0.023439 ENSMUSG00000025264 Tsr2 271.9468 0.3220907 0.1 3.172 0.001514 0.015469 ENSMUSG00000061032 Rrp1 883.4412 0.3217988 0.11 2.8386 0.004531 0.034902 ENSMUSG00000054808 Actn4 2052.22 0.3190099 0.1 3.0654 0.002174 0.020244 ENSMUSG00000025173 Wdr45b 388.3049 0.3159612 0.1 3.1098 0.001872 0.018272 ENSMUSG00000037852 Cpe 19791.22 0.3132243 0.09 3.4269 0.000611 0.007533 ENSMUSG00000004207 Psap 7990.285 0.3129545 0.11 2.8273 0.004694 0.035929 ENSMUSG00000058655 Eif4b 1548.772 0.311016 0.11 2.7974 0.005151 0.038421 ENSMUSG00000022890 Atp5j 430.851 0.3072559 0.11 2.8683 0.004127 0.032536 ENSMUSG00000030662 Ipo5 813.3218 0.3063233 0.1 2.9648 0.003029 0.025932 ENSMUSG00000028788 Ptp4a2 632.0572 0.3034762 0.11 2.7768 0.00549 0.0402 ENSMUSG00000028618 Tmem59 1616.54 0.3026028 0.1 3.1601 0.001577 0.015998 ENSMUSG00000042750 Bex2 887.9193 0.3024324 0.09 3.4969 0.000471 0.006205 ENSMUSG00000027406 Idh3b 332.2494 0.3000538 0.11 2.6871 0.007207 0.049163 ENSMUSG00000025428 Atp5a1 3211.876 0.2909876 0.08 3.4255 0.000614 0.007559 ENSMUSG00000018770 Atp5g3 610.3408 0.2905936 0.11 2.6803 0.007356 0.049834 ENSMUSG00000036256 Igfbp7 705.2952 0.2841732 0.1 2.7758 0.005507 0.040274 ENSMUSG00000036438 Calm2 1122.712 0.2725424 0.09 3.073 0.002119 0.019951 ENSMUSG00000021794 Glud1 976.7777 0.2718232 0.08 3.2941 0.000987 0.011116 ENSMUSG00000021303 Gng4 1327.942 0.2700219 0.1 2.7594 0.005791 0.041701 ENSMUSG00000006273 Atp6v1b2 2687.273 0.2668586 0.1 2.7127 0.006675 0.046399 ENSMUSG00000062995 Ica1 688.7639 0.2631679 0.09 2.7986 0.005133 0.038343 ENSMUSG00000019087 Atp6ap1 1558.08 0.2526504 0.08 3.0559 0.002244 0.020648 ENSMUSG00000006304 Arpc2 758.1295 0.2518873 0.09 2.7295 0.006343 0.0446 ENSMUSG00000025393 Atp5b 2994.146 0.2484689 0.09 2.9002 0.003729 0.030022 ENSMUSG00000020265 Sumo3 796.9087 0.2423649 0.09 2.7371 0.006199 0.04378 ENSMUSG00000044600 Smim7 762.8216 0.230025 0.08 2.7627 0.005733 0.041388 ENSMUSG00000031532 Saraf 2864.864 0.2104613 0.07 2.9299 0.003391 0.027961 Diabetes Page 62 of 85

ENSMUSG00000071659 Hnrnpul2 1092.222 -0.212504 0.08 -2.7744 0.00553 0.040423 ENSMUSG00000022185 Acin1 971.4977 -0.235291 0.08 -2.944 0.00324 0.027085 ENSMUSG00000026553 Copa 3422.766 -0.239706 0.08 -3.1048 0.001904 0.018469 ENSMUSG00000019961 Tmpo 562.3537 -0.255393 0.09 -2.7263 0.006404 0.044903 ENSMUSG00000027519 Rab22a 696.2189 -0.259443 0.09 -2.7534 0.005898 0.042308 ENSMUSG00000007850 Hnrnph1 1612.585 -0.26058 0.09 -2.8568 0.004279 0.033415 ENSMUSG00000031392 Irak1 1128.552 -0.261633 0.09 -2.7847 0.005357 0.039534 ENSMUSG00000022995 Enah 547.1831 -0.266878 0.09 -2.8555 0.004297 0.033524 ENSMUSG00000001440 Kpnb1 1461.444 -0.273453 0.08 -3.5358 0.000407 0.005503 ENSMUSG00000021474 Sfxn1 395.5001 -0.276046 0.1 -2.7941 0.005204 0.038697 ENSMUSG00000031785 Adgrg1 1610.613 -0.277502 0.09 -3.0358 0.002399 0.021605 ENSMUSG00000032114 Slc37a4 403.5371 -0.289474 0.11 -2.6858 0.007235 0.049284 ENSMUSG00000026848 Tor1b 632.3108 -0.2943 0.11 -2.799 0.005126 0.038332 ENSMUSG00000021824 Ap3m1 480.0575 -0.296276 0.11 -2.6919 0.007104 0.048666 ENSMUSG00000026878 Rab14 649.3251 -0.298402 0.1 -2.8887 0.003868 0.030917 ENSMUSG00000041720 Pi4ka 1011.821 -0.301137 0.1 -3.0704 0.002137 0.020036 ENSMUSG00000035569 Ankrd11 1138.8 -0.30119 0.11 -2.8018 0.005082 0.038117 ENSMUSG00000027367 Stard7 615.9439 -0.308129 0.11 -2.9331 0.003356 0.027799 ENSMUSG00000032340 Neo1 772.8984 -0.308237 0.09 -3.4834 0.000495 0.00644 ENSMUSG00000042626 Shc1 1002.055 -0.309068 0.11 -2.6896 0.007153 0.048956 ENSMUSG00000028434 Epb41l4b 731.011 -0.309996 0.09 -3.3084 0.000938 0.010634 ENSMUSG00000041341 Atg2b 419.7702 -0.312614 0.1 -3.2831 0.001027 0.011344 ENSMUSG00000040390 Map3k10 247.558 -0.312969 0.12 -2.7134 0.00666 0.046385 ENSMUSG00000046329 Slc25a23 367.1135 -0.313877 0.11 -2.778 0.005469 0.040107 ENSMUSG00000059995 Atxn7l3 352.2659 -0.314229 0.12 -2.7118 0.006692 0.046495 ENSMUSG00000027288 Zfp106 1113.117 -0.316393 0.11 -2.8965 0.003774 0.030313 ENSMUSG00000024601 Isoc1 378.6617 -0.317554 0.12 -2.681 0.00734 0.04977 ENSMUSG00000053841 Txlna 810.7754 -0.318384 0.1 -3.0359 0.002398 0.021605 ENSMUSG00000042055 Wdr11 281.5566 -0.321145 0.12 -2.779 0.005452 0.040051 ENSMUSG00000057738 Sptan1 1576.598 -0.321743 0.1 -3.114 0.001846 0.018074 ENSMUSG00000031386 Hcfc1 706.3143 -0.326539 0.12 -2.7863 0.005332 0.039434 ENSMUSG00000002221 Paxip1 570.5758 -0.32674 0.12 -2.7054 0.006823 0.047185 ENSMUSG00000028826 Tmem57 563.9181 -0.328969 0.1 -3.2277 0.001248 0.013247 ENSMUSG00000022994 Adcy6 757.9243 -0.330567 0.1 -3.2208 0.001278 0.013521 ENSMUSG00000038280 Ostm1 214.9082 -0.332903 0.12 -2.6824 0.007309 0.049698 ENSMUSG00000017686 Rhot1 253.0845 -0.333004 0.11 -2.9005 0.003725 0.030005 ENSMUSG00000048578 Mlec 3006.478 -0.333158 0.08 -4.2835 1.84E-05 0.000468 ENSMUSG00000053519 Kcnip1 409.6329 -0.333689 0.1 -3.2113 0.001321 0.013859 ENSMUSG00000024769 Cdc42bpg 222.9927 -0.335268 0.12 -2.7 0.006934 0.047723 ENSMUSG00000044933 Sstr3 1193.412 -0.335911 0.08 -4.3894 1.14E-05 0.000324 ENSMUSG00000041879 Ipo9 509.6392 -0.336071 0.11 -2.9476 0.003202 0.026859 ENSMUSG00000106864 Gtf3c2 405.9256 -0.33707 0.12 -2.7187 0.006553 0.045729 Page 63 of 85 Diabetes

ENSMUSG00000020340 Cyfip2 2512.065 -0.337217 0.12 -2.7282 0.006368 0.04475 ENSMUSG00000041164 Zmiz2 563.5338 -0.338823 0.11 -2.9631 0.003046 0.025932 ENSMUSG00000037470 Uggt1 1994.759 -0.339489 0.08 -4.4557 8.36E-06 0.000256 ENSMUSG00000035469 Rcbtb1 535.7471 -0.339925 0.1 -3.3871 0.000706 0.008456 ENSMUSG00000026142 Rhbdd1 283.901 -0.340283 0.12 -2.7705 0.005597 0.04071 ENSMUSG00000021893 Capn7 404.1461 -0.342103 0.12 -2.7394 0.006155 0.043597 ENSMUSG00000010025 Aldh3a2 491.5887 -0.343911 0.12 -2.9458 0.003221 0.026972 ENSMUSG00000038533 Cbfa2t2 286.4472 -0.345943 0.12 -2.9925 0.002767 0.024198 ENSMUSG00000027168 Pax6 2037.498 -0.345983 0.11 -3.2645 0.001097 0.011973 ENSMUSG00000050812 AI314180 732.4017 -0.346324 0.09 -3.6795 0.000234 0.003604 ENSMUSG00000009741 Ubp1 474.6703 -0.34793 0.12 -2.909 0.003626 0.029417 ENSMUSG00000054199 Gon4l 490.3756 -0.348949 0.11 -3.2585 0.00112 0.012183 ENSMUSG00000002017 Fam98a 365.0411 -0.349022 0.12 -2.8528 0.004334 0.03371 ENSMUSG00000039523 Cep104 480.4344 -0.349459 0.12 -2.8715 0.004086 0.032302 ENSMUSG00000039671 Zmynd8 779.5499 -0.349605 0.11 -3.1979 0.001384 0.014351 ENSMUSG00000072704 Smim10l1 377.968 -0.3498 0.12 -2.8696 0.00411 0.032457 ENSMUSG00000031537 Ikbkb 256.1035 -0.352559 0.11 -3.1824 0.001461 0.014996 ENSMUSG00000042203 Tbc1d22b 497.1897 -0.35738 0.13 -2.7821 0.005402 0.039801 ENSMUSG00000040044 Orc3 258.7849 -0.35746 0.12 -3.0314 0.002434 0.021833 ENSMUSG00000040728 Esrp1 1003.504 -0.360039 0.11 -3.38 0.000725 0.008611 ENSMUSG00000035181 Heatr5a 189.162 -0.3605 0.13 -2.7063 0.006805 0.047105 ENSMUSG00000039068 Zzz3 556.6356 -0.362351 0.11 -3.2629 0.001103 0.012014 ENSMUSG00000042700 Sipa1l1 316.0685 -0.362895 0.13 -2.8572 0.004274 0.033397 ENSMUSG00000035299 Mid1 253.0677 -0.36391 0.13 -2.8095 0.004961 0.037406 ENSMUSG00000047412 Zbtb44 147.1536 -0.364546 0.14 -2.6881 0.007186 0.049044 ENSMUSG00000048307 Ankrd46 187.1903 -0.365883 0.13 -2.7859 0.005337 0.039443 ENSMUSG00000022098 Bmp1 483.8643 -0.366563 0.12 -3.1325 0.001733 0.017213 ENSMUSG00000038212 Hiatl1 182.4166 -0.367519 0.13 -2.7475 0.006005 0.042865 ENSMUSG00000042066 Tmcc2 222.8774 -0.367831 0.13 -2.7673 0.005652 0.040995 ENSMUSG00000005533 Igf1r 406.182 -0.368314 0.12 -3.0567 0.002238 0.020638 ENSMUSG00000062729 Ppox 198.48 -0.368513 0.13 -2.8511 0.004357 0.033846 ENSMUSG00000039233 Tbce 264.0376 -0.370042 0.13 -2.7858 0.005339 0.039443 ENSMUSG00000015944 Gatsl2 1623.069 -0.370357 0.1 -3.6072 0.000309 0.004431 ENSMUSG00000031012 Cask 290.4318 -0.37253 0.14 -2.6815 0.00733 0.049752 ENSMUSG00000007880 Arid1a 881.0163 -0.373284 0.12 -3.2293 0.001241 0.013206 ENSMUSG00000017421 Zfp207 581.7739 -0.376856 0.14 -2.7462 0.006028 0.042946 ENSMUSG00000021910 Nisch 2943.571 -0.377866 0.1 -3.7244 0.000196 0.003173 ENSMUSG00000036989 Trim3 250.7581 -0.378645 0.13 -2.8054 0.005026 0.037777 ENSMUSG00000021870 Slmap 272.0932 -0.380019 0.13 -3.0317 0.002432 0.021824 ENSMUSG00000041729 Coro2b 683.9341 -0.380073 0.13 -2.9973 0.002724 0.023916 ENSMUSG00000040035 Disp2 2950.131 -0.380818 0.1 -3.6862 0.000228 0.003525 ENSMUSG00000035311 Gnptab 145.2913 -0.381324 0.13 -2.8527 0.004335 0.03371 Diabetes Page 64 of 85

