Multi-Tissue Probabilistic Fine-Mapping of Transcriptome-Wide Association Study Identifies Cis-Regulated Genes for Miserableness

bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Multi-tissue probabilistic fine-mapping of transcriptome-wide association study identifies cis-regulated genes for miserableness

Calwing Liao1,2 BSc, Veikko Vuokila2, Alexandre D Laporte2 BSc, Dan Spiegelman2 MSc, Patrick A. Dion2,3 PhD, Guy A. Rouleau1,2,3 * MD, PhD

1Department of Human Genetics, McGill University, Montréal, Quebec, Canada 2Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada 3Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada

Short summary: The first transcriptome-wide association study of miserableness identifies many genes including c7orf50 implicated in the trait.

Word count: 1,522 excluding abstract and references Tables: 3

Keywords: Miserableness, transcriptome-wide association study, TWAS

*Correspondence: Dr. Guy A. Rouleau Montreal Neurological Institute and Hospital Department of Neurology and Neurosurgery 3801 University Street, Montreal, QC Canada H3A 2B4. Tel: +1 514 398 2690 Fax: +1 514 398 8248 E-mail: [email protected]

Abstract (141 words)

Miserableness is a behavioural trait that is characterized by strong negative feelings in an individual. Although environmental factors tend to invoke miserableness, it is common to feel miserable ‘for no reason’, suggesting an innate, potential genetic component. Currently, little is known about the functional relevance of common variants associated with miserableness. To further characterize the trait, we conducted a transcriptome-wide association study (TWAS) on 373,733 individuals and identified 104 signals across brain tissue panels with 37 unique genes. Subsequent probabilistic fine-mapping prioritized 95 genes into 90%-credible sets. Amongst these prioritized hits, C7orf50 had the highest posterior inclusion probability of 0.869 in the brain cortex. Furthermore, we demonstrate that many GWAS hits for miserableness are driven by expression. To conclude, we successfully identified several genes implicated in miserableness and highlighted the power of TWAS to prioritize genes associated with a trait.

Introduction

Miserableness is characterized by emotional distress, typically caused by an event invoking negative feelings in an individual1. Although environmental factors may cause feelings of miserableness, it is common for certain individuals to feel miserable independent of environmental influences, suggesting that underlying biologic and genetic factors might play a role in miserableness. Several large-scale genome-wide association studies (GWAS) have focused on characterizing the genetics of neuroticism items such as miserableness2,3. No genetic factors fully overlap both miserableness and other neuroticism traits, which suggests that there are variants and/or genes that are specific to miserableness4. For instance, previous interrogation of neuroticism items found that miserableness had the highest genetic correlation with feeling “fed- up” (0.88) and “experiencing mood swings” (0.86), suggesting that there are genetic differences4. However, identifying the biological functionality of these variants remains difficult.

Transcriptomic imputation has recently been used to integrate genotype and expression data to identify predictive cis-eQTLs, which in turn can be applied to independent datasets in a tissue- specific manner5. Transcriptome-wide association studies (TWAS) can identify cis-eQTL regulated bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

genes by integrating expression panels from large consortia such as GTEx and the CommonMind Consortium (CMC) with GWAS data6. Furthermore, probabilistic fine-mapping of these TWAS hits can be done by modelling correlation among TWAS hits and assigning a probability for each gene within the risk region to prioritize genes7.

To understand cis-eQTL regulated candidate genes in miserableness, we conducted a TWAS consisting of 373,733 individuals using the summary statistics from a recent study dissecting the genetic heterogeneity of neuroticism4. The participants were asked whether they tend to ‘feel miserable’ for no particular reason. A total of 104 TWAS signals with 37 unique genes were transcriptome-wide significant across brain tissue panels. Probabilistic fine-mapping identified a number of putatively causal genes, including C7orf50 in GPX1 in the frontal cortex with a posterior inclusion probability (PIP) of 0.869 and MTCH2 in the nucleus accumbens with a PIP of 0.573. Conditioning on the transcriptome-wide significant hits showed that the hits accounted for >75% of the GWAS signal present. To conclude, miserableness genetics is explained partially by cis-eQTLs driving the expression of certain genes. Additional studies are needed to characterize other sources of non-coding variation such as 3’-aQTLs.

Results

Transcriptome-wide association study identifies 104 signals associated with miserableness

A multi-tissue TWAS using FUSION identified 104 TWAS signals associated with miserableness after Bonferroni-correction (Table 1, Figure 1). Across all signals, there were 37 genes identified in at least one imputation panel (Supplementary table 1). Amongst all signals, the top five hits in

-10 chronological order consisted of GPX1 (PBonferroni= 5.18 x 10 ) in the frontal cortex, RNF123

-8 -7 (PBonferroni=3.67 x 10 ) in the cerebellum, GPX1 (PBonferroni=3.09 x 10 ) in the cerebellum, RBM6

-7 -6 (P=5.12x10 ) in the caudate basal ganglia, and MST1R (PBonferroni=1.29 x 10 ) in the prefrontal cortex. Amongst the signals, several implicated RNA-coding genes, reinforcing the notion that non-coding genes are relevant to complex traits (Table 1).

Top GWAS signals are largely explained by expression

To determine how much GWAS signal remains after the expression association from TWAS is removed, conditional testing was done for transcriptome-wide significant TWAS signals. For most of the GWAS signals, the expression accounted for >75% of the variance (Table 2, Supplementary Figures 1-14). For RP11-74E22.6, RP11-798G7.5, and DNF-AS, conditioning on the expression accounted for 100% of the signal. There were less TWAS signals compared to the GWAS significant signals for miserableness, suggesting that other genetic mechanisms are driving those signals.

Fine-mapping of TWAS association causally implicates several genes with miserableness

To identify causal genes, FOCUS was used to assign a posterior inclusion probability for genes at each TWAS region and for relevant tissue types. Across all panels, there were 95 hits included in the 90% credible gene set (Table 3). The gene, C7orf50, had the highest posterior inclusion probability (PIP) of 0.869 in the brain cortex. Additionally, the top multi-tissue TWAS hit from the FUSION results, GPX1, was included in the credible sets with a PIP of 0.192 in the frontal cortex. Several other genes also had high PIPs, such as RP11-127L20.3 in the hippocampus with a PIP of 0.304, MTCH2 in the nucleus accumbens with a PIP of 0.573, ORC4 in the hypothalamus with a PIP of 0.524, ATAD2B in the cerebellar hemisphere with a PIP of 0.264, FANCL in the dorsolateral prefrontal cortex with a PIP of 0.446, and CTC-467M3.3 in the frontal cortex with a PIP of 0.567.

Discussion

With the influx of several large-scale biobanks and GWAS studies, many loci are being identified. The next step is to identify biologically- and phenotypically- relevant genes found by GWAS. To date, few studies have attempted to understand the genetics of miserableness, despite the high prevalence of the trait. Here, we conducted the largest TWAS to date using the summary statistics of 373,733 individuals to further understand this neuroticism item. A total of 104 TWAS signals were transcriptome-wide significant across brain tissues with 37 unique genes.

We identified a total of 104 transcriptome-wide signals across brain tissues with 37 unique genes. The top two signals included GPX1 frontal cortex and RNF123 in the cerebellum. The gene, GPX1, encodes for a cytosolic enzyme, glutathione peroxidase-1, expressed in many different tissues8. bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

This gene has previously been implicated in Alzheimer’s disease affecting cortical neurons9. Furthermore, neurons lacking GPX1 leads have a greater susceptibility to oxidative-driven cell death8. The Z-scores for all GPX1 hits were positive, suggesting that increased expression leads to susceptibility to miserableness. Currently, little is known about the effects of increased GPX1 in the nervous system. The RNF123 gene, encodes for a ubiquitin-protein ligase, and expression has been correlated with depressive disorder, which likely has genetic overlap with miserableness10,11.

Often, an implicated GWAS locus contains many genes. Common GWAS mapping techniques would assign the SNP association to the closest gene, however, this has been shown to be suboptimal12–14. After conditioning on the TWAS signal for each transcriptome-wide significant hit, most of the signal was explained by the expression of the conditioned gene.

Fine-mapping of the TWAS signals identified many genes included in the credible set, where C7orf50 had the highest PIP of 0.869 in the brain cortex. Currently, the literature is sparse on C7orf50, however, querying the gene using the tissue-specific gene network (GIANT), showed potential implications in autism spectrum disorder and epilepsy15. For the brain cortex, GIANT implicated CCDC85B as the top functionally related gene to C7orf50. Previous studies have shown that CCDC85B is implicated in neural tube development16.

We conclude this study with some caveats and potential follow-up ideas. First, TWAS only measures the effects of cis-eQTLs and may not capture other genetic regulatory effects that contribute towards miserableness. Second, future large studies with wide ranges of phenotypes such as the All of Us initiative will allow to successfully measure the genetic susceptibility to miserableness in other ethnic populations. Here, we successfully demonstrated that behavioural traits such as miserableness have a strong genetic basis and many signals are driven by cis-eQTL. Genes such as GPX1, RNF123, C7orf50 and MTCH2 should be further investigated to understand the molecular consequences of dysregulated expression.

Methods Genotype data and patient information bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Summary statistics were obtained from Nagel et al. (2018)4. Details pertaining to participant ascertainment and quality control were previously reported by Nagel et al. (2018)4. Succinctly, the data was derived from the UK BioBank and miserableness was determined by asking “Do you ever feel ‘just miserable’ for no reason?”. A total of 373,733 individuals were included, with 45% of them saying “yes”. There were 47% of females who responded “yes”, and 43% of males who responded “yes”.

Transcriptomic imputation Transcriptomic imputation (TI) was done using eQTL panels created from tissue-specific gene expression coupled with genotypic data17. Here, we used all the brain tissue types from GTEx 53 v7 and the CommonMind Consortium (CMC)6. A strict Bonferroni-corrected study-wise threshold was used: P=4.97E-07 (0.05/100,572) (total number of genes across panels). FUSION was used to conduct the transcriptome-wide association testing17. The 1000 Genomes v3 LD panel was used for the TWAS. FUSION utilizes several penalized linear models such as GBLUP, LASSO, Elastic Net17. Furthermore, a Bayesian sparse linear mixed model (BSLMM) is used. FUSION works by computing an out-sample R2 to determine the best model by performing a fivefold cross- validating of every model. Further details can be found in the original manuscript.

Conditionally testing GWAS signals To determine how much GWAS signal remains after the expression association from TWAS is removed, joint and conditional testing was done for genome-wide Bonferroni-corrected TWAS signals. The joint and conditional analyses help to determine genes with independent genetic predictors associated with miserableness from genes that are simply co-expressed with a genetic predictor. Each miserableness GWAS SNP association was conditioned on the joint gene model one SNP at a time.

Fine-mapping of TWAS associations To address the issue of co-regulation in TWAS, we used the program FOCUS (Fine-mapping of causal gene sets) to directly model predicted expression correlations and to provide a posterior bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

causal probability for genes in relevant tissue types7. FOCUS identifies genes for each TWAS signal to be part of a 90%-credible set while simultaneously controlling for pleiotropic effects of SNPs. Furthermore, the same TWAS reference panels for FUSION were used.

References 1. Vandercammen, L., Hofmans, J. & Theuns, P. Relating Specific Emotions to Intrinsic Motivation: On the Moderating Role of Positive and Negative Emotion Differentiation. PLoS One 9, e115396 (2014). 2. Luciano, M. et al. Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism. Nat. Genet. 50, 6–11 (2018). 3. Nagel, M. et al. Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways. Nat. Genet. 50, 920–927 (2018). 4. Nagel, M., Watanabe, K., Stringer, S., Posthuma, D. & van der Sluis, S. Item-level analyses reveal genetic heterogeneity in neuroticism. Nat. Commun. 9, 905 (2018). 5. Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245–252 (2016). 6. Consortium, Gte. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017). 7. Mancuso, N. et al. Probabilistic fine-mapping of transcriptome-wide association studies. Nat. Genet. 51, 675–682 (2019). 8. de Haan, J. B. et al. Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress- inducing agents paraquat and hydrogen peroxide. J. Biol. Chem. 273, 22528–36 (1998). 9. Crack, P. J., Cimdins, K., Ali, U., Hertzog, P. J. & Iannello, R. C. Lack of glutathione peroxidase-1 exacerbates Aβ-mediated neurotoxicity in cortical neurons. J. Neural Transm. 113, 645–657 (2006). 10. Teyssier, J.-R., Rey, R., Ragot, S., Chauvet-Gelinier, J.-C. & Bonin, B. Correlative gene expression pattern linking RNF123 to cellular stress–senescence genes in patients with depressive disorder: Implication of DRD1 in the cerebral cortex. J. Affect. Disord. 151, 432–438 (2013). 11. Chaturvedi, P., Khanna, R. & Parnaik, V. K. Ubiquitin ligase RNF123 Mediates Degradation of Heterochromatin Protein 1α and β in Lamin A/C Knock-Down Cells. PLoS One 7, e47558 (2012). 12. Liao, C. et al. Transcriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes. bioRxiv 642231 (2019). doi:10.1101/642231 13. Mancuso, N. et al. Large-scale transcriptome-wide association study identifies new prostate cancer risk regions. Nat. Commun. 9, 4079 (2018). 14. Gusev, A. et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat. Genet. 50, 538–548 (2018). 15. Greene, C. S. et al. Understanding multicellular function and disease with human tissue- bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

specific networks. Nat. Genet. 47, 569–576 (2015). 16. Markham, N. O. et al. DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia. Mol. Biol. Cell 25, 2592–603 (2014). 17. Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat. Genet. 48, 245–252 (2016).

Acknowledgements This work was supported by a Canadian Institutes of Health Research Foundation Scheme grant (#332971). G.A.R. holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences. C.L. is a recipient of the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR). C.L. conducted the experiments, analyses and drafted the manuscript. V.V. helped with analyses. A.D.L, D.S. helped with bioinformatics. P.A.D. and G.A.R. oversaw the analyses and helped draft the manuscript.

Conflicts of Interest We report no conflicts of interest.

