Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

AJRCMB Articles in Press. Published on 23-June-2015 as 10.1165/rcmb.2014-0381OC Page 1 of 157

Wei Luo 1,2* , Ma’en Obeidat 3,4* , Antonio Fabio Di Narzo 1,6, Rong Chen 1,6, Don D. Sin 3,4 , Peter D. Paré 3,4 and Ke Hao 5,1,6

1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 2. College of Computer Science and Technology, Huaqiao University, Xiamen 361021, China 3. The University of British Columbia Center for Heart Lung Innovation, St Paul’s Hospital, Vancouver, Canada 4. Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, Canada 5. Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China 6. Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

*These authors contributed equally

Corresponding Author : Ke Hao, [email protected]

Running Head: Airway Epithelial eQTLs Reveal Asthma Genes Key Words : Airway Epithelium, Asthma, Expression Quantitative Trait Loci, Airway Diseases

Word Count (N=4,754) Author Contribution: Conception and design: WL, MO, DS, PP and KH; Analysis and interpretation: WL, MO, AD, RC, DS, PP and KH; Drafting the manuscript for important intellectual content: WL, MO, DS, PP and KH

ABSTRACT Background: Genomewide association studies (GWAS) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. Methods: We utilized publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways, and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. Results: For the small airways (N=105), we discovered 660 eQTLs at a 10% FDR (false discovery rate) among which 315 eQTLs were not previously reported in a largescale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from ENCODE showing that the eQTLs reside in regulatory elements (57.5% and 67.6% of cis and transeQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2 fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL4 signaling (FDR=5.2x10 4). Conclusion: The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway related conditions.

INTRODUCTION Recent genomewide association studies (GWAS) have identified loci that harbor susceptibility genes for many respiratory diseases including asthma and related phenotypes 116 . Many of the most significant GWAS hits are at loci with unknown function that had not been previously considered biologically plausible candidates for disease pathogenesis. Extensive linkage disequilibrium (LD) within many of these loci makes it difficult to identify the casual susceptibility variant, let alone which genes or proteins they influence. Moreover, the associated polymorphisms can only explain a relatively small proportion of the variability of the phenotype in human populations 9,17 . Some of the missing heritability may be due to the limited power of GWAS, which miss disease susceptibility SNPs of smalltomoderate effect sizes. Integrative genomics is a promising new approach to identify causal genes and variants, with improved statistical power. By using gene expression as a phenotype and examining how DNA polymorphisms contribute to both gene expression (expression quantitative trait loci – eQTLs) and disease phenotypes, true causal relationships can be discovered 1820 .

A recently published large study of lung expression quantitative trait loci (eQTLs) 21 has been used to inform respiratory GWAS signals 22,23 . Since many eQTLs have been shown to be tissue and cell type specific 18,24 , and because the airway epithelium plays an important role in the pathogenesis of respiratory diseases 2529 , we used publically available genetic and genomic data to discover airway epithelial cell eQTLs. In this study, we report eQTLs from small and large airways, which will complement lung tissue eQTLs. Further, we demonstrate the utility of the airway epithelial eQTLs in mining publically available GWAS data (e.g. asthma GWAS) and identifying causal pathways.

MATERIALS AND METHODS Data Sets Airway epithelial gene expression and genotype data sets 30,31 were retrieved from NCBI Gene Expression Omnibus (GEOaccession: GSE5057 and GSE40364). Gene expression data were generated on Affymetrix HGU133 Plus 2.0 microarray using a standard protocol 31 . The gene expression levels were quantified from Affymetrix CEL files using the latest version of the CDF file, where probes that harbor frequent SNPs were masked. The Affymetrix expression array includes 11 separate probes for each probeset and the Robust MultiArray Analysis (RMA) algorithm was applied for expression level quantification, where outlier probes have little impact. The genotype data were generated from blood DNA using Affymetrix 5.0 microarrays 31 . The published GWAS result catalog, which contained 11,598 unique SNPs, was downloaded from the NHGRI website 32 on Nov 1, 2013. We manually curated this table and determined that 538 SNPs were associated with pulmonary diseases and related phenotypes. The GABRIEL asthma meta analysis GWAS results were retrieved from the publication website 9. The ENCODE regulatory elements database was downloaded from regulomeDB 33 . Human lung tissue eQTLs were retrieved from the published study’s online supplement 21 .

Data Quality Control We normalized the gene expression data from small (N=112) and large (N=40) airways, separately, using a robust multiarray average (RMA) method. Sex was inferred by identifying expression for the Ylinked gene RPSY41. We also performed quality control (QC) on genetic data. We excluded SNPs that had a low call rate (<0.9) or deviated significantly from HardyWeinberg equilibrium (pvalue<1e6). Genotype imputation was performed using 1000G cosmopolitan reference and the MaCH pipeline.34 We removed all imputed SNPs that had a low imputation score (ie, MaCH r 2<0.3). eQTL Discovery We used a previously described Bayesian method 35 to determine whether the paired RNA and DNA samples were derived from the same individual. Discordance was found in seven small airway and one large airway samples, which were then excluded in this

analysis, reducing the sample size to 105 and 39 small and large airway samples, respectively. Common SNPs (minor alleles that were observed at least five times in dataset) were used to identify cis and transeQTLs following a method similar to that described previously 19 .