ENSMUSG00000030279 C2cd5 266.4839 -0.383821 0.13 -2.8924 0.003823 0.030603 ENSMUSG00000028127 Abcd3 955.0486 -0.384208 0.12 -3.2884 0.001008 0.011202 ENSMUSG00000019790 Stxbp5 351.623 -0.385396 0.13 -2.8883 0.003873 0.030924 ENSMUSG00000040738 Ints8 158.5069 -0.385442 0.14 -2.6807 0.007348 0.0498 ENSMUSG00000024350 Dnajc18 196.7727 -0.385896 0.12 -3.3533 0.000799 0.009288 ENSMUSG00000023951 Vegfa 2222.477 -0.386061 0.11 -3.4302 0.000603 0.007455 ENSMUSG00000018160 Med1 243.0202 -0.386229 0.13 -2.8665 0.004151 0.032677 ENSMUSG00000024165 Hn1l 579.9928 -0.388318 0.12 -3.1244 0.001782 0.017589 ENSMUSG00000003031 Cdkn1b 291.5198 -0.388569 0.14 -2.8152 0.004875 0.036924 ENSMUSG00000073139 BC023829 275.492 -0.389118 0.14 -2.7048 0.006834 0.047234 ENSMUSG00000034853 Acot11 267.0378 -0.390036 0.13 -2.9207 0.003492 0.0286 ENSMUSG00000068923 Syt11 306.18 -0.390142 0.14 -2.7977 0.005146 0.038404 ENSMUSG00000028245 Nsmaf 401.4752 -0.392361 0.09 -4.2014 2.65E-05 0.000625 ENSMUSG00000031256 Cstf2 163.336 -0.392546 0.14 -2.7445 0.00606 0.04308 ENSMUSG00000028015 Ctso 351.8763 -0.39264 0.12 -3.3991 0.000676 0.008149 ENSMUSG00000002748 Baz1b 969.1067 -0.393715 0.11 -3.5344 0.000409 0.005522 ENSMUSG00000027200 Sema6d 250.0913 -0.394336 0.14 -2.7672 0.005653 0.040995 ENSMUSG00000006010 BC003331 304.2583 -0.395009 0.12 -3.3789 0.000728 0.008622 ENSMUSG00000032777 Gtf3c1 611.6285 -0.395047 0.09 -4.5603 5.11E-06 0.000173 ENSMUSG00000025203 Scd2 2377.625 -0.395645 0.13 -3.0472 0.00231 0.02105 ENSMUSG00000020326 Ccng1 512.3944 -0.396091 0.14 -2.7966 0.005164 0.038467 ENSMUSG00000024743 Syt7 2226.287 -0.396573 0.1 -4.0876 4.36E-05 0.000934 ENSMUSG00000026991 Pkp4 892.2482 -0.397773 0.13 -3.0832 0.002048 0.019473 ENSMUSG00000034940 Synrg 706.6502 -0.398414 0.11 -3.7019 0.000214 0.003385 ENSMUSG00000001229 Dpp9 698.7215 -0.398905 0.14 -2.7853 0.005348 0.039489 ENSMUSG00000032898 Fbxo21 721.8863 -0.399276 0.13 -3.1041 0.001909 0.018477 ENSMUSG00000036606 Plxnb2 2361.026 -0.399357 0.12 -3.2444 0.001177 0.012698 ENSMUSG00000033295 Ptprf 2605.954 -0.399932 0.11 -3.5886 0.000332 0.004714 ENSMUSG00000001211 Agpat3 659.4698 -0.401896 0.14 -2.926 0.003434 0.028231 ENSMUSG00000043411 Usp48 802.2751 -0.401992 0.1 -3.9534 7.71E-05 0.001494 ENSMUSG00000039428 Tmem135 245.4358 -0.402258 0.13 -3.0445 0.002331 0.021181 ENSMUSG00000025575 Cant1 421.6011 -0.402719 0.11 -3.6516 0.000261 0.003952 ENSMUSG00000021711 Trappc13 218.6563 -0.402894 0.15 -2.7296 0.00634 0.0446 ENSMUSG00000015189 Casd1 126.1822 -0.403096 0.14 -2.8727 0.00407 0.032217 ENSMUSG00000033623 Pcgf3 222.8437 -0.403519 0.14 -2.8235 0.00475 0.036253 ENSMUSG00000021115 Vrk1 241.3765 -0.403937 0.13 -3.2019 0.001365 0.014228 ENSMUSG00000025223 Ldb1 543.1928 -0.404421 0.15 -2.765 0.005693 0.041139 ENSMUSG00000032356 Rasgrf1 1484.454 -0.404514 0.09 -4.5187 6.22E-06 0.000203 ENSMUSG00000057406 Whsc1 404.581 -0.405193 0.13 -3.0386 0.002377 0.021486 ENSMUSG00000033075 Senp1 198.8807 -0.405452 0.13 -3.1271 0.001766 0.017463 ENSMUSG00000044348 Slc25a53 104.6828 -0.406069 0.15 -2.7661 0.005673 0.041035 ENSMUSG00000074698 Csnk2a1 616.6725 -0.406767 0.1 -4.2519 2.12E-05 0.000525 Page 65 of 85 Diabetes

ENSMUSG00000037896 Rcor1 240.3833 -0.406971 0.15 -2.7062 0.006805 0.047105 ENSMUSG00000026516 Nvl 226.3498 -0.407467 0.12 -3.3519 0.000803 0.009327 ENSMUSG00000032418 Me1 269.8042 -0.407572 0.14 -2.9728 0.002951 0.025345 ENSMUSG00000025224 Gbf1 1140.505 -0.407641 0.08 -4.8171 1.46E-06 6.45E-05 ENSMUSG00000020175 Rab36 195.3869 -0.407997 0.15 -2.809 0.00497 0.037437 ENSMUSG00000034269 Setd5 988.9979 -0.408181 0.14 -2.9191 0.00351 0.028701 ENSMUSG00000020074 Ccar1 451.3595 -0.4083 0.13 -3.105 0.001903 0.018469 ENSMUSG00000052105 Mtcl1 398.6009 -0.40856 0.15 -2.7965 0.005165 0.038467 ENSMUSG00000030873 Scnn1b 1417.76 -0.408601 0.14 -3.0055 0.002652 0.023396 ENSMUSG00000041997 Tlk1 678.3047 -0.409494 0.11 -3.721 0.000198 0.003202 ENSMUSG00000040029 Ipo8 230.0537 -0.409768 0.13 -3.1735 0.001506 0.015439 ENSMUSG00000057672 Pkn1 380.3662 -0.40984 0.14 -3.0348 0.002407 0.021653 ENSMUSG00000028468 Rgp1 419.1817 -0.409981 0.11 -3.6139 0.000302 0.004353 ENSMUSG00000033253 Szt2 310.7382 -0.410566 0.13 -3.0442 0.002333 0.021181 ENSMUSG00000034471 Caskin2 160.9555 -0.411237 0.14 -2.9383 0.0033 0.027417 ENSMUSG00000020576 Nbas 1044.39 -0.412369 0.11 -3.8855 0.000102 0.001866 ENSMUSG00000031441 Atp11a 627.4117 -0.412702 0.15 -2.6866 0.007219 0.049199 ENSMUSG00000024947 Men1 157.1194 -0.41387 0.14 -2.9072 0.003646 0.029516 ENSMUSG00000022521 Crebbp 315.2421 -0.414298 0.14 -2.9573 0.003103 0.026238 ENSMUSG00000054874 Pcnxl3 464.1602 -0.416827 0.14 -2.9368 0.003316 0.027512 ENSMUSG00000038116 Phf20 240.1699 -0.416861 0.15 -2.7795 0.005445 0.04003 ENSMUSG00000034557 Zfyve9 198.7352 -0.417039 0.13 -3.1703 0.001523 0.015525 ENSMUSG00000050947 Amigo1 448.6748 -0.417151 0.12 -3.6137 0.000302 0.004353 ENSMUSG00000040928 S100pbp 210.7883 -0.417295 0.14 -2.8932 0.003814 0.03055 ENSMUSG00000028580 Pum1 219.9208 -0.418128 0.13 -3.1185 0.001817 0.017837 ENSMUSG00000031617 Tmem184c 197.261 -0.418145 0.14 -2.9452 0.003227 0.027007 ENSMUSG00000032589 Bsn 264.3847 -0.41875 0.13 -3.132 0.001736 0.01723 ENSMUSG00000028382 Ptbp3 992.3885 -0.419472 0.16 -2.6837 0.007282 0.049581 ENSMUSG00000044148 1810030O07Rik206.6207 -0.41987 0.14 -2.9238 0.003457 0.02838 ENSMUSG00000031242 2610002M06Rik173.5769 -0.420574 0.15 -2.8835 0.003933 0.031354 ENSMUSG00000031983 2310022B05Rik600.9531 -0.420668 0.12 -3.3741 0.000741 0.008753 ENSMUSG00000018442 Derl2 483.6085 -0.420898 0.13 -3.2102 0.001327 0.013892 ENSMUSG00000030091 Nup210 550.4551 -0.421517 0.11 -3.9277 8.57E-05 0.001624 ENSMUSG00000025743 Sdc3 518.5838 -0.422384 0.11 -3.9939 6.50E-05 0.001302 ENSMUSG00000026442 Nfasc 1029.377 -0.422575 0.13 -3.3584 0.000784 0.009173 ENSMUSG00000062203 Gspt1 816.7091 -0.422575 0.14 -3.0498 0.00229 0.020948 ENSMUSG00000063450 Syne2 454.0527 -0.422595 0.15 -2.8693 0.004114 0.032476 ENSMUSG00000078622 Ccdc47 654.7976 -0.42282 0.09 -4.6321 3.62E-06 0.000131 ENSMUSG00000010277 2610507B11Rik1314.32 -0.423752 0.12 -3.4086 0.000653 0.007953 ENSMUSG00000078684 5830417I10Rik307.8814 -0.424603 0.12 -3.6137 0.000302 0.004353 ENSMUSG00000027312 Atrn 354.5079 -0.424884 0.12 -3.4472 0.000566 0.007137 ENSMUSG00000028439 Fam219a 609.2895 -0.425013 0.11 -3.7319 0.00019 0.003115 Diabetes Page 66 of 85

ENSMUSG00000040818 Dennd6a 159.2485 -0.425432 0.14 -2.9506 0.003171 0.026668 ENSMUSG00000027901 Dennd2d 291.4882 -0.427386 0.14 -2.9604 0.003073 0.026102 ENSMUSG00000038774 Ascc3 824.2494 -0.428439 0.12 -3.4963 0.000472 0.006213 ENSMUSG00000029635 Cdk8 605.6373 -0.428556 0.12 -3.5089 0.00045 0.005957 ENSMUSG00000041977 Arhgef11 610.4347 -0.429526 0.15 -2.9318 0.00337 0.027849 ENSMUSG00000024045 Akap8 343.4999 -0.430119 0.12 -3.7159 0.000202 0.003238 ENSMUSG00000028991 Mtor 375.7451 -0.430281 0.1 -4.2715 1.94E-05 0.00049 ENSMUSG00000016933 Plcg1 378.2848 -0.431081 0.13 -3.299 0.00097 0.010964 ENSMUSG00000028803 Nipal3 994.2317 -0.431691 0.13 -3.4366 0.000589 0.007349 ENSMUSG00000013878 Rnf170 103.0647 -0.433287 0.15 -2.875 0.00404 0.032054 ENSMUSG00000036712 Cyld 480.9195 -0.433537 0.14 -3.1136 0.001848 0.018085 ENSMUSG00000062373 Tmem65 992.4392 -0.434102 0.14 -3.0482 0.002302 0.021041 ENSMUSG00000039988 Ankrd13c 249.7186 -0.434384 0.16 -2.7772 0.005483 0.040178 ENSMUSG00000048271 Rbm33 502.2561 -0.435972 0.16 -2.699 0.006956 0.04783 ENSMUSG00000028444 Cntfr 309.1942 -0.436168 0.16 -2.7574 0.005826 0.041913 ENSMUSG00000020312 Shc2 254.2951 -0.436597 0.14 -3.0396 0.002369 0.021431 ENSMUSG00000028484 Psip1 430.1044 -0.436814 0.14 -3.1186 0.001817 0.017837 ENSMUSG00000023017 Asic1 252.4618 -0.437082 0.12 -3.5158 0.000438 0.005843 ENSMUSG00000023473 Celsr3 447.0451 -0.438839 0.14 -3.1025 0.001919 0.018541 ENSMUSG00000061607 Mdc1 266.2553 -0.438913 0.15 -2.9113 0.0036 0.02925 ENSMUSG00000066640 Fbxl18 134.8031 -0.439105 0.15 -2.9261 0.003432 0.028231 ENSMUSG00000046613 Vwa5b2 875.336 -0.440182 0.13 -3.3544 0.000795 0.00928 ENSMUSG00000020783 1200014J11Rik207.5533 -0.441144 0.12 -3.6877 0.000226 0.003516 ENSMUSG00000042508 Dmtf1 210.0375 -0.441158 0.16 -2.6893 0.00716 0.048982 ENSMUSG00000026944 Abca2 626.3399 -0.44121 0.12 -3.7821 0.000156 0.002628 ENSMUSG00000038178 Slc43a2 1459.848 -0.444339 0.12 -3.7879 0.000152 0.002592 ENSMUSG00000031134 Rbmx 230.733 -0.444784 0.15 -2.9532 0.003145 0.026518 ENSMUSG00000027544 Nfatc2 324.2776 -0.44519 0.16 -2.8105 0.004947 0.037354 ENSMUSG00000031583 Wrn 91.48929 -0.44531 0.16 -2.7219 0.006491 0.045383 ENSMUSG00000020964 Sel1l 1659.221 -0.445716 0.12 -3.5696 0.000357 0.004981 ENSMUSG00000020387 Jade2 363.6039 -0.44574 0.15 -2.9634 0.003043 0.025932 ENSMUSG00000042446 Zmym4 335.4876 -0.446039 0.14 -3.2912 0.000997 0.011165 ENSMUSG00000036561 Ppp6r2 201.7359 -0.446195 0.14 -3.1081 0.001883 0.018352 ENSMUSG00000000600 Krit1 304.7796 -0.44621 0.15 -2.9423 0.003258 0.027173 ENSMUSG00000018196 Glrx2 134.9117 -0.446489 0.16 -2.8097 0.004959 0.037405 ENSMUSG00000029263 Pigg 104.3312 -0.448056 0.16 -2.7198 0.006532 0.045621 ENSMUSG00000089715 Cbx6 1005.149 -0.4483 0.11 -4.2033 2.63E-05 0.000622 ENSMUSG00000032580 Rbm5 635.9488 -0.448959 0.16 -2.7332 0.006271 0.044247 ENSMUSG00000030406 Gipr 350.0496 -0.449023 0.17 -2.6868 0.007214 0.049191 ENSMUSG00000042410 Agps 165.7034 -0.449486 0.13 -3.516 0.000438 0.005843 ENSMUSG00000057530 Ece1 3900.435 -0.450663 0.16 -2.8859 0.003903 0.03113 ENSMUSG00000048833 Slc39a9 696.093 -0.451322 0.1 -4.6053 4.12E-06 0.000145 Page 67 of 85 Diabetes