Table 1. Multi-tissue significant TWAS hits for miserableness. Gene Tissue eQTL Z-score Uncorrected Bonferroni P- P-value value AF131215.2 ROSMAP rs17724226 -5.57 2.51E-08 3.92E-03 Brain Cerebellar rs17724226 -5.93 3.11E-09 4.86E-04 Hemisphere ROSMAP AF131215.3 rs2409745 -6.13 8.79E-10 1.37E-04 Brain Brain Cortex rs3448 -3.49 2.05E-07 3.20E-02 Caudate Basal rs9834003 -4.89 7.18E-08 1.12E-02 Ganglia AMT ROSMAP rs7619016 -11.57 6.45E-08 1.01E-02 Brain Hippocampus rs17689471 -4.07 1.89E-08 2.95E-03 Nucleus ARHGAP27 Accumbens rs17689471 5.94 2.91E-09 4.54E-04 Basal Ganglia C1QTNF4 Brain Cortex rs12286721 6.41 1.41E-10 2.20E-05 CRHR1-IT1 Brain Cortex rs17689471 5.17 2.37E-07 3.70E-02 bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Nucleus Accumbens rs8072451 5.74 9.67E-09 1.51E-03 Basal Ganglia Caudata Basal rs17763086 5.88 4.10E-09 6.40E-04 Ganglia Hypothalamus rs17763086 5.99 2.06E-09 3.22E-04 Frontal Cortex rs17763086 6.02 1.71E-09 2.67E-04 BA9 Putamen rs17689471 6.05 1.43E-09 2.23E-04 basal ganglia Hippocampus rs17689471 6.43 1.31E-10 2.05E-05 Dorsolateral ERI1 prefrontal rs7826478 5.95 2.74E-09 4.28E-04 cortex Dorsolateral prefrontal rs7844834 5.44 5.47E-08 8.54E-03 FAM167A cortex ROSMAP rs10102600 5.93 3.08E-09 4.81E-04 Brain FAM212A Cerebellum rs7372966 5.860692 4.61E-09 7.20E-04 ROSMAP FAM66A rs12676145 -5.39 7.16E-08 1.12E-02 Brain ROSMAP FAM66D rs12550733 5.21 1.90E-07 2.97E-02 Brain ROSMAP FAM85B rs2945251 5.64 1.72E-08 2.69E-03 Brain Dorsolateral FAM86B1 prefrontal rs11998678 -5.46 4.90E-08 7.65E-03 cortex Frontal Cortex rs2948286 5.5 3.69E-08 5.76E-03 BA9 ROSMAP rs2945230 5.65 1.57E-08 2.45E-03 brain FAM86B3P Cerebellar rs876954 6.25 4.14E-10 6.47E-05 hemisphere Cerebellum rs2980436 6.5 7.99E-11 1.25E-05 Brain Cortex rs2945230 6.5 7.91E-11 1.24E-05 ROSMAP FNBP4 rs7929014 -6.23 4.77E-10 7.45E-05 Brain FTSJ2 Brain Cortex rs3757440 5.805551 6.42E-09 1.00E-03 Caudate Basal GPX1 rs11130186 5.680812 1.34E-08 2.09E-03 Ganglia bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Cerebellar rs1873625 5.847834 4.98E-09 7.78E-04 hemisphere Dorsolateral prefrontal rs4955430 5.944679 2.77E-09 4.33E-04 cortex ROSMAP rs4955430 6.35984 2.02E-10 3.15E-05 brain Cerebellum rs9853683 7.035615 1.98E-12 3.09E-07 Frontal cortex rs7617480 7.878335 3.32E-15 5.18E-10 BA9 Cerebellum rs17689918 5.51 3.65E-08 5.70E-03 Hippocampus rs8072451 5.84 5.23E-09 8.17E-04 Brain Cortex rs17689918 5.86 4.53E-09 7.07E-04 Nucleus accumbens rs8072451 5.87 4.40E-09 6.87E-04 basal ganglia Frontal cortex rs8072451 5.87 4.35E-09 6.79E-04 KANSL1-AS1 BA9 Putamen rs8072451 5.88 4.21E-09 6.57E-04 basal ganglia Caudate basal rs17689471 5.88 4.04E-09 6.31E-04 ganglia Cerebellar rs17689918 6.01 1.83E-09 2.86E-04 hemisphere Hypothalamus rs8072451 6.12 9.41E-10 1.47E-04 Dorsolateral LRP4 prefrontal rs10838635 -5.59 2.31E-08 3.61E-03 cortex LRRC37A Cerebellum rs169201 5.45 5.15E-08 8.04E-03 Brain cortex rs199534 5.43 5.61E-08 8.76E-03 Cerebellum rs169201 5.66 1.49E-08 2.33E-03 Hippocampus rs169201 5.67 1.41E-08 2.20E-03 Cerebellar rs169201 5.7 1.22E-08 1.91E-03 hemisphere Frontal cortex LRRC37A2 rs199439 5.78 7.63E-09 1.19E-03 BA9 Nucleus accumbens rs199439 5.79 6.90E-09 1.08E-03 basal ganglia Putamen rs199439 5.79 6.88E-09 1.07E-03 basal ganglia bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Hypothalamus rs199439 5.81 6.14E-09 9.59E-04 Brain cortex rs17689918 -5.38 7.49E-08 1.17E-02 Caudate basal rs8072451 -5.86 4.68E-09 7.31E-04 ganglia Putamen rs8072451 -5.86 4.68E-09 7.31E-04 basal ganglia Hippocampus rs8072451 -5.86 4.56E-09 7.12E-04 Nucleus LRRC37A4P accumbens rs8072451 -5.86 4.51E-09 7.04E-04 basal ganglia Cerebellar rs8072451 -5.87 4.45E-09 6.95E-04 hemisphere Cerebellum rs17689471 -5.87 4.44E-09 6.93E-04 Frontal cortex rs17763086 -5.91 3.45E-09 5.39E-04 BA9 Hypothalamus rs8072451 -6.01 1.83E-09 2.86E-04 Cerebellar rs17763086 -5.88 4.10E-09 6.40E-04 hemisphere Frontal cortex rs17689882 -5.9 3.55E-09 5.54E-04 BA9 MAPT Dorsolateral prefrontal rs17689471 -6.24 4.40E-10 6.87E-05 cortex Brain cortex rs17689882 -6.36 2.04E-10 3.19E-05 Dorsolateral prefrontal rs2526388 5.226389 1.73E-07 2.70E-02 cortex MST1R Cerebellum rs2856236 6.563222 5.27E-11 8.23E-06 ROSMAP rs11713193 6.833558 8.28E-12 1.29E-06 brain Brain cortex rs7947730 -5.15 2.55E-07 3.98E-02 MTCH2 ROSMAP rs4752856 -5.55 2.85E-08 4.45E-03 brain ROSMAP MTMR9 rs2246606 5.44 5.39E-08 8.42E-03 brain Nucleus NICN1 accumbens rs11130186 5.260183 1.44E-07 2.25E-02 basal ganglia Brain Cortex rs11012 5.21 1.94E-07 3.03E-02 PLEKHM1 Cerebellar rs8072451 -5.9 3.63E-09 5.67E-04 hemisphere bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Cerebellum rs17689918 -6.39 1.65E-10 2.58E-05 ROSMAP rs6765484 -5.375061 7.66E-08 1.20E-02 brain Dorsolateral prefrontal rs9311446 -5.785099 7.25E-09 1.13E-03 cortex Putamen rs2240329 -5.843777 5.10E-09 7.96E-04 basal ganglia Frontal cortex rs2681780 5.852691 4.84E-09 7.56E-04 BA9 RBM6 Cerebellar rs11713193 -5.870895 4.33E-09 6.76E-04 hemisphere Nucleus accumbens rs4688755 -5.912526 3.37E-09 5.26E-04 basal ganglia Cerebellum rs6446193 -6.056184 1.39E-09 2.17E-04 Brain cortex rs6765484 -6.185421 6.19E-10 9.67E-05 Caudate basal rs2014830 -6.965004 3.28E-12 5.12E-07 ganglia Dorsolateral prefrontal rs2352974 5.465525 4.62E-08 7.21E-03 cortex Cerebellar rs7634902 5.474334 4.39E-08 6.86E-03 hemisphere Brain cortex rs7634902 5.559422 2.71E-08 4.23E-03 RNF123 Frontal cortex rs7634902 5.924265 3.14E-09 4.90E-04 BA9 ROSMAP rs2352974 6.269043 3.63E-10 5.67E-05 brain Caudate basal rs11716575 6.449052 1.13E-10 1.76E-05 ganglia Cerebellum rs11716575 7.327323 2.35E-13 3.67E-08 RP11-I65J3.6 Cerebellum rs7025805 5.16009 2.47E-07 3.86E-02 RP11- ROSMAP rs4841662 -5.51 3.63E-08 5.67E-03 481A20.11 brain RP11- Cerebellar rs896817 -6.05 1.46E-09 2.28E-04 750H9.5 hemisphere ROSMAP SEMA3F rs2247510 -5.798856 6.68E-09 1.04E-03 brain ROSMAP SLC38A3 rs1061474 -5.503226 3.73E-08 5.82E-03 brain bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Dorsolateral prefrontal rs12616678 -5.354554 8.58E-08 1.34E-02 UBXN2A cortex ROSMAP rs7588286 -5.926861 3.09E-09 4.83E-04 brain ROSMAP XKR6 rs7821914 -5.52 3.41E-08 5.33E-03 brain

Table 2. Variance explained of GWAS signals by conditioning on expression for miserableness. Lead GWAS Conditioned Tissue Before After Variance SNP on conditioning conditioning explained P-value P-value rs12612492 AC008073.7 Hippocampus 4.68E-08 0.0717 0.893 Rs9586 AMT Hypothalamus 1.57E-08 0.173 0.942 rs1850344 RP11- Putamen Basal 1.84E-08 0.0344 0.859 115H18.1 Ganglia rs4840157 RP3- Cerebellum 1.02E-07 0.0278 0.829 467N11.1 rs11764590 FTSJ2 Caudate basal 9.48E-11 1.3E-06 0.441 ganglia rs6463710 RPA3 Caudate basal 1.56E-06 0.148 0.909 ganglia rs2715147 PCLO Nucleus 5.5E-07 0.141 0.914 accumbens basal banglia rs7853605 RP11-165J3.5 Cerebellum 1.9E-07 0.499 0.983 rs11030009 DNF-AS Frontal Cortex 1.9E-06 1.000 1.000 rs11039149 LRP4 Nucleus 1.88E-13 0.00204 0.824 accumbens basal ganglia rs174549 FADS3 Cerebellar 0.00035 0.129 0.82 Hemisphere rs2013515 RP11-74E22.6 Caudate basal 1.27E-10 1.000 1.000 ganglia rs12945855 TTC19 Nucleus 6.75E-09 0.00767 0.788 accumbens basal ganglia rs8072451 RP11- Cerebellar 2.04E-12 1.000 1.000 798G7.5 Hemisphere Rs1292060 VMP1 Cerebellar 1.2E-07 0.0889 0.897 Hemisphere

Table 3. Fine-mapped genes for miserableness. bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

Region Gene Tissue TWAS Posterior Z-score probabilit y for causality 1:173097989- RP11- brain cortex -4.76 0.0074 1:175089768 160H22.5 1:7247335- H6PD brain hippocampus 1.86 0.0189 1:9365093 RERE brain cortex -4.39 0.0176

UTS2 brain cerebellar hemisphere -2.94 0.0106

H6PD brain cortex 2.62 0.00839

PARK7 brain dorsolateral prefrontal cortex 2.79 0.00442

10:106695048 RP11- brain hippocampus -5.26 0.304 - 127L20.3 10:108726491 11:44694135- C1QTNF4 brain cerebellar 0.0275 5.26 11:47003304 hemisphere

LRP4 brain dorsolateral prefrontal cortex -5.28 0.0269

HSD17B12 brain amygdala -2.55 0.0153

F2 brain cerebellum 5.14 0.0104

PRDM11 brain dorsolateral prefrontal cortex -2.91 0.01

11:47007278- MTCH2 brain caudate basal ganglia -5.68 0.127 11:49865926 FAM180B brain cerebellar hemisphere -6.23 0.0153

MTCH2 brain nucleus accumbens basal -6.18 0.573 ganglia

12:109025901 KCTD10 brain cerebellum 5.12 0.177 - 12:110336719 MMAB brain dorsolateral prefrontal cortex -4.69 0.0216

VPS29 brain cortex 2.32 0.00618

RP11- brain caudate basal ganglia -2.66 0.00387 423G4.7 KCTD10 brain cerebellar hemisphere 4.12 0.00361

15:76398987- ADAMTS7 brain caudate basal ganglia -3.74 0.0717 15:78516053 LINGO1 brain cerebellar hemisphere -2.48 0.0618

RP11- brain cerebellar hemisphere -2.18 0.0148 762H8.2 LINGO1 brain cerebellum -1.29 0.00406

CHRNA5 brain hypothalamus 2.9 0.00391

2:147277162- ORC4 brain cerebellar hemisphere 3.78 0.0822 2:150210292 LYPD6 brain cortex -3.21 0.0187

ORC4 brain hypothalamus 4.33 0.524

2:171226245- DYNC1I2 brain cerebellar hemisphere -3.21 2:173138562 0.01 SLC25A12 brain cerebellum 3.13 0.0184 DYNC1I2 brain cerebellum -2.99 0.00374 SLC25A12 brain cortex 3.39 0.0402 SLC25A12 brain nucleus accumbens basal ganglia 3.21 0.0147 2:23342019- brain cerebellar hemisphere 2:24686630 ATAD2B 5.08 0.264 brain cerebellum ATAD2B 5 0.175 brain cerebellum SUCLA2P3 -2.67 0.00204 brain dorsolateral prefrontal cortex UBXN2A -4.74 0.0559 brain substantia nigra KLHL29 3.23 0.00312 2:57429100- FANCL brain dorsolateral prefrontal cortex -4.28 0.446 2:58296890 bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