The gene expression data were adjusted for the top five transcriptomederived principal components (PCs) and sex using a robust linear model to mitigate the effects of confounders and outliers. Residuals from this linear model were subjected to inverse normal transformation and then used for eQTL construction. One potential limitation of this approach was that the PCs may have consumed some of the true genetic variance signal, resulting in false negatives. To investigate this possibility, five additional GWAS analyses were performed, in which the top 5 PCs were treated as phenotypes (i.e. one PC for each GWAS). We did not observe any associations that surpassed the genome significance threshold of p<5e8; thus, it was unlikely that PCs contained a significant amount of true genetic signal. We employed both a linear model and Efficient Mixed Model Association eXpedited (EMMAX) methods 36 to evaluate the relationship between genotypes and transcriptomic expression. These two methods provided similar findings. For parsimony, we present data from linear models in this report. R statistical package (version 3.02) and metaeQTL software suite were used in data analysis 37 .

The magnitude of the enrichment of GWAS SNPs as airway eSNPs was calculated as the proportion of the eSNPs among GWAS SNPs divided by the proportion of the eSNPs among all SNPs on Affymetrix SNP 5.0 microarrays. The significance level of the enrichment was assessed by resampling, where we randomly sampled the same number of SNPs as the GWAS SNPs and examined the proportion of airway eSNPs in the random SNPs.

GWAS datasets GWAS summary statistics (association pvalues and coefficients) of five studies were retrieved from web resources described in the GWAS reports, including asthma

(GABRIEL meta GWAS) 9, Alzheimer's disease 38 , type 2 diabetes 39 , obesity 40 and schizophrenia 41,42 .

Rankrank plot

For a GWAS dataset (e.g. GABRIEL asthma meta GWAS), we were interested in examining whether a subset of the studied SNPs (e.g. airway eSNP) were enriched for small GWAS pvalues. First, we ranked all SNPs by GWAS p ascendingly; the SNP with smallest p got the lowest rank value, one. Using this method, each eSNP would be assigned a rank value, and we were interested in whether eSNPs were enriched for low ranked p values. We standardized ranks for each SNP as; standardized rank = (rank) / (number of SNPs in GWAS study). For example, the SNP with smallest p had standardized rank value = 1/N, where N is the number of SNP surveyed in GWAS. In the rankrank plot the yaxis is the observed standardized rank value of the eSNPs and the x axis is the expected standardized rank value of the eSNPs if the eSNPs were uniformly distributed in the ranked SNP list.

RESULTS

Genome wide association analysis for expression trait loci (eQTL) We identified cis and trans acting eQTLs and quantified the false discovery rate through imputation using established methods 19 . For parsimony, we assumed that each individual transcript could have no more than one cis eQTL, which was defined as a significant association between a SNP and its transcriptomic expression within 500kb (up or downstream) of the putative gene. Trans eQTLs were defined as association signals from SNPs located more than 500kb from the probeset, or on a different chromosome. Peak eSNP for a particular probeset was defined as the SNP that was most significantly associated (i.e. having the lowest P value) with the expression trait. A summary of the eQTLs identified at a 10% false discovery rate (FDR) is shown in Table S1. We identified 616 and 44 cis and trans eQTLs, respectively, in the small airway epithelium. Despite the modest sample size (N=105), we discovered a large number of eQTLs because the eQTL effect sizes were generally large with a median r 2 value of 0.34 (Figure 1A ). Consistent with a previous observation 21 , the average trans eQTLs’ r2 value (0.70) was larger than that for cis eQTLs (0.31), likely owing to the higher threshold required to achieve statistical significance for trans eQTLs. Because of the smaller sample size for the large airway analysis (n=39), we had limited statistical power for eQTL discovery in this dataset. Only four cis and three transeQTLs were discovered at a 10% FDR ( Table S1 ). All of the four ciseQTLs in the large airways were also cis eQTLs in the small airways.

We found that 315 (48%) of the airway epithelial eQTLs were not discovered in lung tissue samples of a previous large study that evaluated lung eQTLs (Table S2 ).21 However, the latter study did not carefully phenotype the lung tissue (e.g. airway, parenchyma, blood vessels, extracellular matrix and inflammatory cells), which could have obscured airwayspecific eQTLs. For example, IL6R, which has been previously implicated in asthma 43 , was regulated by a very strong eQTL in small airway epithelium (with a large effect size, r 2=0.24) but not in lung tissue. 21

A notable feature of airway specific eQTLs was that they had, in general, large effect sizes. For example, GSTT2 expression was strongly controlled by a cis eQTL (rs9620341, r2=0.68 and pvalue=5.8e30) in small airway epithelium. Overall, the median effect size (r 2) of the airway specific eQTLs was 0.34 (Figure 1B), which was very similar to that of all eQTLs (regardless of airway specificity) discovered in small airway epithelium (Figure 1A). It should be noted that some airway eQTLs, which were discovered in the present study ( Table S2 ), have been previously reported to be eQTLs in other tissues and organs (e.g. liver 44 , lymphoblastoid cell lines (http://www.sanger.ac.uk/resources/software/genevar/), and whole blood 45 . This indicates that some eQTLs in small airways may also be regulatory in other tissues.