ENSMUSG00000041895 Wipi1 266.2587 -0.452747 0.15 -3.0959 0.001962 0.018872 ENSMUSG00000040850 Psme4 980.1476 -0.452997 0.14 -3.1381 0.0017 0.01699 ENSMUSG00000020522 Mfap3 182.3569 -0.454851 0.15 -2.9895 0.002795 0.024378 ENSMUSG00000028030 Tbck 112.8296 -0.455289 0.15 -2.9914 0.002777 0.024249 ENSMUSG00000043323 Fbrsl1 343.0046 -0.455393 0.15 -2.9988 0.00271 0.023812 ENSMUSG00000046798 Cldn12 225.451 -0.455493 0.15 -3.1013 0.001927 0.018605 ENSMUSG00000028637 Ccdc30 67.41513 -0.455842 0.17 -2.7089 0.006751 0.046842 ENSMUSG00000063870 Chd4 1666.236 -0.457307 0.11 -4.0435 5.27E-05 0.001092 ENSMUSG00000061536 Sec22c 197.891 -0.457709 0.14 -3.2579 0.001122 0.012186 ENSMUSG00000036550 Cnot1 976.5203 -0.457836 0.16 -2.7901 0.005269 0.039084 ENSMUSG00000027184 Caprin1 1076.762 -0.458117 0.1 -4.694 2.68E-06 0.000104 ENSMUSG00000027201 Myef2 356.8572 -0.458682 0.13 -3.5734 0.000352 0.004922 ENSMUSG00000055670 Zzef1 644.0046 -0.460286 0.12 -3.9236 8.73E-05 0.001644 ENSMUSG00000024044 Epb41l3 1184.739 -0.460852 0.12 -3.9716 7.14E-05 0.001408 ENSMUSG00000034126 Pomt2 406.7196 -0.461572 0.15 -3.0708 0.002135 0.020036 ENSMUSG00000009575 Cbx5 418.8294 -0.461732 0.13 -3.624 0.00029 0.004266 ENSMUSG00000042642 Flad1 156.6198 -0.46236 0.15 -3.0369 0.00239 0.021569 ENSMUSG00000006675 P4htm 182.7224 -0.463091 0.14 -3.1949 0.001399 0.01447 ENSMUSG00000032086 Bace1 430.1707 -0.464176 0.11 -4.2022 2.64E-05 0.000624 ENSMUSG00000039478 Micu3 140.075 -0.464504 0.16 -2.9524 0.003154 0.026571 ENSMUSG00000026490 Cdc42bpa 578.9221 -0.464639 0.13 -3.476 0.000509 0.006609 ENSMUSG00000063160 Numbl 156.4879 -0.465367 0.15 -3.0063 0.002644 0.023358 ENSMUSG00000028357 Kif12 1598.825 -0.465413 0.12 -3.8033 0.000143 0.002462 ENSMUSG00000026181 Ppm1f 105.9974 -0.465856 0.16 -2.9086 0.00363 0.029419 ENSMUSG00000027947 Il6ra 616.0044 -0.466592 0.15 -3.1833 0.001456 0.014964 ENSMUSG00000029475 Kdm2b 327.6427 -0.466673 0.17 -2.7961 0.005172 0.038499 ENSMUSG00000036572 Upf3b 296.5365 -0.466778 0.13 -3.6982 0.000217 0.003417 ENSMUSG00000031834 Pik3r2 224.701 -0.466795 0.17 -2.7 0.006934 0.047723 ENSMUSG00000040351 Ankib1 218.0713 -0.467099 0.14 -3.362 0.000774 0.009078 ENSMUSG00000006281 Tep1 185.2911 -0.467307 0.15 -3.0795 0.002073 0.019605 ENSMUSG00000003623 Crot 158.8044 -0.468039 0.15 -3.1711 0.001519 0.015502 ENSMUSG00000036555 Iqce 209.8591 -0.468083 0.17 -2.6905 0.007135 0.048856 ENSMUSG00000028467 Gba2 171.0252 -0.468203 0.17 -2.8063 0.005012 0.037708 ENSMUSG00000013663 Pten 467.8069 -0.468312 0.15 -3.1365 0.00171 0.017062 ENSMUSG00000024160 Spsb3 135.3931 -0.468566 0.17 -2.6975 0.006986 0.048014 ENSMUSG00000035798 Zdhhc17 187.1804 -0.469874 0.16 -3.0201 0.002527 0.022535 ENSMUSG00000034349 Smc4 112.5616 -0.470309 0.17 -2.76 0.005781 0.041651 ENSMUSG00000056673 Kdm5d 230.2985 -0.47064 0.14 -3.4182 0.00063 0.007715 ENSMUSG00000033257 Ttll4 195.6636 -0.470796 0.15 -3.1265 0.001769 0.017483 ENSMUSG00000023977 Ubr2 879.015 -0.471666 0.11 -4.2967 1.73E-05 0.000448 ENSMUSG00000034462 Pkd2 339.0798 -0.471749 0.17 -2.7303 0.006328 0.04456 ENSMUSG00000003575 Crtc1 378.0656 -0.471825 0.11 -4.1668 3.09E-05 0.000711 Diabetes Page 68 of 85

ENSMUSG00000032737 Inppl1 432.1289 -0.47187 0.15 -3.1032 0.001914 0.018509 ENSMUSG00000058318 Phf21a 300.105 -0.472133 0.14 -3.2978 0.000975 0.011002 ENSMUSG00000004565 Pnpla6 145.0263 -0.472797 0.17 -2.757 0.005833 0.041941 ENSMUSG00000022526 Zfp251 140.775 -0.473298 0.16 -2.9328 0.003359 0.027809 ENSMUSG00000031822 Gse1 1080.517 -0.47454 0.15 -3.2346 0.001218 0.013012 ENSMUSG00000021519 Mterf3 163.9862 -0.474891 0.16 -2.9886 0.002802 0.024406 ENSMUSG00000022472 Desi1 934.5134 -0.475391 0.15 -3.166 0.001546 0.015713 ENSMUSG00000036568 Gltscr1l 199.7878 -0.476172 0.17 -2.7461 0.006032 0.042949 ENSMUSG00000040407 Akap9 808.3385 -0.476282 0.15 -3.2444 0.001177 0.012698 ENSMUSG00000070733 Fryl 645.0577 -0.476311 0.16 -2.9399 0.003284 0.027305 ENSMUSG00000004455 Ppp1cc 393.4864 -0.476316 0.11 -4.2646 2.00E-05 0.000504 ENSMUSG00000028528 Dnajc6 231.9126 -0.476569 0.17 -2.7876 0.00531 0.039323 ENSMUSG00000055531 Cpsf6 231.1792 -0.478101 0.15 -3.099 0.001942 0.018726 ENSMUSG00000021782 Dlg5 358.9775 -0.479028 0.14 -3.4497 0.000561 0.007092 ENSMUSG00000036333 Kidins220 1431.064 -0.480306 0.15 -3.194 0.001403 0.0145 ENSMUSG00000037400 Atp11b 406.146 -0.480539 0.15 -3.156 0.0016 0.016205 ENSMUSG00000005506 Celf1 743.1267 -0.480663 0.11 -4.4038 1.06E-05 0.000309 ENSMUSG00000038827 Fam206a 152.3406 -0.480665 0.15 -3.2713 0.001071 0.011714 ENSMUSG00000025199 Chuk 416.6684 -0.4808 0.11 -4.1905 2.78E-05 0.000648 ENSMUSG00000032875 Arhgef17 900.4853 -0.48127 0.12 -4.1402 3.47E-05 0.000783 ENSMUSG00000025369 Smarcc2 1246.627 -0.481509 0.1 -4.9099 9.11E-07 4.45E-05 ENSMUSG00000022668 Gtpbp8 90.59456 -0.481577 0.17 -2.7832 0.005383 0.039701 ENSMUSG00000054263 Lifr 420.2463 -0.482062 0.16 -2.9306 0.003383 0.027919 ENSMUSG00000020594 Pum2 703.4303 -0.482629 0.13 -3.6151 0.0003 0.004353 ENSMUSG00000024187 Fam234a 862.7107 -0.482959 0.17 -2.7899 0.005272 0.039084 ENSMUSG00000038822 Hace1 104.9591 -0.483063 0.14 -3.3385 0.000842 0.009703 ENSMUSG00000038014 Fam120a 1084.259 -0.483153 0.1 -4.8978 9.69E-07 4.68E-05 ENSMUSG00000044950 Pwwp2a 77.53484 -0.483665 0.17 -2.7724 0.005565 0.040604 ENSMUSG00000004815 Dgkq 122.254 -0.484975 0.17 -2.8642 0.00418 0.032823 ENSMUSG00000041258 Zfp236 223.4497 -0.485148 0.16 -3.0429 0.002343 0.021237 ENSMUSG00000041459 Tardbp 638.8837 -0.485452 0.13 -3.7847 0.000154 0.002612 ENSMUSG00000026743 Mllt10 239.9395 -0.485515 0.13 -3.8557 0.000115 0.002065 ENSMUSG00000027309 4930402H24Rik536.2239 -0.485665 0.15 -3.2413 0.00119 0.012798 ENSMUSG00000045482 Trrap 727.6303 -0.485681 0.13 -3.6372 0.000276 0.004132 ENSMUSG00000037286 Stag1 268.3689 -0.486654 0.13 -3.6078 0.000309 0.004425 ENSMUSG00000040009 Gnaz 534.359 -0.487517 0.15 -3.2629 0.001103 0.012014 ENSMUSG00000004221 Ikbkg 209.8026 -0.487868 0.14 -3.3922 0.000693 0.008334 ENSMUSG00000018379 Srsf1 309.5071 -0.489117 0.12 -3.9342 8.35E-05 0.001589 ENSMUSG00000029165 Agbl5 143.7336 -0.489138 0.17 -2.9545 0.003131 0.026431 ENSMUSG00000027220 Syt13 4544.068 -0.489908 0.16 -2.9748 0.002932 0.025228 ENSMUSG00000024006 Stk38 254.5455 -0.491495 0.17 -2.9235 0.003461 0.028381 ENSMUSG00000000823 Znf512b 492.8019 -0.491782 0.14 -3.4022 0.000668 0.008096 Page 69 of 85 Diabetes

ENSMUSG00000003992 Ssbp2 122.7683 -0.492426 0.17 -2.8435 0.004462 0.034495 ENSMUSG00000047909 Ankrd16 167.9652 -0.492441 0.14 -3.5862 0.000336 0.004749 ENSMUSG00000030411 Nova2 82.7772 -0.492647 0.16 -3.0481 0.002303 0.021041 ENSMUSG00000042249 Adrbk2 1183.784 -0.49283 0.15 -3.3883 0.000703 0.008434 ENSMUSG00000044447 Dock5 116.8842 -0.493408 0.18 -2.7642 0.005706 0.041213 ENSMUSG00000027665 Pik3ca 265.8795 -0.493431 0.15 -3.363 0.000771 0.009055 ENSMUSG00000068615 Gjd2 1079.67 -0.49381 0.16 -3.1669 0.001541 0.015672 ENSMUSG00000014763 Fam120b 321.637 -0.495384 0.15 -3.2394 0.001198 0.012838 ENSMUSG00000038855 Itpkb 1457.554 -0.496442 0.17 -2.9051 0.003671 0.029641 ENSMUSG00000055745 Ldoc1l 225.7017 -0.496476 0.15 -3.2768 0.00105 0.011531 ENSMUSG00000059890 Ube4a 353.9489 -0.496613 0.14 -3.5525 0.000382 0.005223 ENSMUSG00000056211 R3hdm1 356.7662 -0.497915 0.12 -4.0383 5.38E-05 0.00111 ENSMUSG00000034673 Pbx2 295.0401 -0.497947 0.13 -3.8046 0.000142 0.002452 ENSMUSG00000027822 Slc33a1 526.8172 -0.497955 0.16 -3.2007 0.001371 0.014267 ENSMUSG00000025586 Cpeb1 632.5278 -0.497997 0.11 -4.4265 9.58E-06 0.000283 ENSMUSG00000052299 Ltn1 268.1497 -0.498126 0.17 -2.915 0.003557 0.029049 ENSMUSG00000039485 Tspyl4 863.6217 -0.498173 0.15 -3.3923 0.000693 0.008334 ENSMUSG00000022656 Pvrl3 401.0907 -0.498197 0.11 -4.6127 3.98E-06 0.000141 ENSMUSG00000038766 Gabpb2 385.5663 -0.499064 0.12 -4.1651 3.11E-05 0.000714 ENSMUSG00000028414 Fktn 200.1046 -0.500024 0.17 -3.0134 0.002583 0.022901 ENSMUSG00000032570 Atp2c1 615.6714 -0.500067 0.15 -3.3553 0.000793 0.009263 ENSMUSG00000035629 1700021K19Rik299.4932 -0.500245 0.14 -3.6669 0.000246 0.003755 ENSMUSG00000000317 Bcl6b 168.9649 -0.500708 0.16 -3.1116 0.001861 0.018184 ENSMUSG00000022718 Dgcr8 99.19391 -0.501084 0.18 -2.7984 0.005135 0.038343 ENSMUSG00000056763 Cspp1 296.7409 -0.50157 0.13 -3.8118 0.000138 0.002399 ENSMUSG00000038141 Tmem181a 422.3705 -0.501887 0.15 -3.3208 0.000898 0.010261 ENSMUSG00000029291 Rufy3 586.1625 -0.502395 0.1 -5.1267 2.95E-07 1.76E-05 ENSMUSG00000021275 Tecpr2 190.164 -0.502653 0.15 -3.3418 0.000832 0.009619 ENSMUSG00000038172 Ttc39b 685.5988 -0.50321 0.16 -3.1865 0.00144 0.014823 ENSMUSG00000038058 Nod1 226.5596 -0.503404 0.15 -3.4598 0.000541 0.006915 ENSMUSG00000028552 Eps15 133.7993 -0.503794 0.16 -3.1953 0.001397 0.014462 ENSMUSG00000019066 Rab3d 1556.811 -0.503915 0.11 -4.6869 2.77E-06 0.000107 ENSMUSG00000005640 Insrr 2353.307 -0.504435 0.18 -2.8772 0.004013 0.031915 ENSMUSG00000020647 Ncoa1 551.4691 -0.504931 0.17 -2.995 0.002745 0.024054 ENSMUSG00000035024 Ncapd3 124.4364 -0.505079 0.18 -2.8257 0.004717 0.036051 ENSMUSG00000052137 Rbm12b2 77.91445 -0.505131 0.18 -2.8046 0.005038 0.037824 ENSMUSG00000022389 Tef 651.5182 -0.505753 0.17 -2.9591 0.003086 0.026138 ENSMUSG00000053693 Mast1 128.5125 -0.505863 0.16 -3.2175 0.001293 0.013657 ENSMUSG00000039414 Heatr5b 179.7467 -0.506035 0.14 -3.5678 0.00036 0.004992 ENSMUSG00000059851 Suv420h2 178.7715 -0.507138 0.18 -2.7417 0.006112 0.043393 ENSMUSG00000059981 Taok2 1240.802 -0.507924 0.11 -4.653 3.27E-06 0.000122 ENSMUSG00000032890 Rims3 946.6615 -0.508284 0.14 -3.6473 0.000265 0.004003 Diabetes Page 70 of 85