3:33255592- RP11- brain cortex -3.51 0.0575 3:35282963 10C24.1

3:47727379- brain frontal cortex ba9 3:49316164 GPX1 5.7 0.192 brain hypothalamus AMT -5.4 0.0558 brain hippocampus AMT -5.31 0.0289 brain cerebellar hemisphere PRSS45 -3.51 0.0123 brain frontal cortex ba9 AMT -5.03 0.00828 3:49317338- brain hypothalamus 3:51830565 AMT -6.18 0.108 brain cerebellar hemisphere NCKIPSD -5.55 0.047 brain dorsolateral prefrontal cortex GPX1 5.2 0.0389 brain frontal cortex ba9 GPX1 5.3 0.0353 brain frontal cortex ba9 AMT -5.35 0.033 5:87390784- CTC- brain frontal cortex ba9 -4.37 0.567 5:88891530 467M3.3 7:1353968- brain amygdala 7:2061783 FTSJ2 5.71 0.134 brain nucleus accumbens basal AC110781.3 ganglia 4.19 0.00391 brain cerebellar hemisphere TMEM184A 1.1 0.00317 brain cerebellar hemisphere GPR146 -2.83 0.00247 brain cerebellum PSMG3-AS1 -2.64 0.00199 7:2062621- 0.869 7:2772047 C7orf50 brain cortex 6 0.0634 FTSJ2 brain caudate basal ganglia 4.92 0.0358 FTSJ2 brain cortex 5.17 FTSJ2 brain cerebellar hemisphere 4.64 0.0122 bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

0.0119 INTS1 brain hypothalamus -3.59 8:1163443- RP11- brain cerebellar hemisphere -3.15 0.012 8:2042942 439C15.5

17:15020965- brain spinal cord cervical c-1 17:16411522 CENPV -5.31 0.027 CENPV brain anterior cingulate cortex ba24 -5.17 0.0161 brain cerebellum ADORA2B -4.92 0.00452 brain cortex ADORA2B -4.8 0.00289 brain dorsolateral prefrontal cortex ADORA2B -4.78 0.00281 17:1930037- RP11- 17:3701935 74E22.6 brain caudate basal ganglia 6.13 0.0504 brain nucleus accumbens basal SERPINF2 ganglia 0.0731 0.0384 brain spinal cord cervical c-1 RPA1 -3.45 0.00857 17:36809344- brain caudate basal ganglia 17:38877404 KRT23 -5.09 0.0457 brain cortex RAPGEFL1 -4.8 0.0257 brain hypothalamus MSL1 -4.66 0.0163 brain cerebellum KRT40 -4.44 0.00738 brain cerebellum MSL1 -4.4 0.0065 17:43056905- brain cerebellar hemisphere 17:45876022 FMNL1 -7.07 0.0255 brain cerebellar hemisphere PLEKHM1 -7.03 0.0253 brain nucleus accumbens basal LRRC37A4P ganglia -7.05 0.0221 brain dorsolateral prefrontal cortex MAPT -7.04 0.0212 RP11- brain caudate basal ganglia 259G18.3 7.01 0.0175 MICE brain putamen basal ganglia -5.5 0.167 bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

6:28018353- brain cerebellum 6:28917091 IFITM4P -5.35 0.104 brain cerebellum ZSCAN9 -4.57 0.1 brain hippocampus ZSCAN23 -1.49 0.0201 brain cerebellum PRSS16 -3.97 0.0102 6:28917832- brain cerebellum 6:29737971 TRIM26 -5.56 0.145 brain nucleus accumbens basal HLA-H ganglia 5.45 0.0872 brain putamen basal ganglia HLA-H 5.31 0.0444 brain putamen basal ganglia ZSCAN31 -2.64 0.0438 brain caudate basal ganglia HLA-H 5.08 0.0342 6:30798168- brain nucleus accumbens basal 6:31570931 DXO ganglia 5.18 0.175 brain hypothalamus STK19P 5.01 0.0529 brain nucleus accumbens basal HLA-L ganglia 4.88 0.0151 brain putamen basal ganglia MSH5 3.3 0.0136 brain dorsolateral prefrontal cortex DDAH2 3.32 0.00593

Multi-tissue probabilistic fine-mapping of transcriptome-wide association study identifies cis-regulated genes for miserableness

Calwing Liao*, Veikko Vuokila*, Alexandre D Laporte, Dan Spiegelman, Patrick A. Dion, Guy A. Rouleau

Supplementary

ITSN2 AC008073.7 FAM228A PFN4 TP53I3 FAM228B EFR3B SF3B6 DNAJC27−AS1 FKBP1B DNAJC27 MFSD2B ADCY3 DTNB UBXN2A CENPO MIR1301 ATAD2B PTRHD1 DNMT3A KLHL29 C2orf44 NCOA1 POMC

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23.0 23.5 24.0 24.5 25.0 25.5 26.0

chr 2 physical position (MB)

Supplementary Figure 1. Regional association plot of chromosome 2 conditioned on AC008073.7 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes. bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

GPX1 GPX1 GPX1 USP4 MIR4271 C3orf62 CACNA2D2 CCDC36 ZMYND10 IP6K2 C3orf84 RASSF1−AS1 NCKIPSD KLHDC8B RASSF1 MIR4793 CCDC71 TUSC2 CELSR3 LAMB2P1 HYAL2 MIR6824 LAMB2 RBM6 TMEM115 MIR711 QRICH1 CAMKV HYAL1 COL7A1 IMPDH2 MST1R HYAL3 UCN2 MIR191 MIR5193 IFRD2 PFKFB4 NDUFAF3 UBA7 LSMEM2 SHISA5 MIR425 BSN MON1A NAT6 TREX1 DALRD3 DAG1 TRAIP MIR6872 ATRIP WDR6 GPX1 FAM212A SEMA3B TMA7 ARIH2 GPX1 CDHR4 SEMA3B−AS1 CCDC51 ARIH2OS AMT GMPPB MIR5787 PLXNB1 SLC25A20 NICN1 IP6K1 RBM5−AS1 DOCK3 SPINK8 PRKAR2A GPX1 RNF123 GNAI2 MAPKAPK3 NME6 SLC26A6 USP19 AMT MST1 RBM6 CYB561D2 ZNF589 CELSR3−AS1 GPX1 RNF123 SLC38A3 MIR4787 CAMP MIR6823 P4HTM RHOA AMIGO3 GNAT1 HEMK1 MIR4443 TMEM89 MIR6890 BSN−AS2 RBM5 C3orf18 VPRBP CDC25A UQCRC1 QARS TCTA APEH RBM6 NPRL2 RBM15B MAP4 FBXW12 PRKAR2A−AS1 RNF123 SEMA3F CISH MANF

8 ●

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● ● ●●●●●●● ●● ●● ● ● ● ● ●●● ● ● ● ●●●● ●●●● ● ● ● ● ●● ●●●● 6 ● ● ● ● ● ● ●● ● ●●● ● ● ● ● ●●●● ● ●● ● ● ●● ●● ● ●●●●●●●●● ●●●● ● ●● ● ●● ● ●● ● ● ●● ● ●●●● ● ●●●● ● ● ●● ● ●● ● ●●● ● ● ●● ●● ●● ● ● ● ● ● ● ● ● ●●●● ● ● ●● ●● ● ● ● ● ● ●● ●●●●● ● ● ● ● ● ● 4 ●● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ●● ● ●● ● ●● ● ● ● ● ● ● ●● ●● ● ●●●●● ● ● ●●● ● ●●●●●●●● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ● − log10(P value) ● ●● ● ● ● ● ● ●●●● ●●● ● 2 ●●●● ● ● ● ● ● ● ●●●● ● ● ● ● ●●●●●● ● ●● ● ● ● ● ● ● ● ●●●●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ●●●● ●● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ●●●●●●●●● ● ● ● ●● ● ● ● ●●●● ●● ●●●● ● ●● ● ●● ●●●● ● ● ● ● ● ● ●●● ●● ● ● ●●● ● ●●●●● ●● ● ●●●●● ● ● ● ● ● ●●●●●●●●●●●●● ● ●●●● ● ● ● ● ● ● ● ●● ● ●●●●● ● ● ● ●● ● ●● ●●●● ●● ● ●●● ● ●●●● ● ● ● ● ●● ● ●● ● ●● ●● ●● ● ●● ●●●●● ●●● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ●●●●● ● ● ● ● ●●●●●● ● ● ● ●● ● ● ● ● ● ● ●● ●●●●● ● ● ●●● ● ●● ● ●●● ● ●● ●● ●●● ● ● ● ● ● ● ● ● ● ●● ● ●●●●●●●●● ●● ●●● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ●●● ● ● ● ● ●●●●● ●● ●●●●●●●●●●●●●●●●●●●●●● ● ●●●●●●● ● ● ● ● ● ● ●● ●● ● ●●●● ● ● ● ● ● ● ●● ● ●●●●●●●●● ● ● ● ●● ●● ●● ●●● ● ●●●●● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ●● ●●● ● ●●● ● ● ● ●●● ● ●●● ● ●●●● ●●●●● ● ● ●● ● ● ●● ● ● ● ● ● ●● ●● ● ●●● ●●●●●● ● ● ● ● ● ● ● ● ● ●●●●●●●●●● ●●● ● ●●● ●●●●●● ●● ● ● ● ●● ●●● ● ● ●●● ●●●●●●●●●●●●● ● ● ●●●●●●● ● ●● ●●●●●●●● ●●● ● ● ● ●● ● ● ●●●●●● ●● ●●●● ●●●● ● ●●●●● ●● ●●●●● ● ●● ● ● ● ● ● ●●●●● ● ● ●●●● ●●● ●● ●●● ●●● ● ●●●● ●● ●● ● ● ● ● ●●●●●●●● ● ●● ●● ● ●● ●●● ●●●● ●●● ●●● ●● ● ● ● ● ● ● ● ● ●●● ●●● ●●●●●● ● ●● ●● ●●●●● ● ●●●●● ●●● ● ● ●● ●●● ● ● ● ●● ●● ● ●●●●●● ● ● ●●●●●● ● ●●● ●●●●●●● ●●● ●●●●●●●● ●● ●●●●●●●● ● ●● ●●●●● ● ● ● ●●●● ●●●●●● ●●● ● ● ● ● ● ●● ● ●●●●●●●●● ● ●●●● ●●●● ● ●● ● ●●●●● ●● ●●●●●● ● ●● ●● ● ●●●●● ●● ● ●●●● ●● ●● ● ● ●● ●●● ● ● ●● ●●●●●●●●● ● ● ●●●●●●●●●● ●● ●●●●●●●●●●●●●●●●●●●●●●● ● ● ● ● ● ●●● ●●●●●●●●●●●●●● ●●●●●●●●●●●● ●●● ●●●●●● 0 ● ●●●● ●●●●●●●●●●●● ●●● ● ●●●●●●●●●●● ●● ●●●●●●●●●●●●● ●●●●● ●●●●● ●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●● ●● ●● ●●●●● ● ● ● ● ● ● ● ● ●●●●●●●●● ● ●●●●● ● ● ●●● ●●●●●● ●●● ●●●●●● ●● ●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●

48.0 48.5 49.0 49.5 50.0 50.5 51.0 51.5

chr 3 physical position (MB)

Supplementary Figure 2. Regional association plot of chromosome 3 conditioned on AMT expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

BBX HHLA2 LOC101929607 IFT57 GUCA1C CCDC54 LINC01215 RETNLB RP11−115H18.1 CD47 DZIP3 LINC00883 LINC00636 KIAA1524 LINC00882 LINC00635 MYH15 TRAT1

8 ● ●

● ●

● 6 ●

●

● ● ● 4 ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ●●● ●●●●● ● ●● ● ● ●● ●● ●● ● ● ●●● ●● ● ● ● ● ● ● ●● ● ● ●●● ●●● ● ● ●● ●● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ●● 2 ● ● ● ● ● ● ● ●● ● ● − log10(P value) ● ● ● ●●● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ●●●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ●● ●● ● ●● ● ●● ● ● ● ● ●●● ●● ●● ● ●● ● ● ●● ● ● ●●●●●●●● ● ● ● ●●● ● ●● ● ● ●● ●● ● ● ● ● ●● ● ●●●●● ● ●●●●● ●● ●● ● ● ● ● ● ● ● ● ● ●●●● ● ● ● ● ● ● ● ●●●● ● ● ●● ●●●● ● ● ●●●● ● ● ●● ●● ● ● ●● ● ● ●●● ● ● ● ● ● ●● ●●● ● ● ● ● ● ● ●●●● ● ● ● ● ●● ● ●●●● ●● ● ●● ● ●● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ●●● ● ● ● ●● ●●●●●● ● ● ● ● ●● ● ● ● ●●● ● ● ●● ●●●● ●● ● ● ●● ● ● ●● ● ● ● ● ● ●●● ● ● ● ● ●● ●●●● ● ●●● ● ●● ●●●● ● ● ● ● ● ●● ●●●● ● ●● ●●● ● ●●●●●●●●●●● ● ● ●● ● ●● ●●●● ● ●●●● ●● ●●● ● ● ● ● ● ● ●●● ● ●●● ●●● ●● ● ● ●● ●●● ● ● ● ●● ● ● ● ●●● ●● ● ●●● ● ● ●●● ●●● ● ● ● ● ● ● ●●● ●● ● ●● ●● ● ● ●● ● ● ● ● ●● ●●●● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ●●●● ● ● ●● ● ●●●● ●● ● ●●● ●● ●● ● ●●●● ● ●●●●●●● ● ●●●● ● ● ●● ● ●●●●●● ●●●● ● ●● ● ●● ●● ● ● ● ● ● ●● ● ● ● ●● ●● ● ●●● ●●● ● ●●●●●●● ●● ● ●● ●● ● ●● ● ● ●● ●●●● ●● ● ● ● ● ● ●● ●●●●●●●●● ● ●●●●● ● ●● ● ●●●●●● ● ●●● ●●● ● ● ● ●●● ● ● ● ● ● ● ● ●● ●● ●●●● ● ● ●●●●●● ●●● ●●●●●●●● ●● ● ●● ●● ●●● ●●●●● ●●● ●● ●●● ● ●● ●●● ● ●●●●●●●● ● ● ● ●●●●●● ● ●●● ●●●●● ●●● ●●● ● ●● ● ●●●●● ●●● ●● ●● ●●● ●●● ●●●●●● ● ● ●● ● ●●● ●●●● ●●● ●● ●●●●● ●● ●●● ●●● ● ● ●● ●●●●●●● ● ● ●● ● ●●● ●● ●● ● ●●● ● ●●● ● ●●●● ● ● ●● ● ●● ●● ●●● ●●● ● ● ● ●●●● ●● ● ●● ●●● ● ● ●●● ●● ● ●●●● ●●●● ●● ●●● ● ● ● ●● ● ● ● ●● ● ●●● ●●●● ● ●●● ● ● ● ● ●●●●●● ● ● ●●●● ● ● ● ●● ●●●● ●●● ●●●●●●●●● ●●● ●● ●●●● ● ● ●●●● ● ●● ●●●●●●● ● ●●●● ●●●●●●●● ●●● ●●●●●●● ●●●● ●●●● ●●● ●● ● ●●●●● ● ● ● ● ● ● ●●● ● ●● ●●●● ● ●●●●●●●● ●● ● ●● ●●● ●●● ● ●●●● ●● ●●●●● ● ● ● ●●●● ●●●● ● ●●●●● ●●●●● ●●●● ●● ● ●●●●● ●●●● ●●●●●● ● ● ●●●●●●●●●●●●●● ● ● ● ●● ●● ●●●●●●●●●●●●● ●●● ●●●●●●●● ●●●●● ● ●●●● ●●●●●●●● ●●● ● ●●● ●●●● ●● ● ●●●●● ● ● ●●●●●●● ●●●● ● ● ●● ●●●●●●● ●● ● ● ● ●●●●●●● ● ● ●●●●●●● ●●●●●●●● ● ● ●●●● ● ● ●●●●●● ● ●●● ● ● ●●●●● ● ● ●● ●●●●●●● ●●● ● ● ●● ● ●●●●●●●●●● 0 ●●●●●●● ●●●● ● ● ●● ●●● ●● ●●●●●●●●●● ●●●●●●●●● ●● ●●● ● ●●●●●●● ●●● ●●●●●●●●● ● ● ●●●●● ● ● ●● ●● ●●●● ●●● ● ●●●● ●●●●● ● ● ● ● ● ● ● ●●● ● ● ●●● ● ●●●●●●●● ● ●●● ●●●● ● ● ●● ●●● ●● ● ●●●●●●●● ● ● ●● ● ●●●● ●● ●●●● ●● ● ●●● ● ●● ● ●●●●●

106.0 106.5 107.0 107.5 108.0 108.5

chr 3 physical position (MB)

Supplementary Figure 3. Regional association plot of chromosome 3 conditioned on RP11- 115H18.1 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

PRDM13 CCNC TSTD3 RP3−467N11.1 USP45 ASCC3 PNISR MCHR2−AS1 COQ3 MCHR2 SIM1 GRIK2

● 7 ●● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ●● 6 ● ●● ● ● ● ● ●● ● ● ●● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● 5 ● ● ● ● ●● ●● ● ● ● ● ● ●●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 4 ● ●● ● ● ● ●● ● ●● ● ● ● ● ●● ● ● ●● ● ● ● ● ●● ●● ●● ● ● ●●●● ● ●● ●●●●● ● ● ● ● ● ● ● ● ●● ●● 3 ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ●● ● ● ● ● ● ●● ●●●● ●● ● ●● ●● ● ● ●● ● ● ● ● ● ●● ●● ● ● ● ●● ● ● ● 2 ● ● ● ●●● ● ●● ● ● ●● ● ● ● ●● ●● ● ● ●● ● ●● ●● ● ● ● ● ● ● ●● ● ● ● ● ●● ●● ● ●● ● ● ● ●●●● ● ● ● ●● ● ● ● ● ●● ● ●● ● ● ●●● ● ● ●● ●●● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ●●● ●● ● ● ●●● ● ●●● ●● ● ●●●● ●● ● ● ● ●● ● ● ● ● ● ● ●● ● ● − log10(P value) ● ● ● ●●● ● ● ● ● ● ● ● ● ●●● ● ● ● ●● ● ● ● ● ●● ● ● ●●●● ● ● ● ●● ● ● ● ● ●● ●●● ● ●●●● ● ● ● ● ●●●● ● ●● ● ● ● ●●● ● ● ● ● ●● ● ● ● ●● ● ● ● ●● ● ● ●● ●● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ●● ●● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●● ● ●●● ● ●●●● ●● ● ● ●●● ● ● ● ●● ●●●●●● ●●●● ● ● ● ● ● ● ●● ● ●●●●●●● ●●● ●● ● ●● ● ● ● ● ● ●● ● ● ●●● ● ● ● ● ● ● ● ● ●●●●● ●● ● ● ● ● ●●●●●●●●● ●● ●● ● ●●●●●●● ● ● ● ● ● ● ● ●● ● ● ● 1 ●●● ●● ● ●●● ● ●● ● ● ● ● ● ● ● ● ●●●●●● ● ● ●● ●● ● ●● ● ● ● ● ● ● ●● ● ● ● ●●● ● ●● ● ●●● ● ●● ● ● ●●●●● ● ●●● ● ●●● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ●●●● ● ● ●●● ● ●●●● ● ●●● ●● ● ●● ● ●● ●●●●● ● ●● ● ●● ● ● ● ● ● ● ● ●●●● ● ●●●●●●● ●●●●● ●●●● ●● ●● ●●● ● ●● ● ● ● ● ●● ●●● ● ● ● ●●● ● ●●●●● ● ● ● ●●● ● ● ●● ● ● ●●● ●●●●●●●●●●●●●●● ●●●● ● ●●●● ●●● ●● ● ● ●● ● ●●● ● ● ● ● ● ●● ● ●●●●● ●●● ●● ● ●●●● ●●●●●●●●●●●● ●●●●●●●●● ●●●●● ●●●● ●● ●● ● ●● ● ● ●●●●● ● ● ●●●●●●●●● ● ●● ● ●● ● ●● ●● ● ● ● ●● ●●●● ● ● ● ●● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●●● ●●●●●●● ● ●●● ● ●● ●●●● ●● ● ● ● ●● ●● ● ●● ●●● ●●●●●●● ●●●● ● ●●●● ●● ●● ● ● ●●●●● ●●● ● ●● ●● ●● ● ● ●●● ● ● ● ●● ● ●●● ●● ●● ● ● ● ●● ●●●●●● ●●● ● ●●● ● ● ● ●● ● ● ●●●●●●●●●●●● ●● ● ● ● ●●●●●● ●●● ●● ● ●●●● ● ● ●●●●● ●● ● ●●●●●● ●●●●●●●●● ●● ● ●●● ● ● ●●●●●●●●●●●● ●●●●● ● ● ● ●● ●●●● ●● ● ●● ●●●●●●●●● ● ● ● ●● ● ● ● ●● ● ● ●●● ● ● ●● ●● ● ● ● ● ● ●●● ●●● ●● ● ●●● ● ●● ●●●●● ● ● ● ● ● ●● ●●● ● ● ●●●● ● ● ●●●● ●● ●● ● ●●●● ● ● ●●● ● ●●●● ●●●●●●● ● ●●●●●●●●● ●●●●●●●● ●● ●●●●●● ●●● ● ●●●● ●●●●● ● ●● ●● ●●● ● ● ● ● ●● ● ● ● ●●●● ● ●● ●● ● ●●● ● ● ● ●●● ●●● ●●●● ●●●●●● ● ●●●●●●●●●● ●●● ● ●●●●●● ● ● ●●●●●●●●● ●● ●●●●● ● ● ● ●●●●●● ●●●● ● ● ●●●● 0 ● ●● ● ●● ● ● ● ●●●●●● ● ● ● ●●●● ●●●● ●●● ● ●●●●●●● ●● ●●● ● ● ● ●● ●● ● ●●● ● ● ● ● ●● ● ●● ● ●●●●● ●●● ● ● ● ● ●● ● ●● ●● ● ●●●●●●●●●● ●●●●● ●● ● ●●●●●●●●● ● ●●●● ●● ● ●●●●●●● ●●●● ● ● ●● ●● ● ●●●● ● ●

100.0 100.5 101.0 101.5 102.0 102.5

chr 6 physical position (MB)

Supplementary Figure 4. Regional association plot of chromosome 6 conditioned on RP3- 467N11.1 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes. bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

GPER1 GRIFIN GPR146 ELFN1 LOC101927181 MIR339 TFAMP1 CHST12 C7orf50 PSMG3−AS1 EIF3B GNA12 CYP2W1 TMEM184A MIR6836 AMZ1 COX19 INTS1 SNX8 IQCE ADAP1 MICALL2 NUDT1 BRAT1 GET4 UNCX MAFK MIR4655 FTSJ2 MIR4648 SUN1LOC101927021 MAD1L1 TTYH3 SDK1 HEATR2 ZFAND2A PSMG3 FTSJ2 LFNG CARD11

● 10 ● ● ●

● ● ● ● ●

● 8 ●

● ●

● ● ● ●● ● ● ● ● ● 6 ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● 4 ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ●● ● ● ●●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●● ● ● − log10(P value) ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ●● ●● ● ●● ●● ●●●● ● ●● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ●● ● ●●●● ● ● ● ● ●● ●●●● ● ● ● ● ●● ● ● ● ● ●● ●● ●● ● ● ●●● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ●●●● ● ● ● ● ●● ●● ● ●●●● ● ● ● ● ●● ●●●● ●● ● ●● ● ●● ●● ●●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●●● ●● ●●● ● ●● ● ● ●● ● ●● ● ●● ● 2 ●●● ●● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●●●● ● ● ● ● ● ● ● ● ●●●● ● ● ●●● ● ● ● ● ● ●●● ● ● ● ●● ●● ● ● ● ●● ●● ●● ● ●● ● ●●●● ● ●●●● ● ● ●● ● ● ● ● ● ● ●● ●●● ●● ● ●●● ●● ● ● ● ● ● ● ● ●● ●● ●●● ●●● ● ● ● ● ●● ● ●● ● ● ● ● ● ●●● ● ●● ●● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●●●●●● ●●●●●●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ●● ●●●● ● ● ● ● ● ● ● ● ● ● ●● ● ●●● ● ●● ●● ●● ● ●● ● ●●●●●● ● ● ● ●● ● ● ● ● ●●● ● ● ●●●● ● ●● ● ● ● ●● ● ● ● ●●● ● ●●● ●●● ● ● ●●● ● ● ●● ●● ● ● ● ●● ● ● ● ● ●● ● ● ● ●●●● ● ●●●● ● ● ● ● ●●● ● ● ● ●● ● ●● ● ● ●● ●●● ● ● ● ●●●● ●●● ●●●● ● ● ● ● ● ●●●● ● ● ● ●● ● ●●●●● ● ● ● ● ● ● ● ●●● ●●●●●●●● ● ● ●●● ● ● ● ●●●● ● ●●● ● ● ● ● ●●●● ●● ●●● ●● ● ● ● ●●●●●● ●● ●●● ●● ●● ● ● ● ● ● ● ● ●●● ●● ● ● ●●● ●● ●● ● ● ●●●● ● ● ● ● ● ●● ● ●●●●●●● ● ● ●● ● ● ●● ●● ● ●●●●●● ●● ●●● ● ● ●●● ● ●●● ● ● ●● ● ●● ●●●●●● ● ● ● ● ● ● ● ● ● ●● ● ●●●●●●● ● ●● ●●●● ● ●● ●●● ●● ● ● ●●● ●● ● ●● ● ● ● ● ●●●●● ●● ●● ● ●● ●●●● ●● ●●● ●●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●●●● ● ● ● ●● ●● ● ●● ●● ●● ● ●● ●● ● ●● ● ●●●●● ●●●● ● ● ● ●● ●●● ● ●●●●● ●●●● ● ●● ● ● ● ● ●●● ●● ●● ●● ● ●●● ● ● ● ● ● ● ● ● ●● ●●● ● ●●● ● ● ● ● ●●●●●●● ● ● ● ●●●● ● ● ●● ● ●●● ●● ●●● ● ● ● ●● ● ● ● ●● ●●●●●● ●● ● ●● ● ●●●● ●● ● ●●●●●●● ● ●● ●●●●●●● ● ●●● ●●● ● ● ● ● ●● ● ●● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●●● ● ● ●● ● ●● ● ●●●●●● ●● ●●●● ● ● ● ●●●● ●●●● ●●● ●● ●● ● ●●● ●●●●●●● ●● ● ● ● ●●●● ●●●● ● ● ●● ●●●●● ● ●●● ●● ● ● ● ● ●● ● ● ●●●● ● ● ●● ●●●●●● ● ● ●● ●●●●● ● ●●● ●●● ●●●●●● ● ● ● ●● ● ● ●●●●● ● ● ● ●●●●● ●● ● ●● ● ●●●●●● ● ●●●●●● ●●●●●●●●●●●● ●●●●●●●●●●●●● ●●●●● ● ●● ●●● ●● ● ● ●● ●● ●●●● ●● ● ● ● ● ● ● ● ●●● ●●●●● ● ●● ● ●● ●●●●●●● ●● ● ● ● ● ●● ● ● ●●●●●●● ●● ●●●●● ● ●● ●●●●● ●●● ●●● ● ● ● ●● ●●●●●●●●●●●●●●● ● ●● ●● ●●● ● ● ●● ●●●●●● ●●●●●●●●●●●●●●●●●●●● ● ●●●●●●●●● ● ● ●●● ●● ●● ●●● ● ●● ● ●●●●● ●●●●●●●●● ● ● ●● ●●● ●●● ● ●●● ● ●●● ● ● ●●●●●● ●●●●●●●● ●● ● ●● ● ● ● ●● ● ● ●●● ● ● ● ● ● ● ●●●●●● ●●●● ●● ●●● ●●● ●●● ●● ●●●●●●●● ● ● ●● ● ●● ●● ● ●● ●●●●●● ●●●●●●●●●●●●●●●●● ●●●●● ●●●●● ● ● ●●●●●●●● ● ● ●●●● ● ● ●● ●● ●●● 0 ●● ●●●●●●●● ● ● ● ● ●●●●● ● ●● ● ● ●●●●●●●●●●●●●● ● ●●● ● ●●●● ●●●●● ●●●● ●●●●● ● ●● ● ● ●●●●●●● ● ●●●●●●●●●● ● ● ● ●●●● ●●●● ● ●●●●●●● ●●●● ● ●●● ● ● ●●●●●●●●●● ● ●●●●● ●●●●●●●●●●● ●●●●● ●●●● ●●● ●●● ●● ●● ●● ●●●● ● ●●● ● ● ●

1.0 1.5 2.0 2.5 3.0 3.5

chr 7 physical position (MB)

Supplementary Figure 5. Regional association plot of chromosome 7 conditioned on FTSJ2 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