ENSMUSG00000066760 Psg16 159.485 -0.508333 0.15 -3.3216 0.000895 0.010243 ENSMUSG00000052917 Senp7 115.3355 -0.508855 0.15 -3.4463 0.000568 0.007152 ENSMUSG00000051786 Tubgcp6 147.5596 -0.509388 0.14 -3.6687 0.000244 0.003731 ENSMUSG00000022957 Itsn1 110.4651 -0.509568 0.17 -3.0434 0.002339 0.021214 ENSMUSG00000028555 Ttc39a 433.44 -0.510151 0.18 -2.8056 0.005022 0.037764 ENSMUSG00000034501 Pcnxl4 83.71565 -0.510753 0.16 -3.1506 0.001629 0.016448 ENSMUSG00000047409 Ctdspl 590.187 -0.510791 0.14 -3.6611 0.000251 0.003837 ENSMUSG00000047045 Tmem164 293.8419 -0.511563 0.18 -2.854 0.004317 0.033638 ENSMUSG00000021327 Zkscan3 274.3779 -0.511699 0.13 -3.9031 9.50E-05 0.001762 ENSMUSG00000032826 Ank2 696.0242 -0.511991 0.12 -4.2198 2.44E-05 0.000587 ENSMUSG00000055737 Ghr 824.1519 -0.512885 0.16 -3.2141 0.001308 0.013771 ENSMUSG00000044468 Fam46c 388.8531 -0.513089 0.14 -3.7011 0.000215 0.003391 ENSMUSG00000064367 ND5 11722.35 -0.513496 0.17 -2.942 0.003261 0.02718 ENSMUSG00000052915 Msl1 444.4005 -0.513941 0.12 -4.2865 1.82E-05 0.000462 ENSMUSG00000021027 Ralgapa1 409.8931 -0.514389 0.18 -2.8265 0.004706 0.036003 ENSMUSG00000047454 Gphn 221.8402 -0.514405 0.18 -2.926 0.003433 0.028231 ENSMUSG00000031902 Nfatc3 227.2569 -0.514837 0.13 -3.8173 0.000135 0.002354 ENSMUSG00000031600 Vps37a 796.7811 -0.514913 0.11 -4.7832 1.72E-06 7.35E-05 ENSMUSG00000011751 Sptbn4 644.64 -0.515829 0.14 -3.622 0.000292 0.004278 ENSMUSG00000037300 Ttc13 141.1148 -0.51595 0.16 -3.285 0.00102 0.011288 ENSMUSG00000005374 Tbl2 397.5634 -0.516678 0.14 -3.7789 0.000158 0.002656 ENSMUSG00000032135 Mcam 163.5963 -0.516869 0.19 -2.7266 0.006398 0.044884 ENSMUSG00000068036 Mllt4 560.0628 -0.516875 0.13 -3.9758 7.02E-05 0.001388 ENSMUSG00000025867 Cplx2 2706.791 -0.518938 0.15 -3.5327 0.000411 0.005547 ENSMUSG00000015968 Cacna1d 838.5364 -0.519183 0.19 -2.7127 0.006673 0.046399 ENSMUSG00000038506 Dcun1d2 121.093 -0.519456 0.18 -2.8256 0.004719 0.036051 ENSMUSG00000031924 Cyb5b 1579.024 -0.519827 0.16 -3.2125 0.001316 0.01383 ENSMUSG00000038534 Osbpl7 102.006 -0.520803 0.16 -3.173 0.001509 0.015446 ENSMUSG00000031840 Rab3a 317.461 -0.520805 0.15 -3.4182 0.00063 0.007715 ENSMUSG00000020463 Smek2 311.2385 -0.52085 0.19 -2.7489 0.00598 0.042748 ENSMUSG00000020422 Tns3 714.9311 -0.521313 0.13 -4.0182 5.86E-05 0.001197 ENSMUSG00000021669 Col4a3bp 392.2165 -0.522091 0.17 -3.0847 0.002038 0.019419 ENSMUSG00000028760 Eif4g3 1063.995 -0.522521 0.13 -3.9853 6.74E-05 0.001344 ENSMUSG00000014498 Ankrd52 370.1866 -0.522646 0.15 -3.5565 0.000376 0.005149 ENSMUSG00000060510 Zfp266 235.321 -0.523214 0.17 -3.1071 0.001889 0.018381 ENSMUSG00000038291 Snx25 185.1361 -0.523497 0.15 -3.3886 0.000703 0.008433 ENSMUSG00000037851 Iars 782.5296 -0.524475 0.19 -2.8214 0.004781 0.036409 ENSMUSG00000034377 Tulp4 1100.593 -0.524563 0.19 -2.8346 0.004588 0.035284 ENSMUSG00000048000 Gigyf2 355.041 -0.524832 0.12 -4.2393 2.24E-05 0.000544 ENSMUSG00000038369 Ncoa6 549.5537 -0.524865 0.15 -3.5242 0.000425 0.005702 ENSMUSG00000028060 2810403A07Rik401.3748 -0.5249 0.14 -3.8868 0.000102 0.001858 ENSMUSG00000035891 Cerk 625.5336 -0.525978 0.12 -4.3053 1.67E-05 0.000435 Page 71 of 85 Diabetes

ENSMUSG00000020917 Acly 10150.71 -0.526575 0.09 -6.1217 9.26E-10 1.28E-07 ENSMUSG00000036292 Gramd1c 101.5673 -0.5275 0.17 -3.0605 0.002209 0.020481 ENSMUSG00000039262 Prrc2b 2656.568 -0.52835 0.11 -4.758 1.96E-06 8.11E-05 ENSMUSG00000053477 Tcf4 278.1397 -0.529237 0.15 -3.435 0.000592 0.007365 ENSMUSG00000066643 Wdr35 243.5779 -0.529411 0.14 -3.9058 9.39E-05 0.001747 ENSMUSG00000058979 Cecr5 219.956 -0.531011 0.14 -3.8292 0.000129 0.002262 ENSMUSG00000031748 Gnao1 1733.852 -0.533263 0.14 -3.8353 0.000125 0.002215 ENSMUSG00000030016 Zfp638 431.378 -0.535002 0.11 -4.8165 1.46E-06 6.45E-05 ENSMUSG00000022822 Abcc5 440.3257 -0.535549 0.14 -3.956 7.62E-05 0.001482 ENSMUSG00000039100 06-Mar 989.4892 -0.537471 0.18 -3.0633 0.002189 0.020305 ENSMUSG00000029163 Emilin1 677.9258 -0.537725 0.12 -4.4222 9.77E-06 0.000288 ENSMUSG00000026737 Pip4k2a 134.6321 -0.538147 0.14 -3.8987 9.67E-05 0.001789 ENSMUSG00000053080 2700081O15Rik124.4014 -0.538482 0.17 -3.2172 0.001295 0.013666 ENSMUSG00000030207 Fam234b 235.3237 -0.538974 0.14 -3.9116 9.17E-05 0.00171 ENSMUSG00000042790 Rnf214 157.2383 -0.539728 0.14 -3.7302 0.000191 0.003132 ENSMUSG00000035067 Xkr6 113.8503 -0.540006 0.15 -3.5681 0.00036 0.004992 ENSMUSG00000035877 Zhx3 279.5477 -0.540013 0.12 -4.3473 1.38E-05 0.000378 ENSMUSG00000028180 Zranb2 271.4658 -0.540123 0.17 -3.1438 0.001667 0.016731 ENSMUSG00000075254 Heg1 504.0242 -0.540704 0.12 -4.3435 1.40E-05 0.000383 ENSMUSG00000066357 Wdr6 1531.042 -0.541144 0.11 -4.8558 1.20E-06 5.49E-05 ENSMUSG00000022973 Synj1 352.3355 -0.541484 0.16 -3.2873 0.001011 0.011218 ENSMUSG00000034973 Dopey1 336.8164 -0.541618 0.18 -3.0212 0.002517 0.022481 ENSMUSG00000048787 Dcun1d3 143.3863 -0.542033 0.19 -2.9056 0.003665 0.029635 ENSMUSG00000029260 Ugt2b34 577.284 -0.543245 0.13 -4.1022 4.09E-05 0.000894 ENSMUSG00000020863 Luc7l3 394.1694 -0.544474 0.15 -3.7452 0.00018 0.002988 ENSMUSG00000039765 Cc2d2a 112.5478 -0.545166 0.19 -2.8199 0.004804 0.036541 ENSMUSG00000058230 Arhgap35 678.6982 -0.545711 0.13 -4.13 3.63E-05 0.000811 ENSMUSG00000009731 Kcnd1 68.31771 -0.546046 0.18 -3.0121 0.002595 0.022987 ENSMUSG00000047747 Rnf150 132.9994 -0.546075 0.2 -2.7364 0.006211 0.04384 ENSMUSG00000071302 2610044O15Rik868.19263 -0.546289 0.18 -2.9755 0.002925 0.025187 ENSMUSG00000024542 Cep192 144.4905 -0.54762 0.17 -3.23 0.001238 0.01319 ENSMUSG00000023050 Map3k12 143.3166 -0.548324 0.14 -3.8944 9.84E-05 0.001811 ENSMUSG00000028556 Dock7 356.0581 -0.549829 0.1 -5.2811 1.28E-07 9.07E-06 ENSMUSG00000033904 Ccp110 102.6289 -0.551452 0.18 -3.1439 0.001667 0.016731 ENSMUSG00000036501 Fam13b 298.0451 -0.551822 0.13 -4.3524 1.35E-05 0.000371 ENSMUSG00000020070 Rufy2 172.713 -0.551872 0.18 -3.0346 0.002408 0.021653 ENSMUSG00000051331 Cacna1c 620.098 -0.552052 0.16 -3.5496 0.000386 0.005271 ENSMUSG00000054387 Mdm4 457.5417 -0.552186 0.15 -3.6489 0.000263 0.003985 ENSMUSG00000015222 Map2 1566.5 -0.552395 0.17 -3.2884 0.001008 0.011202 ENSMUSG00000026159 Agfg1 600.8309 -0.552701 0.13 -4.225 2.39E-05 0.000576 ENSMUSG00000029004 Kmt2e 607.5047 -0.553119 0.2 -2.7388 0.006167 0.043597 ENSMUSG00000033237 Arid2 361.2272 -0.55313 0.18 -3.0901 0.002001 0.019166 Diabetes Page 72 of 85

ENSMUSG00000040785 Ttc3 710.6291 -0.553489 0.11 -4.8868 1.03E-06 4.88E-05 ENSMUSG00000067851 Arfgef1 1096.251 -0.555813 0.1 -5.8086 6.30E-09 6.87E-07 ENSMUSG00000013033 Adgrl1 752.8612 -0.556704 0.14 -4.0993 4.14E-05 0.0009 ENSMUSG00000027006 Dnajc10 812.3101 -0.558715 0.13 -4.4157 1.01E-05 0.000294 ENSMUSG00000029438 Bcl7a 141.3522 -0.560052 0.18 -3.1329 0.001731 0.017199 ENSMUSG00000025907 Rb1cc1 305.7748 -0.560217 0.19 -3.0161 0.00256 0.022756 ENSMUSG00000051329 Nup160 135.9842 -0.56031 0.19 -2.9654 0.003023 0.025904 ENSMUSG00000042978 Sbk1 101.9484 -0.560594 0.18 -3.1568 0.001595 0.016169 ENSMUSG00000063317 Usp31 278.6067 -0.560801 0.19 -3.0168 0.002555 0.022745 ENSMUSG00000030451 Herc2 908.8923 -0.561629 0.13 -4.4536 8.45E-06 0.000258 ENSMUSG00000026637 Traf5 104.7841 -0.561833 0.16 -3.4354 0.000592 0.007365 ENSMUSG00000026113 Inpp4a 782.842 -0.56189 0.16 -3.6142 0.000301 0.004353 ENSMUSG00000008763 Man1a2 315.944 -0.562037 0.16 -3.5365 0.000405 0.005493 ENSMUSG00000002324 Rec8 246.2135 -0.562357 0.18 -3.12 0.001808 0.01779 ENSMUSG00000042363 Lgalsl 107.9291 -0.562928 0.19 -2.912 0.003591 0.02923 ENSMUSG00000025495 Ptdss2 67.48459 -0.563045 0.19 -3.0413 0.002356 0.021336 ENSMUSG00000054942 Fam73a 1677.663 -0.563103 0.17 -3.3992 0.000676 0.008149 ENSMUSG00000040712 Camta2 333.5636 -0.563956 0.13 -4.4191 9.91E-06 0.000291 ENSMUSG00000042129 Rassf4 289.4093 -0.565578 0.17 -3.2798 0.001039 0.011436 ENSMUSG00000027889 Ampd2 881.6285 -0.565945 0.12 -4.7621 1.92E-06 8.03E-05 ENSMUSG00000034612 Chst11 497.518 -0.566221 0.16 -3.6364 0.000277 0.004138 ENSMUSG00000025241 Fyco1 391.6217 -0.566982 0.15 -3.7053 0.000211 0.003348 ENSMUSG00000046111 Cep295 109.4475 -0.567741 0.2 -2.8355 0.004575 0.035221 ENSMUSG00000071660 Ttc9c 179.2959 -0.567794 0.16 -3.601 0.000317 0.00453 ENSMUSG00000034714 Ttyh2 453.8362 -0.567889 0.1 -5.9147 3.33E-09 3.89E-07 ENSMUSG00000022419 Deptor 1017.091 -0.567986 0.2 -2.9032 0.003694 0.029784 ENSMUSG00000068154 Insm1 822.3648 -0.568219 0.18 -3.2411 0.001191 0.012801 ENSMUSG00000027130 Slc12a6 357.4618 -0.56827 0.16 -3.4709 0.000519 0.006676 ENSMUSG00000027365 Trpm7 289.8949 -0.568924 0.19 -2.9186 0.003516 0.028734 ENSMUSG00000026754 Golga1 256.4573 -0.569198 0.14 -4.2012 2.66E-05 0.000625 ENSMUSG00000045934 Mtmr11 267.5831 -0.5697 0.16 -3.4942 0.000475 0.006239 ENSMUSG00000038545 Cul7 392.609 -0.569927 0.16 -3.5582 0.000373 0.005135 ENSMUSG00000030671 Pde3b 484.3884 -0.571404 0.18 -3.1923 0.001411 0.014572 ENSMUSG00000038241 Cep250 152.4338 -0.572222 0.19 -3.0798 0.002072 0.019602 ENSMUSG00000074892 B3galt5 229.5584 -0.572418 0.21 -2.6998 0.006938 0.047731 ENSMUSG00000027933 Ints3 698.1746 -0.57369 0.17 -3.4432 0.000575 0.007208 ENSMUSG00000022641 Bbx 398.2372 -0.574619 0.16 -3.6925 0.000222 0.003475 ENSMUSG00000063455 D630045J12Rik180.5696 -0.575119 0.19 -3.0825 0.002053 0.019473 ENSMUSG00000015342 Xk 92.74959 -0.576283 0.2 -2.9543 0.003134 0.026434 ENSMUSG00000043391 2510009E07Rik360.1477 -0.576489 0.13 -4.2916 1.77E-05 0.000454 ENSMUSG00000038807 Rap1gap2 4121.869 -0.576905 0.14 -4.0446 5.24E-05 0.00109 ENSMUSG00000053646 Plxnb1 528.0569 -0.577183 0.1 -5.8923 3.81E-09 4.38E-07 Page 73 of 85 Diabetes

ENSMUSG00000020032 Nuak1 180.0211 -0.578885 0.18 -3.2427 0.001184 0.012746 ENSMUSG00000042323 Pbrm1 508.3477 -0.580183 0.19 -3.0188 0.002538 0.022612 ENSMUSG00000096687 AA474331 56.23467 -0.581159 0.21 -2.7221 0.006486 0.045383 ENSMUSG00000061313 Ddhd2 256.4276 -0.581561 0.11 -5.1182 3.08E-07 1.81E-05 ENSMUSG00000041592 Sdk2 1208.861 -0.581764 0.16 -3.6019 0.000316 0.004519 ENSMUSG00000052707 Tnrc6a 681.9312 -0.582923 0.15 -3.8209 0.000133 0.002326 ENSMUSG00000021111 Papola 1192.042 -0.583457 0.12 -4.7762 1.79E-06 7.57E-05 ENSMUSG00000057230 Aak1 760.2358 -0.583538 0.16 -3.7549 0.000173 0.002887 ENSMUSG00000022788 Fgd4 194.7469 -0.583833 0.19 -3.0685 0.002152 0.020112 ENSMUSG00000063077 Kif1b 1621.111 -0.583931 0.16 -3.7175 0.000201 0.003224 ENSMUSG00000022946 Dopey2 464.6423 -0.584138 0.14 -4.3129 1.61E-05 0.000425 ENSMUSG00000028698 Pik3r3 264.291 -0.584972 0.14 -4.1221 3.75E-05 0.000833 ENSMUSG00000055024 Ep300 623.0274 -0.585614 0.18 -3.2342 0.00122 0.013019 ENSMUSG00000035161 Ints6 175.9715 -0.586339 0.21 -2.8012 0.005092 0.038144 ENSMUSG00000021591 Glrx 230.4636 -0.587018 0.15 -3.9342 8.35E-05 0.001589 ENSMUSG00000066043 Phactr4 220.9414 -0.587191 0.13 -4.3627 1.28E-05 0.000358 ENSMUSG00000027272 Ubr1 330.5209 -0.588622 0.2 -2.944 0.00324 0.027085 ENSMUSG00000078899 Gm14430 215.0729 -0.589015 0.21 -2.7727 0.00556 0.040598 ENSMUSG00000024241 Sos1 234.8735 -0.589271 0.22 -2.7159 0.00661 0.046105 ENSMUSG00000027641 Rbl1 51.64755 -0.589721 0.21 -2.8429 0.00447 0.034505 ENSMUSG00000039372 04-Mar 280.1857 -0.589969 0.14 -4.1178 3.82E-05 0.000846 ENSMUSG00000068284 Gm608 228.7191 -0.590162 0.2 -2.9305 0.003384 0.027919 ENSMUSG00000040560 Wdr7 397.9262 -0.590532 0.15 -3.8662 0.000111 0.001993 ENSMUSG00000039431 Mtmr7 556.933 -0.592056 0.14 -4.3812 1.18E-05 0.000334 ENSMUSG00000039529 Atp8b1 1386.576 -0.592297 0.11 -5.3069 1.12E-07 7.99E-06 ENSMUSG00000021704 Mtx3 126.6364 -0.592771 0.16 -3.6447 0.000268 0.004034 ENSMUSG00000023039 Krt7 1919.952 -0.593278 0.22 -2.7323 0.006289 0.044311 ENSMUSG00000025860 Xiap 240.9105 -0.593335 0.17 -3.5692 0.000358 0.004981 ENSMUSG00000056091 St3gal5 196.3609 -0.593636 0.18 -3.3813 0.000721 0.008595 ENSMUSG00000040265 Dnm3 93.65777 -0.59503 0.16 -3.7559 0.000173 0.002883 ENSMUSG00000016552 Foxred2 201.915 -0.595228 0.16 -3.635 0.000278 0.004143 ENSMUSG00000034667 Xpot 791.4773 -0.595415 0.18 -3.3155 0.000915 0.010432 ENSMUSG00000034427 Myo15b 200.2106 -0.595573 0.19 -3.1688 0.001531 0.015583 ENSMUSG00000034111 Tmed8 863.4017 -0.595707 0.15 -4.0443 5.25E-05 0.00109 ENSMUSG00000033400 Agl 416.7192 -0.596828 0.14 -4.1948 2.73E-05 0.00064 ENSMUSG00000039840 Epg5 241.4473 -0.597572 0.12 -4.8778 1.07E-06 5.06E-05 ENSMUSG00000036198 Arhgap36 59.53191 -0.598263 0.22 -2.6971 0.006994 0.048049 ENSMUSG00000022861 Dgkg 168.6302 -0.598423 0.16 -3.6351 0.000278 0.004143 ENSMUSG00000031596 Slc7a2 1491.947 -0.59927 0.22 -2.7444 0.006062 0.04308 ENSMUSG00000057880 Abat 678.8824 -0.599854 0.17 -3.4453 0.00057 0.00716 ENSMUSG00000021140 Pcnx 712.0757 -0.599871 0.16 -3.8049 0.000142 0.002451 ENSMUSG00000026004 Kansl1l 73.09824 -0.600551 0.18 -3.4173 0.000632 0.00773 Diabetes Page 74 of 85