CCZ1B RSPH10B2 ZNF12 ZNF853 C7orf26 RPA3OS GRID2IP MIOS KDELR2 LOC101927391 DAGLB RSPH10B COL28A1 RAC1 ZNF316 LOC101927354 ICA1 FAM220A PMS2CL C1GALT1 RPA3 GLCCI1 NXPH1 CYTH3 ZDHHC4 LOC100131257 LOC100505921

6 ●

● ●

5 ● ●● ● ● ● ● ● ● ● ●● ●● ● ●●●● ● ● ●●● ● ● ● ● ● ● ● ●● ● ● ● ● 4 ●● ● ●● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● 3 ● ●● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ●● ●● ● ● ●●●● ● ●● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ●●● ● ● ● ●● ● ● ●●● ● 2 ● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ●● ● ● ●●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● − log10(P value) ● ● ● ● ● ● ● ●●● ● ● ● ● ●●● ● ● ●● ●● ● ● ● ● ● ● ● ●●●● ● ●● ● ● ●●●●● ● ● ● ● ● ●● ● ●●● ● ● ● ● ●● ● ●●● ● ●● ●● ● ● ●● ● ● ●●● ● ●●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●●● ● ● ● ●●● ●●● ●● ● ●● ● ● ● ●● ● ●● ●● ● ●●● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ●● ●●●●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●●●● ● ● ●● ●● ● ●● ● ●●● ● ● ● ● ● ● ● ● ●● ● ●●● ● ● ●● ● ● ●●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ●●● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ●●●●●●● ●● ●● ●● ● ●●● ● ●●●●● ● ● ●● ● ●● ●●● ● ● ● ●● ● ● ● ● ● ●●●● 1 ● ● ● ●● ● ●● ● ● ●●● ●● ● ● ● ● ●●● ● ●●● ● ●●● ● ● ●●● ● ●● ● ● ● ● ● ●●● ●● ●● ● ● ● ●● ● ● ●●●● ● ●●●● ● ●●●●●● ●● ● ● ● ● ●●●● ● ● ● ●● ● ● ● ● ●●●●●●● ● ●● ●● ● ● ●● ● ●● ● ● ●● ● ● ● ●●● ●● ● ● ● ●●●● ●● ●● ● ●●●●● ●● ● ● ●●●●●● ● ● ● ● ●● ●● ● ●● ●●●● ●● ● ●●● ●● ● ● ● ●●● ●● ● ● ●●●●● ●● ● ● ● ●● ●●●●●● ●● ●●●● ● ●●●● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ●● ●● ● ●●●● ●● ● ●● ●● ● ● ● ●●● ●●●●●● ●● ● ● ● ●●●● ●● ●●● ● ● ●● ●●●●● ●● ● ●● ●● ●● ● ● ● ● ●● ● ● ●●● ●● ● ●● ● ●● ● ● ● ●● ● ● ●●● ●●●●●●●●● ● ●●●● ●● ● ●● ●●● ●● ●● ● ●● ●●●● ●● ● ● ● ●●●● ● ●●● ●● ● ●●● ●●● ●● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ●●● ● ●●●●● ● ● ● ● ●● ● ● ● ● ●●●●● ●● ●●●● ● ● ● ●●● ● ●● ●●●●●●●● ● ● ● ●● ●●● ● ● ● ● ●● ●● ● ● ● ●●● ●●● ●● ● ●●●●● ● ●● ● ●●● ●●● ● ●● ● ●●●● ●● ● ●●●●●●●● ● ● ● ●●●●●● ●● ● ●●●●● ●●● ●● ●●● ●● ● ●● ●●● ●● ● ●●●● ● ●● ● ● ● ● ● ●●●●●● ● ●● ● ●● ● ● ●●● ● ●●●●●●● ● ●●●●●●● ● ●●● ● ● ● ● ● ● ●● ● ● ● ●● ●●● ●●●● ● ●●●●●● ●●●●●●● ●●● ● ● ●● ●● ●●● ● ●●●●● ● ●●●●●● ●●●●●●●●●● ● ● ●● ●●●●●●● ●● ● ● ● ●● ●●● ●● ●● ● ● ●●●● ●●●● ●●● ● ● ●●● ● ●●●●●●●● ●●●●● ●● ●●●●● ●●●●●●●● ● ●●●● ● ● ●● ● ●● ● ● ● ●● ●● ● ●● ● ● ● ●●● ●●●● ●●● ●●●●●● ● ●●●●● ● ●●●● ●●●●● ● ● ●● ●●●●●●●● ●● ●●●● ●●●●●●● ●●●● ● ● ● ●●●● ●●●● ● ●● ●● ●● ●● ● ● ● ●●●●●●●● ●●●●● ● ●●●●●●●●●● ● ●●● ●● ● ●●● ●● ●● ●●●●●●●●●● ● ●●●●●●●●●●●●●● ● ●●●●● ●●●● ●● ● ● ● ●● ● ●●●●●●● ●●● ● ●●● ● ● ● ● ● ●●●●●●● ● ● ● ● ● ●●●●●●●● ● ● ● ● ● ● ● ●●●●●●●● ●●● ● ●●● ●●●●●● ●● ●●●●●●●●● ●●●●●● ●●●● ●●●●●● ●●● ●●● ● ●●●●●●● ● ●●●● ●●● ● ● ●●●●●●●●●●●●●●●●●●● ● ●● ●●●● ● ●● ●●● ● ●●●●● ● ●●●●●●● ●●●●●●●●● ● ●●●●● ● ●●●●●●● ●●●●●●●●●●●● ●● ● ● ●●●●●●● ● ● ● ● ●● ●●●●●● ●●●●●●●●● ●●●●● ●●●● ●●●●●●●●● ● ●●●●●●● ●●●●● ● ●●●●●● ● ● ●● ●●●● ●●●●●●●● ●●●●●●●●●● ●●●●●●●●●●●●●● ●●●●●● ●●● ●● ●● ●●●● ● ●●● ●● ●●●●●●●●●●● ● ●●●●●●●●●● ● ●●●●●●●●●● ●●●●●●●● ●●●●●● ●●●●●● ●●●●●●●● ●●●●●●●● ●●●●●●● ● ●●●● ●●●●●●● ●● ● ●●●● ●● ●●● ●●● ●●● ● ●● ●●●●●●●● ●●●●●●●●●●● ● ●●●● ●●● ●●● ●●● ●●●●●● ●●● ● ● ● ● ●●●● ● ● ●●●●●●● ●●●●●●●●●●● ●● ●●●●● ●●●●●●●●● ●●●● ●●●●●●●●● ●●●●● ●●●● ● ● ● ●●●●● ●●●●●●●●●● ● ●●●●●● ●●●●● ●●● ●●●●●● ●● ●●●●● ●●●● ●●●●●●●●●●●●● ●●●●● ●●● ●●●● 0 ● ●●●●●● ●● ● ●●● ●●●● ●● ●● ●● ● ●● ●●● ●● ●● ● ●●●●●●●●●●●●●●●●●●● ● ●● ● ●●●●● ● ●●●● ●●●●●●●●●●●●● ●●●●● ●● ●●●● ● ●●●●●●●●● ●●●●●●●●● ● ●●● ●●● ●●●●●●●●●●● ●●● ●●●●● ● ●●●●● ● ●●●●● ● ● ●●●● ●●●●●●●●●●●● ●● ●● ●● ●●●● ●●●●●●●●●●●● ●●●●●● ●●●● ●● ●●●●●● ●●●●●●●●●● ●●

6.5 7.0 7.5 8.0 8.5 9.0

chr 7 physical position (MB)

Supplementary Figure 6. Regional association plot of chromosome 7 conditioned on RPA3 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

SEMA3A CACNA2D1 SEMA3E HGFLOC101927356 PCLO MIR7976 LOC101927378

● 6 ● ● ● ●● ● ● ●

●● ● 5 ● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ● 4 ● ● ●● ●● ●● ●● ● ● ● ● ● ● ● 3 ● ● ● ●● ● ●● ●● ●● ●● ● ●● ● ● ● ●● ●● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ●● ● ● ●● ● ● ● ● ● 2 ● ● ● ●●●● ● ● ● ● ● ●●● ● ●● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ● ●● ● ● ● ●● ● ●● ●● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●●●● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ●●●● ●● ● ● ● ● ●●● ● ● ● ● ● ●● ●●● ●● ●● ●● ● ● ● ●● ● ● ● ●●●● ● ● ● ● ●●● ● − log10(P value) ● ● ● ● ● ● ●●● ●● ● ●● ●● ● ●●●● ● ● ● ●●●●●● ● ●●● ● ● ● ● ●● ●● ● ●● ● ● ● ●●● ● ● ● ● ● ● ● ● ●● ●●●● ● ● ● ● ● ●●● ●● ●●● ●● ● ●● ● ● ●● ● ●● ● ● ● ● ●● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ●● ●● ● ●●●● 1 ● ● ● ● ● ●● ●●●● ●● ●●●●●●● ● ●● ● ● ●●●●●●●● ●●● ● ● ● ● ● ●● ●● ● ●● ● ●●● ● ● ●● ●● ● ● ● ●●●● ● ●● ● ●● ●●●●● ● ●●● ●● ● ● ●● ●●●●● ●● ●● ● ● ●●●●●● ● ●●●● ●●● ●●●●●● ● ● ● ● ● ● ●● ● ● ●● ●● ●● ● ● ●● ● ● ● ● ●●●● ●●● ● ●● ●● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ●●● ●●● ●●●●●● ●●●●●● ●● ●●●●● ● ● ●●●●● ● ●●● ● ● ●●●● ● ●●● ● ●● ●●● ● ●●●● ● ● ●● ● ●● ● ● ●●● ●●● ●● ●●●●● ● ● ●● ●● ●●●●●●● ●● ●● ● ●●●● ● ●● ●● ●●● ● ● ● ●●● ● ●● ● ●● ●●● ●●●●● ●● ●● ● ● ●● ● ● ● ●● ●● ●●● ● ● ●●●●● ●● ● ● ● ●● ●●● ●● ●● ● ●●●● ● ●●●●●●●● ●●●● ● ●● ●● ●● ● ● ● ●●● ● ● ● ● ●●●●●●● ● ● ● ●● ● ● ● ● ●●● ● ●●●●● ●●● ●●●●●●●●●● ●●● ●● ●● ●●●● ●●●●● ●● ● ●●●●●● ●● ●● ●● ● ●●●●●● ●●●●● ●●●● ●● ●●● ● ● ● ●●● ● ●●● ●● ●● ●●●●●● ●● ●●●●●● ●● ●●●●●●●●● ● ● ●●●● ●●●● ●● ● ● ●●● ●●●● ● ● ●● ● ●●●● ● ● ●●● ● ● ● ● ● ●● ● ●●● ●●●●● ●● ● ●●●●●●●●● ●●●● ●●●●●●●● ●●● ●●●●● ●●● ● ● ●● ●●● ● ● ●●●●●●●●● ● ● ●● ● ● ● ● ●● ●●● ● ● ●●● ●● ●● ●●●●●●● ● ●● ●●●● ●● ●● ●●●●●● ● ●●●●●●●●●●● ● ●●● ●●●● ● ● ●● ● ● ●●●● ●● ● ● ●●●●●● ●● ●● ● ●● ●● ● ●●●● ● ●●● ● ●●● ● ●● ●●●●●●●●●●●●●● ●●●●●●● ●●●●●●● ●●●●●●●●●●●●●●● ●● ●●● ●●● ● ●● ● ● ●●●● ●●●●●●●●●●● ● ●● ●●●●●●●●● ●●●●●●● ●●●● ● ● ●●● ●● ● ●● ●●●●●●●●●●● ●●●●●●● ● ●● ●● ●●●●● ●●●●●● ●●●●●●●●●●●● ● ● ●●● ● ●●● ●●●●●●●● ● ● ●●●●●●●●●● ● ●●●●●●● ●●● ● ●●●●● ● ●●●●●●● ● ●●●●●●● ●●●● ●●● ●● ●● ● ●●●●● ●●●●●●●●● ● ●● ●● ●● ●●●●●●●●●●●●●●● ●●●● ●●●●● ●●●●● ●●●●●●●●● ●●●●●●●●●●●●●●●● ●●● ●●● ●● ● ●●●● ● ● ●● ● ●●●●●● ●● ● ●●●●● ● ●●●●●●●●●●●●● ● ● ●●● ●●●●●●●●● ●●●● ●●●● ●●●●●●●●●● ●●●●●● ●● ● ●● ●● ●● ● ● ●●●● ●●●● ●●●●● ● ●●● ●●● ●●●● ●●● 0 ●●●● ●●●●●●● ●●● ● ●●●● ●● ●●●●●●●●●●●●●● ●● ● ●●●●●●● ●●●●●●●●●●● ●●●●●●●●● ●●●●● ●● ●●●●●●●●● ●●● ●● ● ●● ● ●●●●● ● ● ●●●● ●● ● ●● ●●●●● ●●●● ● ●●●●●●●●●●●●●●●● ●●●●● ● ● ●●●●●●●●● ● ●● ● ● ●●●●● ●●● ● ● ● ●●●●●●●●●●● ●●●●●●●●●● ●●● ●●● ● ● ● ●●●●●●● ●● ●● ● ● ●● ●●● ●● ●● ●●●●●● ● ● ●

81.5 82.0 82.5 83.0 83.5 84.0

chr 7 physical position (MB)

Supplementary Figure 7. Regional association plot of chromosome 7 conditioned on PCLO expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

MIR4670 OMD OGN WNK2 HIATL1 CENPP NINJ1 LOC100132077 NOL8LOC100128361 NUTM2F SNORA84 C9orf89 MIRLET7D FBP1 MIR3651 BICD2 SUSD3 PHF2 MIRLET7DHG LINC00475 IPPK FGD3 FAM120A MIRLET7F1 LOC100128076 LOC642943 FAM120AOS BARX1 ZNF169 SPTLC1 ASPN ZNF484 RP11−165J3.5 PTPDC1 FBP2 MIR2278 ROR2 IARS ECM2 ANKRD19P C9orf129 MIR4291 MIRLET7A1 C9orf3