ENSMUSG00000020261 Slc36a1 423.4109 -0.602536 0.14 -4.1741 2.99E-05 0.000692 ENSMUSG00000020747 2310067B10Rik350.6112 -0.603298 0.17 -3.612 0.000304 0.004371 ENSMUSG00000053166 Cdh22 113.4019 -0.603883 0.21 -2.8418 0.004485 0.034584 ENSMUSG00000038271 Iffo1 364.3439 -0.604486 0.14 -4.3914 1.13E-05 0.000323 ENSMUSG00000030275 Etnk1 1236.173 -0.604767 0.16 -3.7239 0.000196 0.003175 ENSMUSG00000033799 Fam208b 648.3651 -0.604816 0.2 -2.9891 0.002798 0.024389 ENSMUSG00000037395 Rcor3 190.6377 -0.604912 0.16 -3.7947 0.000148 0.002525 ENSMUSG00000031229 Atrx 687.131 -0.605549 0.22 -2.6939 0.007063 0.048452 ENSMUSG00000041530 Ago1 322.1455 -0.606219 0.15 -3.9774 6.97E-05 0.001384 ENSMUSG00000025958 Creb1 229.931 -0.606248 0.15 -4.0377 5.40E-05 0.00111 ENSMUSG00000078350 Smim1 255.2403 -0.606908 0.17 -3.6225 0.000292 0.004273 ENSMUSG00000020220 Vps13d 498.4319 -0.607672 0.17 -3.4839 0.000494 0.006434 ENSMUSG00000030337 Vamp1 162.0211 -0.60821 0.15 -4.0569 4.97E-05 0.00104 ENSMUSG00000014355 Anapc1 539.7423 -0.608848 0.11 -5.6355 1.75E-08 1.67E-06 ENSMUSG00000035722 Abca7 445.705 -0.609062 0.17 -3.687 0.000227 0.003518 ENSMUSG00000042638 Gucy2c 226.8202 -0.611357 0.15 -4.193 2.75E-05 0.000643 ENSMUSG00000024897 Apba1 182.1587 -0.611626 0.17 -3.6364 0.000277 0.004138 ENSMUSG00000027981 Rnpc3 62.76213 -0.612219 0.22 -2.7742 0.005534 0.040434 ENSMUSG00000053460 Ggcx 210.1873 -0.613161 0.13 -4.6404 3.48E-06 0.000127 ENSMUSG00000045752 Tssc4 669.6847 -0.613639 0.2 -3.0052 0.002654 0.023405 ENSMUSG00000040537 Adam22 297.7054 -0.614153 0.16 -3.759 0.000171 0.002857 ENSMUSG00000052331 Ankrd44 399.8393 -0.614185 0.16 -3.7278 0.000193 0.003141 ENSMUSG00000034480 Diap2 98.93717 -0.615388 0.2 -3.0528 0.002267 0.020793 ENSMUSG00000004798 Ulk2 213.0304 -0.616474 0.16 -3.7743 0.00016 0.002699 ENSMUSG00000014932 Yes1 91.27814 -0.617443 0.19 -3.2808 0.001035 0.011406 ENSMUSG00000024294 Mib1 556.7215 -0.61757 0.21 -2.9771 0.00291 0.025097 ENSMUSG00000032842 Abcc10 123.3046 -0.617803 0.17 -3.7292 0.000192 0.003135 ENSMUSG00000032849 Abcc4 294.5117 -0.617831 0.15 -4.1229 3.74E-05 0.000831 ENSMUSG00000028136 Snx27 262.0765 -0.618571 0.13 -4.7443 2.09E-06 8.59E-05 ENSMUSG00000018740 Slc25a35 51.68669 -0.619279 0.22 -2.8222 0.004769 0.036353 ENSMUSG00000096847 Tmem151b 40.69073 -0.620682 0.22 -2.8752 0.004037 0.032054 ENSMUSG00000022961 Son 2732.156 -0.620877 0.18 -3.3799 0.000725 0.008611 ENSMUSG00000002428 Hltf 206.9634 -0.621647 0.16 -4.0019 6.28E-05 0.001268 ENSMUSG00000037902 Sirpa 801.3614 -0.622174 0.18 -3.4228 0.00062 0.007622 ENSMUSG00000027603 Ggt7 227.4174 -0.622493 0.13 -4.6886 2.75E-06 0.000107 ENSMUSG00000036779 Papd5 121.4528 -0.622721 0.19 -3.3535 0.000798 0.009288 ENSMUSG00000043940 Wdfy3 550.5207 -0.622892 0.21 -2.9945 0.002749 0.024076 ENSMUSG00000022012 Enox1 59.26923 -0.622902 0.21 -2.9993 0.002706 0.023785 ENSMUSG00000050965 Prkca 720.4936 -0.623278 0.13 -4.6674 3.05E-06 0.000116 ENSMUSG00000030213 Atf7ip 321.7543 -0.623693 0.19 -3.2103 0.001326 0.013892 ENSMUSG00000031161 Hdac6 1702.073 -0.62375 0.11 -5.4306 5.62E-08 4.56E-06 ENSMUSG00000028344 Invs 115.4942 -0.624199 0.15 -4.1032 4.07E-05 0.000893 Page 75 of 85 Diabetes

ENSMUSG00000068740 Celsr2 117.7818 -0.624471 0.16 -3.8009 0.000144 0.002477 ENSMUSG00000016200 Syt14 366.4516 -0.625674 0.19 -3.3343 0.000855 0.009836 ENSMUSG00000027652 Ralgapb 574.7278 -0.627455 0.14 -4.5998 4.23E-06 0.000148 ENSMUSG00000106924 Gm42857 77.30972 -0.63035 0.18 -3.5473 0.000389 0.005313 ENSMUSG00000048154 Kmt2d 928.1126 -0.63036 0.15 -4.0787 4.53E-05 0.000964 ENSMUSG00000049672 Zbtb14 246.153 -0.630411 0.12 -5.1419 2.72E-07 1.66E-05 ENSMUSG00000041966 Dcaf17 61.80422 -0.631889 0.23 -2.7203 0.006523 0.045581 ENSMUSG00000042286 Stab1 44.16064 -0.632487 0.21 -3.0339 0.002414 0.021694 ENSMUSG00000028456 Unc13b 332.77 -0.632919 0.14 -4.3902 1.13E-05 0.000324 ENSMUSG00000048915 Efna5 46.02781 -0.633506 0.23 -2.7811 0.005417 0.039873 ENSMUSG00000099083 Atf7 262.1757 -0.63479 0.14 -4.5765 4.73E-06 0.000164 ENSMUSG00000062198 2700097O09Rik44.07812 -0.634915 0.23 -2.7794 0.005446 0.04003 ENSMUSG00000037685 Atp8a1 310.955 -0.63534 0.16 -3.884 0.000103 0.001875 ENSMUSG00000060657 Marf1 329.7817 -0.635748 0.12 -5.4996 3.81E-08 3.33E-06 ENSMUSG00000027778 Ift80 157.9038 -0.636331 0.14 -4.7083 2.50E-06 9.87E-05 ENSMUSG00000035504 Reep6 463.98 -0.637431 0.22 -2.8748 0.004043 0.032054 ENSMUSG00000017756 Slc12a7 818.765 -0.639828 0.14 -4.4189 9.92E-06 0.000291 ENSMUSG00000045967 Gpr158 588.1053 -0.640572 0.22 -2.8529 0.004332 0.03371 ENSMUSG00000054619 Mettl7a1 490.8388 -0.640589 0.17 -3.7205 0.000199 0.003202 ENSMUSG00000079620 Muc4 685.0156 -0.641879 0.21 -3.0241 0.002494 0.022296 ENSMUSG00000017446 C1qtnf1 36.34441 -0.642705 0.23 -2.8301 0.004653 0.035655 ENSMUSG00000007613 Tgfbr1 275.2563 -0.642867 0.19 -3.3889 0.000702 0.008429 ENSMUSG00000004113 Cacna1b 79.39362 -0.643633 0.17 -3.7149 0.000203 0.003243 ENSMUSG00000025262 Fam120c 146.4401 -0.644365 0.23 -2.8255 0.00472 0.036051 ENSMUSG00000021265 Slc25a29 100.8767 -0.644457 0.19 -3.3657 0.000763 0.008986 ENSMUSG00000039801 2410089E03Rik275.7533 -0.644839 0.12 -5.29 1.22E-07 8.68E-06 ENSMUSG00000053617 Sh3pxd2a 1335.129 -0.645263 0.16 -4.0184 5.86E-05 0.001197 ENSMUSG00000075256 Cerkl 138.4369 -0.645298 0.19 -3.4737 0.000513 0.006647 ENSMUSG00000034205 Loxl2 221.1401 -0.646185 0.18 -3.6483 0.000264 0.003991 ENSMUSG00000033671 Cep350 415.3683 -0.646241 0.19 -3.3839 0.000715 0.008535 ENSMUSG00000040699 Limd2 342.1269 -0.646773 0.23 -2.859 0.00425 0.033245 ENSMUSG00000046667 Rbm12b1 52.78415 -0.646791 0.22 -2.9866 0.002821 0.02453 ENSMUSG00000059142 Zfp945 76.78997 -0.646842 0.22 -2.9766 0.002914 0.025106 ENSMUSG00000041842 Fhdc1 388.0684 -0.647426 0.23 -2.8185 0.004825 0.036641 ENSMUSG00000037461 Ints7 184.195 -0.648497 0.16 -4.0629 4.85E-05 0.00102 ENSMUSG00000026904 Slc4a10 156.9743 -0.648781 0.22 -2.9821 0.002863 0.024767 ENSMUSG00000046844 Vat1l 519.1409 -0.649651 0.12 -5.3333 9.65E-08 7.27E-06 ENSMUSG00000026923 Notch1 345.0068 -0.652254 0.14 -4.5686 4.91E-06 0.000168 ENSMUSG00000042473 Tbc1d8b 216.522 -0.652405 0.17 -3.8132 0.000137 0.002387 ENSMUSG00000024073 Birc6 919.4703 -0.652473 0.2 -3.2888 0.001006 0.011202 ENSMUSG00000047037 Nipa1 105.9879 -0.652895 0.17 -3.9235 8.73E-05 0.001644 ENSMUSG00000003452 Bicd1 198.8161 -0.655107 0.2 -3.3137 0.000921 0.010458 Diabetes Page 76 of 85

ENSMUSG00000059713 Rcan3 1316.889 -0.655593 0.13 -5.0903 3.58E-07 2.03E-05 ENSMUSG00000079481 Nhsl2 66.74988 -0.655615 0.18 -3.6095 0.000307 0.004406 ENSMUSG00000057716 Tmem178b 295.8561 -0.655782 0.19 -3.4684 0.000524 0.006727 ENSMUSG00000040387 Klhl32 430.5296 -0.656379 0.17 -3.9429 8.05E-05 0.001543 ENSMUSG00000037341 Slc9a7 229.3904 -0.656419 0.23 -2.9087 0.00363 0.029419 ENSMUSG00000031906 Smpd3 218.7553 -0.656664 0.22 -2.9885 0.002803 0.024406 ENSMUSG00000037486 Asxl2 341.8754 -0.656826 0.2 -3.3489 0.000811 0.009415 ENSMUSG00000063659 Zbtb18 176.9337 -0.657315 0.18 -3.5803 0.000343 0.004835 ENSMUSG00000029208 Guf1 129.6571 -0.657979 0.2 -3.3431 0.000829 0.009583 ENSMUSG00000055923 Aasdh 56.3185 -0.659116 0.23 -2.9191 0.00351 0.028701 ENSMUSG00000033943 Mga 522.8334 -0.659332 0.21 -3.1966 0.001391 0.01441 ENSMUSG00000024122 Pdpk1 532.2586 -0.659574 0.2 -3.3151 0.000916 0.010435 ENSMUSG00000031327 Chic1 1434.7 -0.659782 0.13 -4.987 6.13E-07 3.16E-05 ENSMUSG00000034487 Kdelc2 53.04155 -0.660123 0.2 -3.3221 0.000893 0.010243 ENSMUSG00000038990 Cables2 144.8595 -0.661069 0.16 -4.0454 5.22E-05 0.001089 ENSMUSG00000028248 Pnisr 430.913 -0.66256 0.16 -4.1001 4.13E-05 0.0009 ENSMUSG00000047789 Slc38a9 37.59035 -0.66398 0.24 -2.8014 0.005088 0.038144 ENSMUSG00000034066 Farp2 80.93736 -0.664304 0.17 -3.8016 0.000144 0.002473 ENSMUSG00000009470 Tnpo1 1055.829 -0.66494 0.23 -2.903 0.003696 0.029784 ENSMUSG00000031574 Star 55.73619 -0.665008 0.22 -3.0874 0.002019 0.019281 ENSMUSG00000027589 Pcmtd2 226.9001 -0.666229 0.19 -3.4525 0.000555 0.007036 ENSMUSG00000040570 Rundc3b 157.192 -0.666246 0.17 -3.933 8.39E-05 0.001595 ENSMUSG00000024426 Atat1 130.2295 -0.666638 0.16 -4.0976 4.17E-05 0.000903 ENSMUSG00000028483 Snapc3 54.43715 -0.667374 0.22 -3.0985 0.001945 0.018733 ENSMUSG00000021945 Zmym2 351.5481 -0.668514 0.19 -3.4314 0.000601 0.007437 ENSMUSG00000043535 Setx 335.387 -0.668858 0.15 -4.4265 9.58E-06 0.000283 ENSMUSG00000034636 Zyg11b 434.4099 -0.669064 0.17 -3.9495 7.83E-05 0.00151 ENSMUSG00000034832 Tet3 300.2238 -0.670806 0.18 -3.6353 0.000278 0.004143 ENSMUSG00000055884 Fancm 90.11799 -0.671334 0.19 -3.5217 0.000429 0.005745 ENSMUSG00000034724 Cnot6l 750.5112 -0.671667 0.11 -5.8712 4.33E-09 4.84E-07 ENSMUSG00000037266 Rsrp1 1467.298 -0.672021 0.19 -3.5126 0.000444 0.005903 ENSMUSG00000035967 Ddx26b 284.8382 -0.67269 0.2 -3.4026 0.000668 0.008096 ENSMUSG00000031959 Wdr59 171.9095 -0.67296 0.17 -3.8943 9.85E-05 0.001811 ENSMUSG00000052512 Nav2 941.7376 -0.673724 0.16 -4.2093 2.56E-05 0.000609 ENSMUSG00000041268 Dmxl2 634.101 -0.674021 0.23 -2.9606 0.00307 0.026095 ENSMUSG00000038664 Herc1 749.4758 -0.674265 0.15 -4.3951 1.11E-05 0.000319 ENSMUSG00000029202 Pds5a 400.4219 -0.674632 0.13 -5.3344 9.58E-08 7.26E-06 ENSMUSG00000051314 Ffar2 166.0228 -0.675235 0.22 -3.0642 0.002182 0.020284 ENSMUSG00000034584 Exph5 233.6282 -0.677034 0.22 -3.0477 0.002306 0.02105 ENSMUSG00000032740 Ccdc88a 173.5976 -0.677073 0.23 -2.9601 0.003075 0.026105 ENSMUSG00000037606 Osbpl5 246.0123 -0.681185 0.16 -4.3345 1.46E-05 0.000398 ENSMUSG00000046982 Tshz1 609.8863 -0.681255 0.15 -4.4413 8.94E-06 0.000268 Page 77 of 85 Diabetes