●● ● ● ● ● 6

5 ●● ● 4

● ● ● ● 3 ● ● ● ● ● ● ● ● ● ●●● ● ● ●● ● ● ● ●●●● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●●●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ●● ●● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●●● ●● ●●● ● ● ● ● ● ● ● ● ●●● ● ●●●●●●● ●●● ●● ● ● ● ● ● ●● 2 ● ● ● ● ● ● ●● ● − log10(P value) ● ● ● ● ● ● ● ●● ●● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●●● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ●●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ●● ● ● ● ● ● ●● ●●● ● ● ●● ● ●● ●● ● ● ●●●●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ●● ● ● ●● ●● ● ● ● ● ● ●●●●● ● ●● ●●● ● ● ●● ●● ●●●●● ● ●●● ● ● ● ●●● ●●●●● ●● ● ●● ●● ● ● ●●● ●● ● ● ● ●● ●● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ●●● ● ● ● ● ● ● ● ● ● ● ●● ●●●●●●● ●●●●●●●● ●● ● ● ● ● ●● ● ● ● ● ● ● ●● ●● ● ● ●●● ● ● ●● ● ●● ●●●●●●●●●●●●● ●●●●●●●●●●●●●● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ●● ● ●●●●● ●●● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ●● ●● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ●●● ●● ● ●● ● ● ● ●● ● ●●● ●●● ●●●●● ● ●●●● ● ●● ● 1 ● ● ● ●●● ●●●● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ●●● ● ●●●● ●● ● ●●●●● ● ● ●●● ● ● ●●● ●●●● ●● ● ● ● ●●●●●● ● ●● ●●●● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ●● ● ● ● ● ● ●● ●● ● ● ● ●●● ● ● ● ●●● ● ● ● ● ●●●● ● ● ● ●● ●●● ●● ●● ●●●●● ● ● ● ● ● ● ●● ● ●● ●● ● ●●●● ●● ● ●● ● ● ● ● ●● ● ●●●●● ●● ●● ●●●● ●● ●●● ● ● ● ●●●●● ● ● ●●● ●●●●● ● ●● ● ●● ● ● ●● ●● ●● ● ● ● ●●●●●●●● ●●● ●● ●● ● ● ● ● ● ● ●● ●●● ● ● ● ● ● ● ● ● ● ●●●● ● ● ●●●● ● ● ● ●●●● ●● ● ● ● ●●●● ●● ●●●● ●●●● ● ● ●●● ●●● ●●● ● ● ●●● ●●● ● ●● ● ● ●●●●●● ●● ●●●● ●●● ● ●●● ● ●● ●●● ●●● ● ● ●●●● ●●● ● ●●●●●●● ● ● ● ●●●●● ●●● ●● ● ● ● ● ● ●● ● ● ●●●●●●●●●●●●●● ● ● ●●● ● ● ●● ● ●●● ● ● ●● ● ● ●●●●● ● ●●●● ● ●●●●●●● ●●● ● ● ●● ● ●● ●● ● ● ● ●● ●●●●●● ● ● ● ● ●●●●● ● ● ●●● ● ● ●● ● ●●●● ● ●●● ● ● ● ●●●● ●●● ● ●● ● ●●●●●● ● ●● ● ●● ● ●● ●● ●● ●●●● ●●●● ●●●● ●● ● ● ●● ●● ● ● ●● ● ●●●● ● ● ●●●● ● ● ●● ● ● ●● ● ●● ●● ●●● ● ●●●● ● ●●● ●● ● ●● ●●● ● ● ●●●●●● ● ●● ● ●● ● ● ●●●● ● ● ● ●●● ● ●● ●●● ● ● ●●●● ● ● ● ●●●● ●●●● ● ● ●●●●●●● ●●●●●● ● ●● ● ● ● ● ● ●● ● ● ● ● ●●● ●● ●●●● ● ● ● ● ●●●●● ● ●●● ●●● ●● ●●● ●● ● ● ● ● ●●●● ●●●● ●●● ● ● ● ●● ●●●● ●● ● ●●● ● ● ● ● ●●● ●● ●● ●● ●● ● ●● ●●● ●●●●● ●●● ● ●●●●● ●● ●●●●●● ●●● ●● ●● ● ●●●● ● ●● ●●●● ●●●●●●●●●● ●● ●● ●●●●●●● ● ●●●● ●●● ●●●●●●● ● ●●●● ●● ●● ● ●●●●●● ●● ● ● ● ●● ● ● ● ●● ●●● ● ●●● ●●●●●● ●● ● ● ●● ●●● ●●● ●● ●● ● ● ● ● ●● ●●●●●●● ● ●● ●●● ●● ● ●● ●●● ● ● ● ● ● ● ●● ● ●● ●● ● ●● ●●● ●●● ●●●●●● ●●●●● ●●●●●●●● ● ● ● ●●●● ●● ● ●●●●● ●●● ● ●● ●● ● ● ● ●● ●●●● ●● ●●●●●●●● ●●●● ●● ●● ●●●●● ● ● ●●●●●● ●●● ●●● ●● ●●●● ●●●●●●●●●●●●●●●●●●●●●● ●● ●●●●●● ● ●● ●● ● ●●●● ●●● ●● ● ● ● ●●● ● 0 ●●●●●●●●●●● ●●●●●●●●●●● ●●●● ●●●●● ●● ●● ●●●● ● ● ●●● ● ●●●●●●● ● ●● ● ● ●● ●●● ● ●● ●●●●●●●● ●● ● ●●●● ● ● ●●●● ● ●● ●●● ●●●● ● ●● ●●●● ●●●● ● ● ●●●●●●●●●●●●●●●●●●●●● ●● ● ●●●●●● ●● ● ●● ●● ● ●● ●●● ● ● ●● ●●● ●

95.0 95.5 96.0 96.5 97.0 97.5

chr 9 physical position (MB)

Supplementary Figure 8. Regional association plot of chromosome 9 conditioned on RP11- 165J3.5 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

BDNF LINC00678 MIR8087 LIN7C SLC5A12 LGR4 MIR610 MUC15 BBOX1 BDNF−AS METTL15 ANO3 FIBIN CCDC34 KIF18A MIR8068

● ● 5 ●

●

● 4 ●

● ● ● ● ●●● ● ● ● ● 3 ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ●● ● ●●● ● ● ●●● ● ● ●● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● 2 ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ●●● ● ● ● ● ● ●● ● ● ●●●● ● ● ●● ● ● ●● ● ● ● ●●●● ● ●●● ● ● ● ● ● ●● ● ● ● ● ●●●● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ●●● ● ● ●● ● ● ● ● ● ● ● ●● ●●●●● ● ● − log10(P value) ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ●● ● ●●●●●●●● ● ● ● ●● ● ● ● ●● ●● ● ● ●●● ● ● ● ● ● ● ● ● ● ●●● ●● ● ●●● ●● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ●●●●●●●●●●●●● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●●●● ● ●● ● ●● ● ● ● ● ● ● ●●●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●●● ●●● ●●●●● ● ● ●● ● ● ●● 1 ● ● ●● ●●● ●● ● ● ●●●●●●●● ● ●● ● ● ● ● ●● ● ● ●● ● ● ●● ●● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ●●●● ● ● ● ●●● ● ●● ● ●●● ● ● ● ● ● ● ● ●●● ●●● ●●●● ●● ● ● ● ●● ● ● ● ● ●●● ● ●●● ● ●●● ●●●● ●●● ●● ● ● ●● ● ●●● ● ●●●● ● ●● ● ● ● ●● ● ● ● ●● ●● ● ●● ●● ● ● ● ● ●●●●●●● ● ● ●● ● ● ● ●● ●●●●●●●● ●● ● ●● ● ● ●● ●● ● ● ●●● ● ●● ● ● ● ● ● ● ● ● ●● ● ●● ●● ● ●●● ● ● ● ● ●● ● ●●●● ● ● ●●●● ● ● ●● ● ●●● ● ●● ● ●● ●● ● ●● ● ●●● ● ● ●●●● ● ●● ●●● ● ● ●● ● ● ●●●● ● ● ●●●●●●● ●●● ● ●● ● ● ●● ● ●●● ● ●●●●●●●● ● ● ● ● ● ● ●● ● ● ● ●●●● ● ●●●●●●●● ● ●●● ● ●● ● ● ● ●●●●●● ● ● ●● ● ● ● ● ● ● ●●● ● ● ● ● ● ●● ●●● ●● ●●●● ● ● ●●● ●● ● ●●● ●●● ● ●● ● ●●●● ● ●● ● ● ●●●● ●●● ●●●● ● ● ● ●●● ●●●● ●●● ● ●● ●● ● ●●● ●●● ●●●●●● ● ●● ●●●● ● ●●● ● ●● ● ● ●● ● ●● ● ●●●●● ●● ● ● ●●● ● ●●●●● ● ● ● ●●●●●●●●● ●● ●●● ● ●●● ● ●● ●●●●●●● ● ● ●● ● ●● ●●●● ● ● ●●●●●●● ●●● ● ●●● ● ● ● ● ●●●●●● ● ●● ● ●● ● ●● ● ●●●● ●●●● ● ● ● ● ●● ● ●● ● ● ● ● ● ●● ●● ● ●● ●●● ●● ●●● ● ●●● ● ●●●●●●●●●●● ● ●●●●● ● ●●● ● ●●●● ●● ●●●● ●●●●●● ● ●●●●●●●●● ●● ●● ● ●● ● ●● ●● ● ●● ●●●●● ● ●● ● ●●●●●●●●●● ●● ● ● ●●● ●●●● ● ● ●● ●● ●● ● ●●●● ● ●● ●● ●●●●●● ●●●●●●●●● ● ●●● ●●● ●●●● ● ●●●●●● ●●●●●●●● ●● ●● ●●●●●● ● ●●●●●●●● ● ●●●●●●●●● ●●●●●● ● ● ● ●● ●● ●●●● ●● ● ● ● ●●●●●●●●● ● ●● ●● ●●●●●●●● ●●● ●●●●●● ● ●● ● ● ● ● ● ●● ●●●● ● ●●●●●●●●●●●● ●●●● ●●●●●●●●●●●●● ●●● ● ● ● ●● ●●● ● ● ● ●●●●●●● ● ●● ●● ●● ●●●●●● ● ● ● ● ●● ● ●●●●●● ●●● ●●● ●● ● ●● ● ●●●●●●● ●●● ● ● ●●●● ●●●●●●●●●● ● ●● ●●●● ●●●● ● ● ● ●● ● ●●●●● ●● ●● ●●●●●●●●● ●● ● ● ●● ● ● ●● ● ● ● ●●● ●●●●●●●● ●● ●● ● ●● ● ●● ●●●●●● ●● ● ● ●●●●●● ●● ●●●●●●●● ● ● ● ●● ●● ● 0 ●●● ●●●● ●● ●● ●●●●●●●● ●●●● ●●●●●●● ●●●●●●●●● ● ●●●●● ● ●● ●●●●●●● ● ●● ● ●●●●●●●●● ● ●● ● ●●●●●●●●●●●●●●●●● ●●●●●●●●●●●●●● ●● ●●● ●● ●●●●●●●● ●●●●● ● ● ●● ● ● ●●●● ● ● ●●●●●●●●●●●●●●●● ●●● ●●●●●●●●●●●●●● ●●● ● ●●●●●●●●●●●●●● ●●●● ●● ● ● ● ● ●●● ● ●● ●

26.0 26.5 27.0 27.5 28.0 28.5 29.0

chr 11 physical position (MB)

Supplementary Figure 9. Regional association plot of chromosome 11 conditioned on BDNF-AS expression. The top panel highlights all genes in the region. The marginally associated TWAS bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

C1QTNF4 MTCH2 NDUFS3 NDUFS3 FAM180B MTCH2 FAM180B LRP4 CELF1 SNORD67 PSMC3 MIR5582 SLC39A13 MIR3160−2 RP11−750H9.5 PHF21A CKAP5 SPI1 GYLTL1B MIR3160−1 MYBPC3 PEX16 AMBRA1 MADD C11orf94 CHRM4 LRP4 NR1H3 OR4A47 MAPK8IP1 ATG13 DDB2 KBTBD4 OR4C45 CRY2 MDK F2 C11orf49 OR4C3 SLC35C1 MIR4688 LRP4 MIR6745 NUP160 OR4S1 DKFZp779M0652 ARHGAP1 ACP2 PTPMT1 OR4X1 LOC100507384 HARBI1 PACSIN3 AGBL2 OR4X2 SYT13 CHST1 DGKZ ZNF408 ARFGAP2 FNBP4 OR4B1 TRIM64C PRDM11 MIR7154 CREB3L1 LRP4−AS1 RAPSN PTPRJ TRIM49B