ENSMUSG00000031202 Rab39b 207.2909 -0.681552 0.19 -3.6275 0.000286 0.004235 ENSMUSG00000031626 Sorbs2 576.4436 -0.682325 0.21 -3.2538 0.001139 0.012332 ENSMUSG00000040998 Npnt 128.2812 -0.682919 0.23 -2.9589 0.003088 0.026138 ENSMUSG00000026443 Lrrn2 55.7233 -0.683367 0.25 -2.7127 0.006673 0.046399 ENSMUSG00000021217 Tshz3 215.966 -0.684063 0.15 -4.5754 4.75E-06 0.000164 ENSMUSG00000054517 Trim65 36.78187 -0.68452 0.22 -3.0444 0.002331 0.021181 ENSMUSG00000052135 Foxo6 92.48604 -0.684681 0.23 -3.0203 0.002525 0.022535 ENSMUSG00000003228 Grk5 192.9785 -0.685272 0.22 -3.0917 0.00199 0.019108 ENSMUSG00000042744 Gm15800 534.4141 -0.687302 0.14 -5.0735 3.91E-07 2.19E-05 ENSMUSG00000041762 Gpr155 51.50495 -0.689615 0.2 -3.388 0.000704 0.008437 ENSMUSG00000031216 Stard8 36.17574 -0.68962 0.25 -2.7699 0.005607 0.040745 ENSMUSG00000035125 Gcfc2 36.15076 -0.69129 0.25 -2.8154 0.004872 0.036921 ENSMUSG00000030096 Slc6a6 2142.303 -0.692069 0.12 -5.8947 3.75E-09 4.35E-07 ENSMUSG00000015243 Abca1 737.3214 -0.692977 0.25 -2.8049 0.005033 0.037808 ENSMUSG00000063142 Kcnma1 273.5391 -0.693491 0.22 -3.1629 0.001562 0.015872 ENSMUSG00000026068 Il18rap 22.30935 -0.694577 0.26 -2.6929 0.007084 0.048551 ENSMUSG00000022672 Prkdc 97.30557 -0.695573 0.2 -3.4015 0.00067 0.00811 ENSMUSG00000027931 Npr1 163.4932 -0.696958 0.15 -4.6128 3.97E-06 0.000141 ENSMUSG00000031378 Abcd1 225.2551 -0.699026 0.2 -3.5802 0.000343 0.004835 ENSMUSG00000016756 Cmah 80.80079 -0.699615 0.21 -3.288 0.001009 0.011209 ENSMUSG00000032293 Ireb2 620.9328 -0.700055 0.2 -3.5254 0.000423 0.005687 ENSMUSG00000063894 Zkscan8 121.4702 -0.701672 0.24 -2.9399 0.003283 0.027305 ENSMUSG00000072501 Phf20l1 485.7478 -0.704152 0.2 -3.5767 0.000348 0.004882 ENSMUSG00000020661 Dnmt3a 832.283 -0.704955 0.11 -6.3983 1.57E-10 2.77E-08 ENSMUSG00000034163 Zfc3h1 230.171 -0.705327 0.16 -4.4971 6.89E-06 0.00022 ENSMUSG00000029173 Sepsecs 379.0124 -0.705409 0.19 -3.6939 0.000221 0.003461 ENSMUSG00000047749 Zc3hav1l 61.25663 -0.707548 0.22 -3.1911 0.001417 0.01462 ENSMUSG00000034601 2700049A03Rik53.27026 -0.707978 0.21 -3.3483 0.000813 0.009428 ENSMUSG00000031189 Aff2 111.3613 -0.709043 0.24 -2.9646 0.003031 0.025932 ENSMUSG00000042834 Nrep 61.81005 -0.709687 0.19 -3.7341 0.000188 0.003094 ENSMUSG00000023033 Scn8a 186.7806 -0.710079 0.18 -3.9503 7.81E-05 0.001507 ENSMUSG00000041491 Cep78 84.90665 -0.710696 0.21 -3.4503 0.00056 0.007082 ENSMUSG00000079487 Med12 488.527 -0.711429 0.11 -6.3906 1.65E-10 2.88E-08 ENSMUSG00000020100 Slc29a3 64.44421 -0.711625 0.22 -3.2923 0.000994 0.011158 ENSMUSG00000022360 Atad2 47.32532 -0.712485 0.26 -2.7862 0.005333 0.039434 ENSMUSG00000022941 Ripply3 118.4003 -0.713712 0.26 -2.7779 0.00547 0.040107 ENSMUSG00000009378 Slc16a12 535.942 -0.713808 0.13 -5.3168 1.06E-07 7.64E-06 ENSMUSG00000066647 Gm5113 39.01767 -0.71425 0.26 -2.772 0.005572 0.040604 ENSMUSG00000056724 Nbeal2 364.3375 -0.717884 0.14 -5.001 5.70E-07 2.99E-05 ENSMUSG00000056379 Taar1 34.33332 -0.717987 0.25 -2.9051 0.003672 0.029641 ENSMUSG00000021245 Mlh3 105.3375 -0.718977 0.19 -3.8005 0.000144 0.002477 ENSMUSG00000027748 Trpc4 31.98357 -0.719191 0.26 -2.7258 0.006414 0.044951 Diabetes Page 78 of 85

ENSMUSG00000074364 Ehd2 45.45336 -0.719406 0.25 -2.928 0.003411 0.028094 ENSMUSG00000029644 Pdx1 612.7435 -0.719535 0.14 -5.0273 4.97E-07 2.67E-05 ENSMUSG00000061331 Gm17132 103.8712 -0.720355 0.25 -2.8662 0.004154 0.032679 ENSMUSG00000106948 Gm42785 119.7512 -0.720439 0.26 -2.8003 0.005105 0.038214 ENSMUSG00000028631 Kcnq4 46.69431 -0.721862 0.24 -3.0555 0.002247 0.020648 ENSMUSG00000042388 Dlgap3 91.67299 -0.721873 0.18 -3.9326 8.40E-05 0.001595 ENSMUSG00000059013 Sh2d3c 42.80887 -0.722516 0.24 -2.9515 0.003162 0.026615 ENSMUSG00000042408 Zmym6 129.8802 -0.722821 0.16 -4.3829 1.17E-05 0.000332 ENSMUSG00000104377 Gm37515 93.2964 -0.722866 0.22 -3.3039 0.000954 0.01079 ENSMUSG00000045838 A430105I19Rik212.3139 -0.723162 0.16 -4.4926 7.04E-06 0.000225 ENSMUSG00000021413 Prpf4b 466.1944 -0.723764 0.17 -4.1378 3.51E-05 0.00079 ENSMUSG00000045871 Slitrk6 163.8362 -0.724005 0.25 -2.8512 0.004356 0.033846 ENSMUSG00000041112 Elmo1 165.034 -0.724111 0.2 -3.5917 0.000329 0.004664 ENSMUSG00000022604 Cep97 38.49982 -0.725254 0.26 -2.7671 0.005656 0.040998 ENSMUSG00000090290 Gm17296 36.07078 -0.726772 0.23 -3.2114 0.001321 0.013859 ENSMUSG00000053347 Zfp943 64.07971 -0.729369 0.2 -3.7403 0.000184 0.003036 ENSMUSG00000001157 Gmcl1 82.00461 -0.729835 0.18 -4.0424 5.29E-05 0.001095 ENSMUSG00000038538 Ubn2 480.2463 -0.730452 0.2 -3.6269 0.000287 0.004239 ENSMUSG00000090112 Shprh 191.1903 -0.731291 0.23 -3.1313 0.00174 0.017248 ENSMUSG00000028842 Ago3 192.4359 -0.732938 0.17 -4.2967 1.73E-05 0.000448 ENSMUSG00000009418 Nav1 643.6641 -0.733691 0.15 -5.0518 4.38E-07 2.39E-05 ENSMUSG00000024620 Pdgfrb 70.2612 -0.734431 0.24 -3.0221 0.00251 0.022433 ENSMUSG00000014303 Glis2 163.6594 -0.734934 0.17 -4.4396 9.01E-06 0.000269 ENSMUSG00000038119 Cdon 315.3229 -0.735727 0.16 -4.6738 2.96E-06 0.000113 ENSMUSG00000070709 1700049G17Rik59.01495 -0.736176 0.25 -2.9767 0.002913 0.025106 ENSMUSG00000033526 Ppip5k1 559.4493 -0.738271 0.14 -5.141 2.73E-07 1.66E-05 ENSMUSG00000029999 Tgfa 31.84743 -0.739278 0.23 -3.2278 0.001247 0.013247 ENSMUSG00000055897 Ppp4r1l-ps 438.3974 -0.739772 0.15 -4.9572 7.15E-07 3.63E-05 ENSMUSG00000051224 Tceanc 39.51022 -0.74078 0.24 -3.0714 0.002131 0.020035 ENSMUSG00000081471 Gm14735 35.95462 -0.740937 0.23 -3.2399 0.001196 0.012823 ENSMUSG00000029471 Camkk2 122.2535 -0.747232 0.19 -3.8321 0.000127 0.002241 ENSMUSG00000039512 Uhrf1bp1 373.543 -0.747382 0.2 -3.7861 0.000153 0.002604 ENSMUSG00000038024 Dennd4c 1039.511 -0.748212 0.15 -4.864 1.15E-06 5.34E-05 ENSMUSG00000064061 Dzip3 56.51541 -0.748249 0.25 -2.94 0.003282 0.027305 ENSMUSG00000004360 9330159F19Rik76.14785 -0.751186 0.19 -3.9762 7.00E-05 0.001387 ENSMUSG00000037617 Spag1 31.98185 -0.751987 0.26 -2.9111 0.003602 0.02925 ENSMUSG00000032253 Phip 396.9717 -0.753324 0.22 -3.4452 0.000571 0.00716 ENSMUSG00000020788 Atp2a3 5721.789 -0.754965 0.14 -5.3806 7.42E-08 5.87E-06 ENSMUSG00000041935 AW549877 285.1169 -0.755645 0.17 -4.3202 1.56E-05 0.000415 ENSMUSG00000056602 Fry 332.7298 -0.755764 0.16 -4.7096 2.48E-06 9.83E-05 ENSMUSG00000036599 Chst12 153.6434 -0.756716 0.21 -3.5424 0.000396 0.005391 ENSMUSG00000064128 Cenpj 165.2711 -0.756852 0.28 -2.7469 0.006015 0.042898 Page 79 of 85 Diabetes

ENSMUSG00000021565 Slc6a19 102.6717 -0.757245 0.18 -4.2123 2.53E-05 0.000604 ENSMUSG00000045917 6330416G13Rik121.4709 -0.758538 0.27 -2.8318 0.004629 0.035526 ENSMUSG00000029009 Mthfr 500.9782 -0.760714 0.25 -3.0309 0.002439 0.021857 ENSMUSG00000032741 Tpcn1 352.9082 -0.761273 0.2 -3.7837 0.000155 0.002618 ENSMUSG00000034647 Ankrd12 322.1497 -0.761613 0.22 -3.51 0.000448 0.005945 ENSMUSG00000107705 Umad1 149.92 -0.761898 0.16 -4.7484 2.05E-06 8.44E-05 ENSMUSG00000026930 Gpsm1 563.2674 -0.764245 0.17 -4.4674 7.92E-06 0.000247 ENSMUSG00000034613 Ppm1h 273.3248 -0.764588 0.19 -4.0129 6.00E-05 0.001219 ENSMUSG00000033705 Stard9 24.8434 -0.766315 0.28 -2.7799 0.005438 0.040007 ENSMUSG00000023764 Sfi1 237.3976 -0.76636 0.18 -4.2324 2.31E-05 0.00056 ENSMUSG00000026544 Dusp23 43.9328 -0.772788 0.25 -3.1352 0.001717 0.017115 ENSMUSG00000056608 Chd9 494.4384 -0.775004 0.22 -3.5336 0.00041 0.005533 ENSMUSG00000047591 Mafa 276.8444 -0.775751 0.23 -3.3734 0.000742 0.008759 ENSMUSG00000031398 Plxna3 169.9795 -0.776757 0.18 -4.2057 2.60E-05 0.000618 ENSMUSG00000000686 Abhd15 205.7083 -0.777012 0.24 -3.1939 0.001403 0.0145 ENSMUSG00000053062 Jam2 116.4389 -0.77752 0.19 -4.059 4.93E-05 0.001032 ENSMUSG00000021256 Vash1 32.70224 -0.78111 0.28 -2.8309 0.004642 0.035607 ENSMUSG00000049038 Mterf2 35.01172 -0.781458 0.25 -3.0883 0.002013 0.019244 ENSMUSG00000042428 Mgat3 374.8984 -0.788018 0.17 -4.6075 4.08E-06 0.000144 ENSMUSG00000078202 Nrarp 28.33257 -0.788723 0.27 -2.898 0.003756 0.030185 ENSMUSG00000000579 Dynlt1c 185.7119 -0.788919 0.18 -4.4392 9.03E-06 0.000269 ENSMUSG00000108249 Gm43960 30.47045 -0.789094 0.29 -2.6884 0.007179 0.049021 ENSMUSG00000030882 Dnhd1 74.3919 -0.790566 0.2 -3.9192 8.89E-05 0.00167 ENSMUSG00000035735 Dagla 376.1171 -0.791031 0.15 -5.2743 1.33E-07 9.28E-06 ENSMUSG00000035954 Dock4 42.14402 -0.796354 0.27 -2.9696 0.002982 0.025584 ENSMUSG00000018199 Trove2 196.5656 -0.797075 0.24 -3.3448 0.000823 0.009539 ENSMUSG00000065947 ND4L 1855.866 -0.798822 0.2 -4.0017 6.29E-05 0.001268 ENSMUSG00000080316 Spaca6 228.429 -0.7989 0.17 -4.7325 2.22E-06 8.95E-05 ENSMUSG00000001901 Kcnh6 405.6568 -0.800201 0.18 -4.4524 8.49E-06 0.000258 ENSMUSG00000025127 Gcgr 181.3234 -0.800206 0.19 -4.3075 1.65E-05 0.000433 ENSMUSG00000036473 Ntn3 231.9336 -0.800766 0.22 -3.6575 0.000255 0.003883 ENSMUSG00000032549 Rab6b 179.1226 -0.80184 0.18 -4.4649 8.01E-06 0.000248 ENSMUSG00000037234 Hook3 310.4109 -0.802986 0.22 -3.5805 0.000343 0.004835 ENSMUSG00000009075 Cabp7 545.3941 -0.804372 0.19 -4.2799 1.87E-05 0.000475 ENSMUSG00000108218 Olfr1372-ps135.17829 -0.804584 0.29 -2.8198 0.004806 0.036541 ENSMUSG00000005410 Mcm5 29.85883 -0.804656 0.28 -2.8465 0.00442 0.034219 ENSMUSG00000040455 Usp45 232.387 -0.805943 0.21 -3.7588 0.000171 0.002857 ENSMUSG00000041141 Pnmal1 187.1342 -0.806407 0.2 -4.0812 4.48E-05 0.000955 ENSMUSG00000042460 C1galt1 465.9626 -0.810769 0.15 -5.2752 1.33E-07 9.28E-06 ENSMUSG00000006711 D130043K22Rik47.71538 -0.812928 0.2 -4.0651 4.80E-05 0.001011 ENSMUSG00000031285 Dcx 84.1264 -0.813029 0.25 -3.2239 0.001264 0.013394 ENSMUSG00000052783 Grk4 35.83447 -0.816304 0.23 -3.5173 0.000436 0.00582 Diabetes Page 80 of 85

ENSMUSG00000005267 Zfp287 58.35053 -0.816663 0.2 -4.0388 5.37E-05 0.001109 ENSMUSG00000057894 Zfp329 105.5402 -0.816771 0.24 -3.4393 0.000583 0.007293 ENSMUSG00000005893 Nr2c2 307.4189 -0.81792 0.18 -4.5439 5.52E-06 0.000183 ENSMUSG00000046442 Ppm1e 40.7591 -0.819449 0.24 -3.3869 0.000707 0.008457 ENSMUSG00000031767 Nudt7 192.7306 -0.819582 0.29 -2.8642 0.004181 0.032823 ENSMUSG00000013236 Ptprs 133.8201 -0.819788 0.15 -5.3451 9.04E-08 6.99E-06 ENSMUSG00000039000 Ube3c 657.5641 -0.820271 0.14 -6.066 1.31E-09 1.76E-07 ENSMUSG00000043668 Tox3 319.4605 -0.823609 0.21 -3.8617 0.000113 0.002024 ENSMUSG00000085328 Gm17131 354.8351 -0.823692 0.18 -4.5518 5.32E-06 0.000177 ENSMUSG00000027677 Ttc14 261.2186 -0.824165 0.17 -4.7397 2.14E-06 8.73E-05 ENSMUSG00000036502 Tmem255a 71.56142 -0.825281 0.21 -3.8487 0.000119 0.002123 ENSMUSG00000000794 Kcnn3 270.3357 -0.825551 0.23 -3.5876 0.000334 0.004727 ENSMUSG00000031255 Sytl4 2235.145 -0.826351 0.19 -4.4643 8.03E-06 0.000248 ENSMUSG00000026834 Acvr1c 32.64296 -0.831522 0.29 -2.823 0.004757 0.036278 ENSMUSG00000005045 Chd5 247.196 -0.831852 0.19 -4.3556 1.33E-05 0.000368 ENSMUSG00000021488 Nsd1 939.1297 -0.832131 0.11 -7.3554 1.90E-13 6.62E-11 ENSMUSG00000080115 Mettl21b 50.04286 -0.832444 0.25 -3.3637 0.000769 0.009038 ENSMUSG00000073664 Nbeal1 158.8627 -0.833311 0.22 -3.8074 0.00014 0.002433 ENSMUSG00000003847 Nfat5 791.5771 -0.836528 0.2 -4.1737 3.00E-05 0.000692 ENSMUSG00000015597 Zfp318 168.3032 -0.839305 0.16 -5.379 7.49E-08 5.89E-06 ENSMUSG00000022883 Robo1 262.4322 -0.840163 0.2 -4.3037 1.68E-05 0.000438 ENSMUSG00000029420 Rimbp2 1867.986 -0.841008 0.19 -4.3983 1.09E-05 0.000316 ENSMUSG00000050967 Creg2 13.92325 -0.842569 0.31 -2.7155 0.006618 0.046137 ENSMUSG00000078902 Gm14443 29.4722 -0.842755 0.27 -3.066 0.00217 0.020219 ENSMUSG00000030110 Ret 632.8908 -0.842999 0.17 -4.8355 1.33E-06 5.96E-05 ENSMUSG00000036745 Ttll7 390.2877 -0.843281 0.19 -4.4111 1.03E-05 0.0003 ENSMUSG00000037336 Mfsd2b 17.78127 -0.844646 0.29 -2.9634 0.003043 0.025932 ENSMUSG00000049148 Plcxd3 28.9017 -0.84909 0.3 -2.8234 0.004751 0.036253 ENSMUSG00000010086 Rnf112 39.21811 -0.849349 0.27 -3.1398 0.00169 0.016903 ENSMUSG00000027330 Cdc25b 35.69677 -0.849456 0.27 -3.1547 0.001606 0.016253 ENSMUSG00000073436 Eme2 362.0186 -0.8495 0.17 -5.0823 3.73E-07 2.10E-05 ENSMUSG00000039519 Cyp7b1 23.58497 -0.849875 0.31 -2.7021 0.006889 0.04753 ENSMUSG00000021287 Xrcc3 120.5117 -0.851759 0.17 -5.016 5.28E-07 2.81E-05 ENSMUSG00000028832 Stmn1 84.95123 -0.853877 0.27 -3.1066 0.001893 0.018386 ENSMUSG00000043991 Pura 429.436 -0.860663 0.18 -4.8045 1.55E-06 6.73E-05 ENSMUSG00000072915 LOC102642717100.9541 -0.861414 0.26 -3.3117 0.000927 0.010516 ENSMUSG00000071337 Tia1 242.3349 -0.862515 0.17 -5.0223 5.11E-07 2.73E-05 ENSMUSG00000016493 Cd46 91.09286 -0.864559 0.24 -3.6228 0.000291 0.004273 ENSMUSG00000037996 Slc24a2 623.8712 -0.865412 0.21 -4.0708 4.68E-05 0.000991 ENSMUSG00000027457 Snph 414.3028 -0.868775 0.16 -5.3776 7.55E-08 5.90E-06 ENSMUSG00000073062 Zxdb 116.7252 -0.869561 0.23 -3.8602 0.000113 0.002031 ENSMUSG00000073016 Uprt 46.50634 -0.875778 0.27 -3.2739 0.001061 0.011624 Page 81 of 85 Diabetes

ENSMUSG00000048965 Mrgpre 134.503 -0.877443 0.25 -3.5688 0.000359 0.004984 ENSMUSG00000023845 Lnpep 200.0178 -0.877603 0.31 -2.788 0.005304 0.039302 ENSMUSG00000002055 Spag5 24.75198 -0.880655 0.32 -2.7325 0.006285 0.044311 ENSMUSG00000020703 5530401A14Rik16.71589 -0.88085 0.31 -2.8138 0.004895 0.037061 ENSMUSG00000020256 Aldh1l2 463.1115 -0.880917 0.26 -3.3507 0.000806 0.00936 ENSMUSG00000038630 Zkscan16 54.50575 -0.883326 0.29 -3.0651 0.002176 0.020247 ENSMUSG00000061601 Pclo 1211.609 -0.884702 0.25 -3.5997 0.000319 0.004544 ENSMUSG00000036353 P2ry12 14.56243 -0.884843 0.31 -2.8884 0.003872 0.030924 ENSMUSG00000040651 Fam208a 196.8673 -0.886435 0.17 -5.1237 3.00E-07 1.78E-05 ENSMUSG00000038126 Mphosph9 121.4998 -0.890418 0.2 -4.3503 1.36E-05 0.000374 ENSMUSG00000051951 Xkr4 26.65182 -0.896381 0.29 -3.0992 0.00194 0.018724 ENSMUSG00000019852 Arfgef3 649.454 -0.896827 0.29 -3.0829 0.00205 0.019473 ENSMUSG00000002265 Peg3 8530.834 -0.902257 0.22 -4.076 4.58E-05 0.000973 ENSMUSG00000044501 Zfp758 37.99268 -0.902447 0.3 -2.9792 0.00289 0.024967 ENSMUSG00000103749 Pcdhgb5 16.90562 -0.902454 0.31 -2.9499 0.003179 0.026711 ENSMUSG00000033972 Zfp944 33.97213 -0.908126 0.25 -3.5769 0.000348 0.004882 ENSMUSG00000027635 Dsn1 9.293957 -0.911296 0.33 -2.7453 0.006045 0.043004 ENSMUSG00000030322 Mbd4 19.71632 -0.915757 0.3 -3.0255 0.002482 0.022211 ENSMUSG00000027495 Fam210b 407.1531 -0.916145 0.16 -5.5732 2.50E-08 2.29E-06 ENSMUSG00000022797 Tfrc 752.2029 -0.916822 0.22 -4.2614 2.03E-05 0.000508 ENSMUSG00000055660 Mettl4 20.1927 -0.918542 0.28 -3.2969 0.000978 0.011028 ENSMUSG00000015093 Clic3 11.0485 -0.919474 0.33 -2.7553 0.005864 0.042149 ENSMUSG00000048779 P2ry6 89.1659 -0.920638 0.27 -3.4352 0.000592 0.007365 ENSMUSG00000050714 Zbtb26 37.37231 -0.921549 0.28 -3.2884 0.001007 0.011202 ENSMUSG00000028312 Smc2 28.06218 -0.928888 0.3 -3.0587 0.002223 0.020543 ENSMUSG00000072722 Gm6588 12.16395 -0.929647 0.34 -2.7576 0.005822 0.041909 ENSMUSG00000078903 Gm14391 148.8707 -0.93124 0.22 -4.1686 3.07E-05 0.000707 ENSMUSG00000071550 Cfap44 13.16639 -0.937253 0.33 -2.856 0.004291 0.03349 ENSMUSG00000028957 Per3 222.4211 -0.941236 0.24 -3.9426 8.06E-05 0.001543 ENSMUSG00000025092 Hspa12a 191.0302 -0.942746 0.24 -3.9843 6.77E-05 0.001348 ENSMUSG00000096780 Tmem181b-ps327.2761 -0.943248 0.14 -6.9326 4.13E-12 1.01E-09 ENSMUSG00000078160 Gm16503 3.004231 -0.943768 0.35 -2.6821 0.007315 0.049719 ENSMUSG00000071748 Gm14698 25.84298 -0.945089 0.26 -3.6125 0.000303 0.004368 ENSMUSG00000040204 2810417H13Rik28.58428 -0.954495 0.28 -3.4583 0.000544 0.006936 ENSMUSG00000054939 Zfp174 71.30262 -0.955256 0.2 -4.8477 1.25E-06 5.67E-05 ENSMUSG00000042761 Mrap2 10.83793 -0.958123 0.32 -2.9849 0.002837 0.0246 ENSMUSG00000036964 Trim17 4.495442 -0.959218 0.36 -2.6789 0.007386 0.049986 ENSMUSG00000051378 Kif18b 7.398774 -0.959316 0.36 -2.6817 0.007325 0.049752 ENSMUSG00000022773 Ypel1 16.48967 -0.960095 0.31 -3.1409 0.001684 0.016855 ENSMUSG00000028873 Cdca8 16.47452 -0.96045 0.35 -2.7538 0.005891 0.042275 ENSMUSG00000036834 Plch1 107.3254 -0.96059 0.27 -3.5368 0.000405 0.005492 ENSMUSG00000042529 Kcnj12 56.35455 -0.961455 0.26 -3.7463 0.000179 0.002978 Diabetes Page 82 of 85