●

12 ●

10 ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● 8 ● ● ● ● ●● ●● ●● ● ● ● ●●●●●●●● ● ●●●●● ● ● ●●●● ● ● ●● ●●● ● ●●●●● ●● ● ●● ● ● ●●● ● ● ●●● ● ●●●●●● ● ●● ● ● ● ●● ●●● ● ●● 6 ● ● ●●●● ● ● ● ●●●●●●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ●● ● ● ● ● ● ● 4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ●●●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ●● ●● ● ● ● ●● ● ● ● ● ●● ● ● − log10(P value) ● ● ● ● ● ●● ●●● ● ●●●●●●●● ●●●●●●● ●● ● ● ●●●●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●●●● ●●●● ● ● ● ● ●● ● ● ●●●● ● ●●● ● ●● ● ● ● ●● ●●●● ● ●●●● ● ●● ● ●●● ● ●● ●● ●● ● ● ●●●●●● ●● ●● ● ● ●● ● ● ● ● ● ●●●● ● ●● ●●● ● ● ●● ●●●●●●●● ●●●●●●●● ● ● ● ●● ●● ● ●● ● ● ● ●●●●●● ●●●●● ● ● ●● ● ●● ● ● ● ● ● ●●● ● ● ● ●●●● ●● ●●●●●● ●● ●●● ● ● ● ●● 2 ●● ●●●●● ●●●● ● ● ● ● ●● ● ● ● ● ●● ●● ● ●● ●● ● ●●●● ● ●●● ● ● ●●● ● ●●● ● ●● ● ● ●● ●●● ●●●●●● ● ●● ●●● ●●●●● ● ● ● ● ● ● ●●● ●● ●●●●● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ●●● ●●●●●●●● ● ●● ● ●●●● ●● ● ●●●●● ● ●●● ●● ● ●● ● ●● ● ● ● ● ●●●● ●●● ●●● ●● ●●● ●● ● ●● ● ● ● ●● ●● ● ●●●● ● ● ● ● ● ● ●●●●●●● ● ●● ● ● ●●●●●●●●● ●●●●● ●● ● ●● ●● ●●●●●● ●● ●●● ●● ●● ● ●● ● ●● ●●●●●●●●●● ● ● ● ●● ●●●●●●●●●●●●●●●● ●● ● ●● ●●●●●● ●● ● ● ●● ● ●● ●●● ● ● ●● ● ● ●● ●●●●●● ●● ●●● ●●●●●●● ●● ● ●●● ●● ● ● ●●●●● ●●●●● ● ● ●● ●● ● ●●●●●●●● ● ● ● ● ●●● ● ● ●●●●●●●● ● ●●● ●●● ●●● ●●●●●● ● ●● ●● ● ●●● ● ● ● ● ●●● ●● ● ● ● ●●●●●●●●●● ●● ●●●● ●●● ●●●●●●●●●● ●● ● ● ● ●●●●●●●● ● ● ● ● ● ● ● ● ● ●●● ● ●●●●●●●●●● ●● ● ● ● ●● ●●● ● ● ● ●● ●●●●●●●●●●●● ●● ●●●●●●●●●●●●● ● ●● ● ● ●● ● ●●●●● ●● ●●● ●●●● ● ● ● ●● ●● ● ● ●●●●●● ● ●● ● ●● ●● ● ● ●● ● ● ●●●● ● ●●●● ● ● ●●●●● ●●●●● ●● ●● ●● ● ● ●● ● ● ● ●●●●●●● ●● ● ● ● ● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●● ●● ●● ●●●●●●●●●●●●● ●● ● ●● ●● ● ● ●●●● ●● ● ●●● ● ●● ● ●●●●● ●● ●● ●●● ●●●● ● ● ●● ● ●●● ●● ● ●●● ●●●● ●●● ● ● ● ●● ● ● ●● ●● ●● ●● ●● ● ●●●● ●●●●●●●● ● ● ● ●●●● ●● ●● ●●●●●●●● ●●●●●●●●●● ●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● ● ●● ● ● ●●●●●● ●●●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●● ●●● ● ● ● ● ●●●●● ●●●●●● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ●● ●● ● ● ●●●●●●●●●●●●● ● ● ● ●●●● ●●●● ●●● ● ●● ●● ● ● ● ● ●● 0 ●●●●●●●● ●●●●●●●●●● ●●●●●●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●● ●●●●● ●● ●● ●● ●●●● ● ●● ●●● ●●●● ● ●●●●● ●●●● ● ● ●●●●● ● ● ● ● ●●● ● ●● ● ● ● ● ●●●●●●●● ●●● ● ●● ●● ●● ●●●●●● ●●●●●●●●●●●●● ● ● ● ● ● ● ●●●●●

46 47 48 49

chr 11 physical position (MB)

Supplementary Figure 10. Regional association plot of chromosome 11 conditioned on LRP4 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes. bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

SLC3A2 SNORD25 SNORD26 SNORD28 SNORD29 SNORD30 MIR6514 NXF1 TMEM223 MIR6748 TMEM179B TAF6L POLR2G TTC9C HNRNPUL2 HNRNPUL2−BSCL2 BSCL2 LRRN4CL UBXN1 SNORA57 METTL12 LOC102288414 FTH1 C11orf48 FADS3 GANAB FADS2 B3GAT3 DKFZP434K028 EML3 SNORD31 CD6 SDHAF2 FEN1 TUT1 STX5 SLC15A3 CPSF7 MYRF MIR6747 TMEM132A TMEM216 MIR1908 MIR3654 TMEM109 TMEM138 MIR611 AHNAK SNORD22 ZP1 CYB561A3 TMEM258 SCGB1A1 SNHG1 LINC00301 DAK DAGLA SCGB2A1 ROM1 SLC22A8 MS4A13 PRPF19 VWCE RPLP0P2 SCGB1D1 MTA2 WDR74 MIR3680−2 MS4A12 PTGDR2 PGA5 SYT7 FADS1 INCENP EEF1G SNORD27 SLC22A10 MS4A1 CCDC86 PGA4 LRRC10B BEST1 ASRGL1 ZBTB3 SLC22A25 MS4A5 MS4A10 PGA3 PPP1R32 RAB3IL1 SCGB1D4 GNG3 SLC22A6 SLC22A9 MS4A14 MS4A15 VPS37C MIR4488 MIR6746 SCGB2A2 C11orf83 SLC22A24 MS4A7 MS4A8 CD5 DDB1 LOC101927495 SCGB1D2 INTS5 CHRM1 MIR3680−1

● 3.5 ● ● ● ● ● ● ● ●● ● ● ● 3.0 ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 2.5 ● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 2.0 ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ●●● ●● ● ●● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●● 1.5 ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ●● ●● ●● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●● ● ● ● ● ● ● ● ●● ● ● ●●● ● ● ● ● ● ●● ●● ●● ●●● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ●● 1.0 ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●●● ● ●● ● ● ● ● − log10(P value) ● ● ●● ● ● ● ● ● ● ●● ● ●● ● ● ● ●●● ● ● ● ● ●●● ● ● ●● ● ● ●●● ● ● ● ●● ● ●● ● ● ● ● ●● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ●●● ● ●●● ● ● ●● ● ●● ● ● ● ● ●● ● ● ● ● ●●●● ● ● ●● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ●●● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ●●● ● ●● ● ● ●● ●●● ● ● ●● ● ●● ● ● ● ●● ●● ● ● ● ●● ● ● ● ●● ● ●● ● ● ● ●● ● ● ● ● ●● ●● ● ●●● ● ● ● ● ● ● ● ●●● ●● ● ●● ●●● ●● ● ● ● ● ●● ● ● ● ●●● ● ● ●● ● ● ● ● ●● ●●● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ● ● ●●● ●● ●● ●● ● ● ● ● ● ●● ● ● ● ● ●● ●● ●●● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ●● ● ●● ● ●● ●● ● ● ●● ● ● ●●● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ●●● ● ● ● ●● ●●● ● ●●● ● ●●● ● ●● ● ●● ● ● ● ● ● ●● ● ● ● ●● ●● ● ●● ●● ● ● ● ● ●● ●● ● ● ● ● ●● ● ● ● ● ● ●●●●● ● ●● ● ● ● ●●● ●● ● ● ● ●● ●● ● 0.5 ●●●● ● ● ● ●● ● ●● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ●● ●● ● ●● ● ●● ●●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●●●● ●● ● ● ● ● ● ● ● ● ●● ● ●● ●● ● ● ●●● ● ●● ● ● ● ● ● ● ●●● ●● ● ● ●●● ●● ● ● ● ●●● ● ● ● ●● ● ● ●● ● ● ●●● ●●●●● ●●● ●●● ●● ● ● ● ● ●●●● ●● ● ● ● ●● ●● ●● ● ● ●●● ● ● ● ● ●●●● ● ●● ●● ●●● ● ● ● ●●●● ● ● ●●● ●● ● ● ● ● ●●● ●● ● ● ●● ● ●●● ● ●● ● ● ● ● ● ●● ● ● ●● ● ● ●● ●● ● ●● ●● ● ●● ●●●● ●●●●●●● ●● ● ● ●● ●● ● ● ●●● ●● ● ●● ●●●● ● ●● ● ● ●●● ●●●● ●● ●●● ●● ● ● ● ● ●● ●● ●●●●●● ● ● ●●● ● ● ●●●● ●● ●●●●● ● ● ● ● ●● ● ● ● ●● ● ●● ● ●●●● ● ● ● ●●● ●● ●●● ●● ● ● ● ● ●● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ●●●●●●●●● ●● ●●●● ●●● ● ●●●● ●●● ●● ●● ● ● ● ●● ● ● ● ● ●●● ●● ● ● ●● ● ● ●● ● ●● ● ●● ●●● ●●●●● ● ● ● ● ● ● ● ●●● ●●● ●●●● ● ●● ●●● ● ● ●●●●●● ●● ●●● ● ●●●● ● ● ● ● ●●● ● ●● ● ●●● ● ● ● ●● ● ● ●●●● ●● ● ● ● ●●●● ●● ●● ●● ● ●● ●●● ● ● ●● ● ●● ●●●● ● ● ●● ● ● ● ● ● ● ●●●● ● ● ●●●● ●● ●●●●●● ● ● ● ●● ●● ● ●●●● ●● ●● ● ● ● ●●●●●●●● ●●●●●● ●●●●●●● ●● ●● ● ●●● ● ● ●● ● ● ● ● ●●● ●● ●● ● ● ● ●●●●● ● ●●● ●● ● ● ●● ●●● ●●● ● ● ● ● ●●●● ●● ●●●● ● ●● ● ● ● ● ● ●●● ● ● ● ● ●●●● ● ● ● ● ●●●●●● ●●● ● ●●● ●● ● ●● ●●●● ●●● ●●● ● ● ● ● ● ● ● ● ● ●● ●● ● ● 0.0 ● ● ● ● ●●●●● ● ● ●● ● ●●●●●●● ●●●●●● ● ● ● ●●● ●●●●●●●●●● ● ●●● ● ● ●●● ●● ● ●●● ● ●● ● ●●● ●●●●● ● ●●● ●● ● ● ● ●● ● ●● ●● ●●●●● ● ● ●●●●●●●● ● ●● ●●●●● ● ● ● ● ● ●● ● ● ● ●

60.5 61.0 61.5 62.0 62.5 63.0

chr 11 physical position (MB)

Supplementary Figure 11. Regional association plot of chromosome 11 conditioned on FADS3 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

SERPINF1 SERPINF2 ASPA MIR22 SPATA22 MIR22HG OR3A4P P2RX5 TLCD2 SGSM2 MIR1253 OR3A1 EMC6 SLC43A2 SNORD91B OR1D4 TAX1BP3 PITPNA SMG6 MIR6776 OR1A1P2RX5−TAX1BP3 PITPNA−AS1 HIC1 TSR1 CLUH OR1A2 CTNS ANKFY1 INPP5K MIR212 METTL16 OR1D2 OR1E2 C17orf85 MYO1C RPA1LOC101927839 OR1D5 OR1E1 GSG2 ZZEF1 CRK PRPF8 MIR132 MNTRP11−74E22.6 OR3A2 TRPV1 ATP2A3 YWHAE WDR81 OVCA2SNORD91A RAP1GAP2 TRPV3 CAMKK1 TUSC5 RILP RTN4RL1 LOC284009 LOC101927911 SHPK P2RX1 BHLHA9 SCARF1 DPH1 SRR PAFAH1B1 OR1G1 OR3A3 ITGAE CYB5D2

● 10 ● ● ● ● ●

●● 8 ●●

●

● ● ● 6 ● ● ● ● ● ●

● ●● ● ● ● ●● ● ● 4 ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ●● − log10(P value) ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ● ● ● ●●●● ● ● ● ● ● ● ●● ●● ● ● ●● ● ● ● ●●● ● ● ●●●● ●● ● ● ● ● ● ● 2 ● ● ● ● ●● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ●●●● ● ● ● ●● ● ●● ● ● ●● ● ● ● ●●● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ●●●● ● ● ● ● ● ●● ● ● ● ● ● ●● ● ●● ● ● ● ● ●●●●●●● ● ● ●● ● ● ● ●●● ●● ●● ● ●● ● ● ●●●● ● ● ● ● ● ●● ● ●●● ● ● ● ● ●●● ●● ●●● ● ● ●●●●●●●● ●● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ● ● ●● ● ●● ● ● ●●●● ● ●●● ●● ●● ●● ● ●●●●●● ●● ● ● ● ● ●● ●●● ●●●● ● ●●●●● ● ●● ● ● ●● ● ● ●● ●●● ● ●● ● ● ●● ● ● ●● ●● ●●● ● ●● ● ●●● ●● ● ● ● ●●● ● ●● ● ● ●● ●●●●●● ●●● ●●●● ● ● ● ● ●● ● ● ● ●●●● ● ●●●●●● ● ● ● ●●● ●●●● ● ●● ●● ● ●●●● ● ● ●●● ● ● ● ●● ● ●●● ● ●●●●● ● ● ●●● ● ●●●● ● ● ● ● ●●●●●● ● ●● ● ● ●●● ●● ● ●●●●●●●●●● ●●● ●● ●●● ●● ● ●● ●●●● ● ● ● ● ●●●● ● ● ● ● ● ● ● ●● ●●●● ●●●● ●● ● ●●●●●●●● ●●● ●●●●●●●●●●● ● ● ●●●●● ● ● ● ● ●● ● ●● ●●● ● ● ●● ●● ● ● ● ●●● ●●● ●● ●●● ●● ●● ● ● ●●● ● ●● ●● ●● ●●● ●●●●● ●●●●● ● ● ●● ● ●●●●● ● ●●● ● ● ● ● ●●● ●●●●●● ● ●● ●● ● ● ●●● ●●●●●● ●●●●●●●●●●●●●●●●● ● ●●● ●● ● ●●● ●●● ●●●●● ●● ● ●●● ●●● ●●●● ● ●●●●●●● ● ●● ● ● ●● ●●●● ●● ● ● ●● ● ●●● ●●● ●● ●●● ● ● ● ●● ● ● ●●● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●●●●●● ● ● ● ●● ●● ●● ●● ● ●●● ●●●●● ●●●●● ●● ●●● ●●●● ● ●●●●● ● ●● ●●●●●●●●●●●● ●● ●● ● ●●●●●● ●●● ● ●● ● ●●●●●●● ● ● ●●●●●●●●● ●●●●●●●●●●●●●● ● ● ● ● ●●● ●● ●●●● ●●●●● ●●●● ●● ●●●●●●● ●● ●● ●●●●●●● ●●●●● ●●● ● ●●● ● ●●●●●●●●●●●●●●●●● ●●● ●●● ● ●●●● ●●●●●●● ● ●●●●●●●●●● ●●●●● ● ● ●●● ●●● ●●●●●● ●●●●●●● ● ●● ●●●● ●● ●●●●●●●●●●●●●● ●●●●● ●● ● ●● ● ●●●●●● ●● ● ●●●●● ● ● ● ●● ● ●● ●●●● ● ●●●●●●●●● ●● ●●● ●● ● ●● ●●●●● ●● ● ●●●● ●●●●●●● ●● ●●●●●● ●●●●●●● ● ●●● ●●● ● ●●● ●●●●●● ●●●● ●●●●● ●●●●●●● ● ●●● ●● ● ●● ●●●● ●●●●●●●● ●●●●●● ●●●● ●● ● ●●●●● ●●●● ●●● ● ● ●● ●● ●● ●●●● ●●● ●●●●●●●●● ● ●● ●●●● ●● ●●● ●● ●●●●● ●●●●●●●● ●● ●● ● ●●● ● ●●●●●●●●●●●●●●● ●● ● ●●●●●●●●●●● ● ● ●●● ● ●● ●●●●●●● ●● ●●●●●●●●●● ●●●●●● ●●●● ●●●●●●● ●●● ●●● ●●●●●●●●●● ●●●●●●●● ●● ●●●●● ●●●●●●●●● ● ●●●●●●● ●●●● ●●●●●●● 0 ● ● ● ●●●● ●●●●●●●●●●●●●● ●●●●●●●●●●●●●●● ●●●● ●● ●● ●●●●●●●●●●● ●●● ●● ●●●● ●● ●● ● ●●●●●●●●●●●●● ●● ●●●●●●●●●●●●●●●●●●●●●●●●●●●● ●●● ●●●●● ●●●●● ●●●●●●● ●●●●● ●● ●●●●● ● ●●●●●●● ●● ●●●●●●●●●●●●●●●●● ●● ●● ●●● ●● ● ●●●●●●●●●●● ● ● ●● ●●●●●● ●●●●●●●●●●●●●●●●●●●●●●●●● ●●●●●●●● ●●●●●●●●●● ●●●●●●●●●● ●●●●●●● ●●●● ●● ●●●