ENSMUSG00000038252 Ncapd2 122.5006 -0.961518 0.26 -3.7197 0.000199 0.003208 ENSMUSG00000090353 Gm17555 12.80481 -0.961692 0.33 -2.9325 0.003363 0.027822 ENSMUSG00000031200 Mtcp1 28.22168 -0.963007 0.25 -3.8443 0.000121 0.002153 ENSMUSG00000054555 Adam12 5.877293 -0.964375 0.36 -2.7082 0.006766 0.046919 ENSMUSG00000044201 Cdc25c 5.142491 -0.965177 0.36 -2.7041 0.00685 0.047324 ENSMUSG00000026188 Tmem169 25.60039 -0.965959 0.26 -3.6494 0.000263 0.003983 ENSMUSG00000092470 Gm20518 59.55603 -0.966071 0.26 -3.6891 0.000225 0.003508 ENSMUSG00000078773 Rad54b 3.486726 -0.966189 0.36 -2.7016 0.0069 0.047578 ENSMUSG00000028546 Elavl4 102.2665 -0.968312 0.19 -5.0035 5.63E-07 2.97E-05 ENSMUSG00000037991 Rmi2 10.21597 -0.969496 0.35 -2.7607 0.005768 0.041598 ENSMUSG00000037355 Uvssa 125.7518 -0.970829 0.19 -5.1097 3.23E-07 1.87E-05 ENSMUSG00000040152 Thbs1 880.8131 -0.971086 0.22 -4.5108 6.46E-06 0.000209 ENSMUSG00000053702 Nebl 61.32118 -0.972901 0.24 -4.1238 3.73E-05 0.000829 ENSMUSG00000081884 Gm11821 3.468924 -0.97293 0.36 -2.7389 0.006165 0.043597 ENSMUSG00000028970 Abcb1b 12.05032 -0.974016 0.32 -3.0588 0.002223 0.020543 ENSMUSG00000025986 Slc39a10 79.32228 -0.974597 0.24 -4.0986 4.16E-05 0.0009 ENSMUSG00000035236 Scai 73.56627 -0.975162 0.24 -4.0378 5.39E-05 0.00111 ENSMUSG00000048108 Tmem72 517.4734 -0.976731 0.16 -5.9722 2.34E-09 2.92E-07 ENSMUSG00000021803 Cdhr1 627.9289 -0.981594 0.12 -8.0698 7.04E-16 3.81E-13 ENSMUSG00000001517 Foxm1 34.45747 -0.983264 0.29 -3.3739 0.000741 0.008753 ENSMUSG00000041219 Arhgap11a 49.53191 -0.983403 0.27 -3.5789 0.000345 0.004855 ENSMUSG00000003779 Kif20a 38.62228 -0.986379 0.32 -3.0561 0.002243 0.020648 ENSMUSG00000078552 Dcdc2b 8.710378 -0.987162 0.34 -2.9197 0.003504 0.028679 ENSMUSG00000074652 Myh7b 15.23911 -0.987544 0.36 -2.776 0.005503 0.040265 ENSMUSG00000048922 Cdca2 11.56836 -0.989558 0.34 -2.9418 0.003263 0.02718 ENSMUSG00000006362 Cbfa2t3 185.6365 -0.991951 0.2 -4.9865 6.15E-07 3.16E-05 ENSMUSG00000000948 Gm38393 11.39737 -0.992376 0.35 -2.8189 0.004818 0.036612 ENSMUSG00000041498 Kif14 6.861166 -0.992686 0.35 -2.7967 0.005163 0.038467 ENSMUSG00000010505 Myt1 342.5332 -0.993089 0.23 -4.3553 1.33E-05 0.000368 ENSMUSG00000030544 Mesp1 4.233992 -0.994456 0.35 -2.8591 0.004248 0.033245 ENSMUSG00000099041 Gm28035 6.398014 -0.994764 0.35 -2.8044 0.005041 0.037832 ENSMUSG00000005373 Mlxipl 1660.355 -0.99555 0.21 -4.7028 2.57E-06 0.000101 ENSMUSG00000037315 Jade3 283.2229 -0.997866 0.2 -5.0049 5.59E-07 2.97E-05 ENSMUSG00000047155 Cyp4x1 12.60948 -1.002017 0.31 -3.2041 0.001355 0.014136 ENSMUSG00000039396 Neil3 15.00847 -1.003772 0.32 -3.1283 0.001758 0.017412 ENSMUSG00000034160 Ogt 513.672 -1.008975 0.2 -4.9308 8.19E-07 4.06E-05 ENSMUSG00000042489 Clspn 9.928056 -1.010131 0.34 -2.9316 0.003372 0.027854 ENSMUSG00000028068 Iqgap3 18.60248 -1.01021 0.29 -3.4885 0.000486 0.006351 ENSMUSG00000020627 Klhl29 16.90015 -1.011147 0.29 -3.485 0.000492 0.006412 ENSMUSG00000029177 Cenpa 17.06764 -1.014187 0.34 -2.9577 0.0031 0.026223 ENSMUSG00000012443 Kif11 29.95947 -1.015651 0.28 -3.6185 0.000296 0.004323 ENSMUSG00000032091 Tmprss4 233.9115 -1.015936 0.22 -4.67 3.01E-06 0.000115 Page 83 of 85 Diabetes

ENSMUSG00000034023 Fancd2 8.760801 -1.016341 0.35 -2.9143 0.003564 0.02909 ENSMUSG00000034990 Otoa 69.97837 -1.01643 0.25 -4.1098 3.96E-05 0.000873 ENSMUSG00000063953 Amd2 15.72758 -1.017738 0.36 -2.8618 0.004213 0.03302 ENSMUSG00000045912 C2cd4c 96.0392 -1.019238 0.25 -4.045 5.23E-05 0.00109 ENSMUSG00000035683 Melk 7.49147 -1.023002 0.35 -2.8894 0.00386 0.03087 ENSMUSG00000027932 Slc27a3 22.50931 -1.023118 0.28 -3.6336 0.00028 0.004161 ENSMUSG00000030621 Me3 286.3576 -1.024217 0.17 -6.2047 5.48E-10 8.26E-08 ENSMUSG00000038943 Prc1 64.41051 -1.025264 0.3 -3.4052 0.000661 0.008028 ENSMUSG00000035394 Cfap53 7.18157 -1.031884 0.35 -2.9641 0.003035 0.025932 ENSMUSG00000033419 Snap91 83.80881 -1.032498 0.18 -5.7581 8.50E-09 8.76E-07 ENSMUSG00000034218 Atm 284.7873 -1.033095 0.15 -6.8618 6.80E-12 1.48E-09 ENSMUSG00000090272 Mndal 47.63274 -1.034156 0.28 -3.6353 0.000278 0.004143 ENSMUSG00000046634 Pkd1l1 19.75419 -1.04128 0.3 -3.4675 0.000525 0.006742 ENSMUSG00000092083 Kcnb2 57.91714 -1.044078 0.22 -4.7577 1.96E-06 8.11E-05 ENSMUSG00000035606 Ky 541.7756 -1.048114 0.17 -6.2865 3.25E-10 5.16E-08 ENSMUSG00000094410 Gm38394 352.9994 -1.05761 0.24 -4.3277 1.51E-05 0.000406 ENSMUSG00000023940 Sgol1 7.451203 -1.0584 0.36 -2.9633 0.003044 0.025932 ENSMUSG00000023909 Paqr4 15.0066 -1.061066 0.3 -3.5005 0.000464 0.006132 ENSMUSG00000054203 Ifi205 24.73112 -1.064921 0.34 -3.0959 0.001962 0.018872 ENSMUSG00000047712 Ust 67.33002 -1.064925 0.27 -3.9185 8.91E-05 0.00167 ENSMUSG00000019429 Ffar3 59.39121 -1.066145 0.26 -4.0366 5.42E-05 0.001112 ENSMUSG00000029638 Glcci1 71.88618 -1.06678 0.3 -3.5772 0.000347 0.004882 ENSMUSG00000037474 Dtl 16.69849 -1.066862 0.31 -3.4643 0.000532 0.006811 ENSMUSG00000039628 Hs3st6 66.76724 -1.069844 0.27 -3.948 7.88E-05 0.001518 ENSMUSG00000051166 Eml5 919.137 -1.072629 0.17 -6.2426 4.30E-10 6.62E-08 ENSMUSG00000021733 Slc4a7 793.7108 -1.073195 0.21 -5.1621 2.44E-07 1.55E-05 ENSMUSG00000030660 Pik3c2a 442.9087 -1.07402 0.22 -4.8105 1.51E-06 6.63E-05 ENSMUSG00000098306 Gm28040 8.489113 -1.076363 0.35 -3.0399 0.002366 0.021421 ENSMUSG00000064357 ATP6 7120.752 -1.082067 0.25 -4.2638 2.01E-05 0.000504 ENSMUSG00000032679 Cd59a 133.1544 -1.083883 0.22 -4.8914 1.00E-06 4.78E-05 ENSMUSG00000019900 Rfx6 439.0096 -1.086744 0.21 -5.109 3.24E-07 1.87E-05 ENSMUSG00000032254 Kif23 14.18293 -1.086951 0.35 -3.1214 0.0018 0.01773 ENSMUSG00000032034 Kcnj5 5.907045 -1.088353 0.35 -3.0661 0.002168 0.020219 ENSMUSG00000021589 Rhobtb3 102.9727 -1.090253 0.18 -6.1745 6.64E-10 9.67E-08 ENSMUSG00000043263 Pyhin1 25.81752 -1.095207 0.33 -3.2896 0.001003 0.011202 ENSMUSG00000078651 Aoc2 51.04406 -1.095974 0.21 -5.2193 1.80E-07 1.17E-05 ENSMUSG00000047787 Flrt1 91.02485 -1.099731 0.2 -5.6122 2.00E-08 1.87E-06 ENSMUSG00000027009 Itga4 160.388 -1.103983 0.23 -4.8986 9.65E-07 4.67E-05 ENSMUSG00000024795 Kif20b 12.81275 -1.104501 0.34 -3.2073 0.00134 0.014012 ENSMUSG00000044365 Cxxc4 286.2658 -1.111225 0.19 -5.7996 6.65E-09 7.09E-07 ENSMUSG00000100855 Gm6976 85.63288 -1.116288 0.26 -4.2767 1.90E-05 0.000481 ENSMUSG00000026683 Nuf2 13.42182 -1.1195 0.34 -3.3396 0.000839 0.009682 Diabetes Page 84 of 85

ENSMUSG00000043467 Zbtb37 101.0177 -1.119769 0.23 -4.8596 1.18E-06 5.44E-05 ENSMUSG00000023505 Cdca3 20.61704 -1.123755 0.35 -3.222 0.001273 0.013476 ENSMUSG00000061126 Cyp4f39 48.29734 -1.126061 0.33 -3.4303 0.000603 0.007455 ENSMUSG00000023015 Racgap1 93.84046 -1.127831 0.25 -4.557 5.19E-06 0.000174 ENSMUSG00000007080 Pole 13.13386 -1.131665 0.34 -3.2894 0.001004 0.011202 ENSMUSG00000000416 Cttnbp2 271.2219 -1.137033 0.16 -6.9255 4.34E-12 1.04E-09 ENSMUSG00000031997 Trpc6 3.445081 -1.146502 0.35 -3.2914 0.000997 0.011165 ENSMUSG00000082277 Gm15807 9.490102 -1.147383 0.34 -3.3535 0.000798 0.009288 ENSMUSG00000041633 Kctd12b 97.44109 -1.149754 0.26 -4.3876 1.15E-05 0.000326 ENSMUSG00000063757 NA 12.99441 -1.151534 0.33 -3.4947 0.000475 0.006235 ENSMUSG00000102443 Gm37102 8.848519 -1.158668 0.34 -3.4584 0.000543 0.006936 ENSMUSG00000037010 Apln 37.35795 -1.171566 0.29 -4.035 5.46E-05 0.001118 ENSMUSG00000024027 Glp1r 587.4596 -1.17962 0.21 -5.6731 1.40E-08 1.36E-06 ENSMUSG00000001403 Ube2c 18.73239 -1.189123 0.33 -3.6383 0.000274 0.004119 ENSMUSG00000022021 Diap3 12.70675 -1.190759 0.32 -3.6976 0.000218 0.003418 ENSMUSG00000037725 Ckap2 15.09359 -1.191268 0.34 -3.4992 0.000467 0.006158 ENSMUSG00000027326 Casc5 9.75521 -1.199774 0.34 -3.5096 0.000449 0.005947 ENSMUSG00000074867 Zfp808 6.616591 -1.20942 0.35 -3.4484 0.000564 0.007119 ENSMUSG00000027469 Tpx2 31.27976 -1.210425 0.35 -3.4913 0.000481 0.00629 ENSMUSG00000083397 Gm5466 5.610136 -1.211619 0.36 -3.4123 0.000644 0.00786 ENSMUSG00000100181 Gm29096 78.50937 -1.21654 0.26 -4.7267 2.28E-06 9.14E-05 ENSMUSG00000072673 Gm10392 11.21472 -1.21776 0.35 -3.477 0.000507 0.006589 ENSMUSG00000074250 Gm10653 3.809279 -1.227027 0.35 -3.4593 0.000542 0.006921 ENSMUSG00000027331 Knstrn 24.46842 -1.2319 0.35 -3.5622 0.000368 0.005072 ENSMUSG00000047534 Mis18bp1 7.73982 -1.232625 0.35 -3.5184 0.000434 0.005802 ENSMUSG00000023795 Pisd-ps2 86.26336 -1.234671 0.19 -6.4566 1.07E-10 1.93E-08 ENSMUSG00000023908 Pkmyt1 30.24631 -1.238957 0.27 -4.5675 4.94E-06 0.000169 ENSMUSG00000032783 Troap 8.022487 -1.241471 0.36 -3.4712 0.000518 0.006674 ENSMUSG00000044453 Ffar1 570.5542 -1.244053 0.18 -6.9622 3.35E-12 8.44E-10 ENSMUSG00000020808 Fam64a 12.56637 -1.252961 0.34 -3.6432 0.000269 0.004051 ENSMUSG00000082286 Pisd-ps1 43.80988 -1.253484 0.25 -5.0035 5.63E-07 2.97E-05 ENSMUSG00000026622 Nek2 30.26565 -1.30414 0.33 -3.9568 7.60E-05 0.001478 ENSMUSG00000027715 Ccna2 28.60616 -1.313552 0.32 -4.1565 3.23E-05 0.000737 ENSMUSG00000041431 Ccnb1 15.72932 -1.32409 0.36 -3.7178 0.000201 0.003224 ENSMUSG00000042808 Gpx2 186.0131 -1.340647 0.29 -4.6429 3.43E-06 0.000126 ENSMUSG00000026536 Mnda 41.21884 -1.357928 0.27 -4.985 6.20E-07 3.18E-05 ENSMUSG00000027306 Nusap1 20.88799 -1.359593 0.34 -3.9941 6.49E-05 0.001302 ENSMUSG00000019942 Cdk1 24.64807 -1.359788 0.33 -4.0721 4.66E-05 0.000987 ENSMUSG00000022033 Pbk 21.41847 -1.36437 0.3 -4.5702 4.87E-06 0.000168 ENSMUSG00000032452 Clstn2 11.39046 -1.375625 0.34 -4.0818 4.47E-05 0.000954 ENSMUSG00000074449 Gm15319 6.16818 -1.383437 0.36 -3.878 0.000105 0.001917 ENSMUSG00000075316 Scn9a 166.4693 -1.413611 0.24 -5.8126 6.15E-09 6.76E-07 Page 85 of 85 Diabetes

ENSMUSG00000038179 Slamf7 19.19515 -1.422531 0.31 -4.6531 3.27E-06 0.000122 ENSMUSG00000033952 Aspm 13.78693 -1.441301 0.35 -4.1265 3.68E-05 0.000821 ENSMUSG00000025997 Ikzf2 35.98309 -1.44173 0.28 -5.2369 1.63E-07 1.09E-05 ENSMUSG00000079553 Kifc1 21.19028 -1.445543 0.34 -4.1925 2.76E-05 0.000643 ENSMUSG00000043747 1520401A03Rik3.767761 -1.451923 0.36 -4.0672 4.76E-05 0.001004 ENSMUSG00000048327 Ckap2l 22.26982 -1.479486 0.32 -4.5635 5.03E-06 0.000171 ENSMUSG00000031004 Mki67 122.3811 -1.51467 0.28 -5.3253 1.01E-07 7.39E-06 ENSMUSG00000006398 Cdc20 24.07089 -1.522783 0.35 -4.3968 1.10E-05 0.000317 ENSMUSG00000020914 Top2a 99.62482 -1.535381 0.3 -5.1921 2.08E-07 1.33E-05 ENSMUSG00000034311 Kif4 13.22261 -1.60282 0.35 -4.5619 5.07E-06 0.000172 ENSMUSG00000045328 Cenpe 24.08265 -1.605287 0.33 -4.8387 1.31E-06 5.90E-05 ENSMUSG00000020330 Hmmr 30.65984 -1.605649 0.32 -4.9583 7.11E-07 3.62E-05 ENSMUSG00000046070 Igfals 166.3962 -1.642024 0.17 -9.5835 9.38E-22 1.71E-18 ENSMUSG00000058290 Espl1 10.13431 -1.738747 0.35 -5.0004 5.72E-07 2.99E-05 ENSMUSG00000026589 Sec16b 278.949 -1.776802 0.17 -10.541 5.61E-26 1.37E-22 ENSMUSG00000015484 Fam163a 52.63139 -1.887967 0.27 -7.096 1.28E-12 3.68E-10 ENSMUSG00000073491 Pydc4 15.73884 -2.034353 0.33 -6.1735 6.68E-10 9.67E-08 ENSMUSG00000026605 Cenpf 27.49475 -2.228919 0.33 -6.7205 1.81E-11 3.68E-09 ENSMUSG00000037849 Gm4955 15.03181 -2.344586 0.35 -6.6667 2.62E-11 5.24E-09