1.0 1.5 2.0 2.5 3.0 3.5 4.0

chr 17 physical position (MB)

Supplementary Figure 12. Regional association plot of chromosome 17 conditioned on RP11- 74E22.6 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

LRRC75A NCOR1 KRT16P2 LOC101928567 SNORD65 MEIS3P1 SNORD49A TBC1D26 SNORD49B SMCR9 TVP23C ZSWIM7 LRRC75A−AS1 FLCN TEKT3 ZNF286A UBB ZNF624 MPRIP MIR4731 TRIM16 TTC19 CENPV FAM106CP NT5M PMP22 CDRT1 ADORA2B TRPV2 USP32P1 PLD6 RASD1 CDRT8TVP23C−CDRT4 MIR1288 CCDC144A COPS3 CDRT7 CDRT4 CDRT15P2 PIGL ZNF287 TNFRSF13B MED9

● ● 8 ● ● ● ●● ●●●● ●

● ●● ●● ● ● ● ● ● ● ● ● ●● ●●●● ●● ●●●● ● ● ●●● ● ● ● ●● ● ● ● ●●● ● ●● 6 ● ●● ● ●● ● ● ●●● ● ●●● ● ●● ● ●●●●● ●● ●● ●● ●● ● ● ● ●● ● ● 4 ● ● ● ● ● ● ● ● ●● ● ● ● ●● ● ● ● ●

● ● ●● ●● ● ● ● ● ● ●●● ● ●● ● ●● ● ● ● ●● ●●● ● ● ●● ● ● ● ●

− log10(P value) ●● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●●●● ● ●● ● ●● ● ● ●● ● ● ● ● 2 ● ● ● ● ●●● ● ● ● ● ● ● ●● ● ● ● ●●● ● ● ● ● ● ● ●●● ● ●● ● ● ●● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ●● ●● ● ● ● ● ●● ●● ● ● ●● ● ● ●●● ● ● ● ● ●● ● ● ●● ● ● ● ●●● ● ● ● ● ● ●● ● ● ● ● ●● ● ●● ● ●●●● ●● ●● ● ●● ● ●● ● ●● ● ● ●● ● ● ●● ● ● ● ●● ●●●●● ● ● ● ●● ● ● ●● ● ●●● ● ● ● ● ●● ● ●● ●● ● ●● ●● ●● ● ● ● ● ● ● ● ● ● ●● ●●● ●● ● ● ●● ● ● ●● ● ● ● ●●● ● ●●●● ● ● ● ● ●●● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ●● ●● ● ● ● ● ●●● ● ● ● ●● ● ● ● ●●● ●●● ● ●● ●● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ● ●●● ●● ● ● ● ●● ●● ● ●● ●● ● ●● ● ●● ●● ● ●●●●●●● ● ●●●● ●● ● ●●●●● ● ● ●● ● ● ● ● ● ● ● ● ●●● ● ● ●●● ● ● ●●● ● ● ● ● ●● ●●●● ●● ● ●● ● ●● ● ● ● ●● ●●●●● ● ●● ● ●●● ● ●● ● ● ●●● ● ● ●● ● ● ●● ● ● ●●● ●● ● ● ● ● ● ● ● ● ● ●● ● ●●●● ● ● ●●● ● ● ● ● ● ●●●●● ●●● ● ● ● ●●●● ● ● ● ●● ● ● ●●●● ● ●●●●●● ●●●●●●● ●● ●●● ● ● ●●● ● ● ● ● ●● ●● ● ● ● ● ● ● ●●●●● ●● ●●●● ●● ●● ● ●●● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ●● ●●● ●● ●●●●● ● ●● ● ● ●● ●●●●● ● ● ● ●●●● ●●●●● ● ● ●●● ● ●●●●● ●●●●●●● ● ● ● ● ● ● ● ● ●● ● ●●●●●●●● ● ●●●● ● ●●●● ●● ● ● ●● ●● ● ●● ●● ● ● ● ●●●●●● ● ● ●● ● ●●● ●● ● ●●● ● ●●● ●●● ● ●● ● ●● ● ● ● ●●●●● ●●●● ●●●●●●●●● ●● ●●●● ● ● ●●●●● ●●●●●●● ●●● ●●●● ●●● ●●●●●●●●● ● ● ●●●●● ●●● ●● ●● ● ● ● ● ● ● ● ● ●● ● ●● ●●● ●●●●● ● ● ●●●●● ● ●●● ● ● ● ● ●● ● ● ● ● ●●●● ●●●● ●●●●●●● ● ● ●●●● ●● ●● ●●●● ●● ●●● ●●●●●●●●●● ●●● ●●● ●● ●● ●● ●● ● ●● ● ● ●● ●●● ● ●●●●●●●●● ●● ● ● ● ●●●● ● ●●● ● ●● ●● ● ●● ●●● ● ●● ● ●● ● ● ●● ●● ●●●●●●● ● ● ●●●●●●● ●● ●● ● ●● ●● ●●●●●● ●●● ●●●●●●●● ● ● ●● ●●●●●●●●●●●●●●●● ●●●●●● ● ●●●●●●●●●●●● ●● ●● ●●● ●●●●●●●●●● ●●●●●●●●● ● ●●●● ● ●●●●● ● ●●●●● ●●●●● ● ●● ●●● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ●●● ●● ● ● ●● ● ●● ●●●●● ●●●●●● ● ● ●● ● ●● ●●● ●● ●●●●●●●●● ●●●● ●●●●●●●●●●●●●● ●●●●● ●●●●●●●●●●●●●●●●●●●●● ● ●●●●●●●● ●●●●●● ● ●●●●●●● ●●● ●●●●●●●●● ●●●●●●● ●●●●●●●● ●● ●●●●●●●● ● ● ●● ● ●●●●●●● ● ● ● ●●●●● ● ● ● ● ● ● ●● ● ● ●● ●●●●● ●● ● ● ●●●●●● ●●●●●●● ●●●●●● ●● ● ●●● ●●●●●●●●● ●● ●●●●●● 0 ●●●● ●●●●●●●●●●●● ●●●●●●● ●●● ●● ●●●●●●●●●●● ●●●●●●●●●●●●●● ● ●●● ●●●●●●●●●●● ●●● ●●●●● ●●●● ●●●●● ●●● ● ●●●●●●●●● ● ● ●● ●● ●●●●● ●●● ● ●●●● ●●●●●●●●● ●●●● ●●●●●● ●●● ●●●●● ● ●●●● ●● ● ● ● ●● ● ● ●●●●●●●●●●●●●● ● ● ●●● ●●●●●● ● ●● ●●●●●●● ● ●● ●●

14.5 15.0 15.5 16.0 16.5 17.0 17.5

chr 17 physical position (MB)

Supplementary Figure 13. Regional association plot of chromosome 17 conditioned on TTC19 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

TEX14 C17orf47 SCARNA20 HSF5 HEATR6 RNF43 MIR4729 TBC1D3P1−DHX40P1 SUPT4H1 GDPD1 LOC101927755 MIR4736 PRR11 TUBD1 USP32 MIR142 PPM1E YPEL2 MIR21LOC653653 BZRAP1−AS1 MIR301A VMP1 LOC645638 BZRAP1 RAD51C MIR454 PTRH2 MIR4737 BCAS3 MPO SEPT4 SKA2 CLTC RNFT1 PPM1D LPOLOC101927688 SMG8 DHX40 RPS6KB1 APPBP2 MKS1 MTMR4 TRIM37 LOC101927728 CA4 C17orf64

7 ● ● ● ●● ●

● ● ●● ● ● ● 6 ●● ● ● ● ●● ●● ● ●● ● ● ● ● 5 ● ●● ● ●●● ● ● ● alue)

4 ●

● ● ● ● ● ● ● 3 ● ● ● ● ● ● ●●● ● ●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●●●●● ●●●● ● ●●● ● ● ● ●●●● ● ●● ● ● ● ● ●●● ● ●● − log10(P v 2 ● ● ● ● ● ● ● ● ● ● ●●●● ● ● ●●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ●● ● ● ●● ● ● ● ●●● ● ● ● ● ● ●● ● ●● ●●● ●●● ● ●●● ● ●● ● ● ● ●●● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ●●● ●● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ●●●● ● ●● ● ●●●● ●●●● ●● ● ● ● ● ●●●● ● ● ●●● ● ●● ●● ● ●●● ● ● ●●●● ● ● ● ● 1 ● ● ● ●● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ●●● ● ● ●● ●● ● ●●●●●● ● ●●● ● ●● ● ●●● ●● ● ●● ●● ● ● ● ● ●● ●●● ●● ●●●●●● ● ●●● ●● ● ● ● ●●● ● ● ● ●● ●● ● ●●●● ● ● ● ●● ● ●● ●●● ● ● ● ●●● ● ● ● ●●●●● ● ● ● ● ●● ● ● ●● ●● ●● ● ●● ●●●●●●●● ●●●●● ●● ●●● ●●● ● ● ● ● ● ●● ● ●● ●● ●● ● ● ●●●●●●●● ● ● ● ● ●● ●●● ● ● ● ● ●● ●● ●● ●● ● ● ● ●● ●●●● ● ● ● ● ●● ●● ●● ● ● ● ● ● ●● ● ● ● ●● ●● ● ● ● ● ● ●●● ●● ●●●● ●● ●● ● ● ●●● ● ● ● ● ● ●● ● ● ● ●● ●●● ● ● ● ●● ● ● ● ● ● ●●● ● ● ●● ●●● ●● ● ● ● ●●● ●● ●● ● ● ● ● ●● ●●●●●● ●● ●● ●● ● ● ● ● ● ● ●●●●● ●●● ●●● ●●●●●●● ● ●●●● ● ● ●● ●●●●● ● ● ● ● ● ●● ● ●●●●●●●● ●●●● ●●● ● ● ● ● ● ● ●● ●●●● ● ● ● ● ●●● ● ● ● ● ●●● ● ● ●●●● ● ● ●●● ● ●● ● ● ● ● ● ●● ●●●● ● ●●●●●● ● ●● ●●●● ●●●●●●●●●●● ● ●● ●● ●● ●● ● ●● ● ●●●●●● ●●●●● ● ● ●● ● ●● ● ● ● ● ● ● ● ● ● ● ●● ●● ●●●● ● ●●●● ●● ●● ● ● ●● ● ●● ●●● ● ● ●●●●●●●●●● ● ●● ●●● ● ●● ●●●● ● ● ● ● ●● ● ●● ●●● ●●● ●●●●●●● ● ● ● ● ●● ●● ● ●●●● ●● ● ● ●●● ● ●● ●●● ● ● ● ●● ● ●●●●● ● ● ● ●●● ● ● ● ● ● ●●●● ● ● ●●●●●● ● ● ● ●● ● ● ●● ●● ●● ●●●●●●●●● ●● ●● ● ● ● ●● ●● ●● ● ● ● ●● ● ●●●● ●● ●● ● ● ●●●●●●● ●●●●●● ●● ● ● ●●● ●● ● ●● ● 0 ●●● ●● ● ●●●●● ● ●● ● ● ●●●●●● ●● ●●●●● ●●●● ● ●● ●● ● ●● ● ●● ● ●●● ● ● ● ●●●● ●● ●●●● ● ●● ● ●●●●●●● ● ●●●● ●●● ● ●● ● ●●● ●●

56.5 57.0 57.5 58.0 58.5 59.0

chr 17 physical position (MB)

Supplementary Figure 14. Regional association plot of chromosome 17 conditioned on VMP1 expression. The top panel highlights all genes in the region. The marginally associated TWAS genes are shown in blue and the jointly significant genes are shown in green. The bottom panel shows a regional Manhattan plot of the GWAS data before (grey) and after (blue) conditioning on the predicted expression of the green genes.

Supplementary Table 1. Within-tissue panel significance thresholds TI Panel Number of genes Within-tissue significance threshold GTEx Brain Anterior Cingulate 8731 5.73E-06 Cortex ba24 GTEx Caudate Basal Ganglia 9145 5.47E-06 bioRxiv preprint doi: https://doi.org/10.1101/682633; this version posted June 26, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license.

GTEx Cerebellar Hemisphere 9451 5.29E-06 GTEx Cerebellum 10002 5.00E-06 GTEx Cortex 9162 5.46E-06 GTEx Frontal Cortex BA9 9031 5.54E-06 GTEx Hippocampus 8535 5.86E-06 GTEx Hypothalamus 8551 5.85E-06 GTEx Nucleus Accumbens 8913 5.61E-06 Basal Ganglia GTEx Brain Putamen Basal 8759 5.71E-06 Ganglia CMC DLPFC 10292 4.86E-06 Total 100572 4.9E-07