Using airway epithelial eQTLs to interpret public GWAS results One important use of eQTLs is to determine the potential functional relevance of published GWAS findings. To this end, we retrieved a list of GWAS hits from the NHGRI public catalog 32,46 using stringent thresholds based on guidelines for statistical significance for replication 32 . From this GWAS hit list, we also identified a subset of SNPs related to pulmonary diseases and related phenotypes, which we called “pulmonary GWAS hits” ( Table 1 ). This list included studies of asthma, COPD, physiological measurements of lung function such as forced expiratory volume in one second (FEV 1), and the ratio of FEV 1 to forced vital capacity (FEV 1/FVC) and biomarkers of pulmonary or systemic inflammation such as Creactive protein. We then integrated the SNPs from the GWAS hit lists with the airway eQTLs using a 10% and 20% FDR, respectively. We found that “all GWAS hits” were significantly enriched as airway epithelial eQTLs. At a 10% FDR, 129 out of 11,598 GWAS hits were airway eSNPs (representing 9.2 fold enrichment). The significant level was assessed using a random sampling method. After 200 iterations, we determined that “all GWAS hits” were significantly enriched as airway epithelial eQTLs at a pvalue<0.005. Although there was a similar magnitude of enrichment for the “pulmonary GWAS hits” as airway eQTLs (9.2 and 9.5 fold enrichment at a 10% and 20% FDR, respectively), the enrichment was not statistically significant in the random resampling analysis. This was probably due to the small number of “pulmonary GWAS hits” and reduced statistical power. Airway eSNP

enrichment was similar between “all GWAS hits” and “pulmonary GWAS hits” mostl likely because some airway eQTLs are eQTLs in other tissue types 47,48 (Table S2) and may contribute to different disease phenotypes.

Ten significant SNPs from the pulmonary GWAS studies which were airway eQTLs are shown in Table 2. An example was SNP rs13233571, which has been previously shown to be associated with circulating Creactive protein levels (CRP) 49 . Interestingly, this SNP resides in a region not known to play a significant role in chronic inflammation, and its genetic association with CRP was originally assigned to the BCL7B gene 49 . Here we showed that rs13233571 is an eSNP controlling the expression of the Claudin 4 (CLDN4) gene (r 2=0.16 and pvalue=3.2e5), which is adjacent to the BCL7B gene.

We found that two SNPs, which had been previously associated with lung function (one 50,51 with baseline FEV 1 and the second with FEV 1 decline ) were strong trans eQTLs.

SNP rs17331332 resides in an intergenic region on Chr4q24 and is associated with FEV 1 (pvalue=1E16) 51 . It controls the expression level of PDZ and LIM domain 3 (PDLIM3) on chr4q35.1 in small airways with a substantial effect size (r 2= 0.35). The second SNP, rs16856186, resides in an intergenic region of chr1q32.1 and has been shown previously 50 to associate with FEV 1 decline in asthmatics (pvalue=9e6) . It controls the expression levels of the ARV1 homolog (S. cerevisiae) (ARV1) (chr1q42.2) and cystatin SN (CST1) (chr20p11.21) genes, both in trans with a r2 value of 0.30.

While most GWAS publications report only the top signals, the GABRIEL consortium 9 released the asthma genetic association results for all SNPs investigated, allowing an in depth analysis. We examined various p value cutoffs for the GWAS and queried whether the SNPs passing these thresholds were eQTLs (Table 3 ). At all cutoffs (1E2, 1E3, 1E 4, and 1E5), the SNPs associated with asthma were enriched as airway eQTLs. At a p value cutoff of 1x10 4, the enrichment was the largest (33.8 fold and 55.9 fold for 10% and 20% FDR, respectively). Enrichment was the lowest at a pvalue cutoff of 1x10 2, indicating reduced signaltonoise ratio. Importantly, we observed higher enrichment at p of 1x10 4and 1x10 5cutoffs when using a 20% FDR for eQTLs ( Table 3 ), suggesting that

some GWAS signals may be mediated by relatively weak eSNPs, which can only be discovered at a less stringent threshold (especially when the sample size is smallto moderate). Among the 567,589 SNPs investigated in the GABRIEL GWAS meta analysis, 1,458 were identified as eSNPs at a 10% FDR in small airways. It should be noted that for this analysis we did not restrict the analysis to the peak eSNP for each eQTL, but rather included all underlying eQTLs as eSNPs as long as their pvalues survived the 10% FDR threshold. The 1,458 eSNPs were significantly enriched for hits in the GABRIEL meta GWAS data ( Figure 2 ). This is consistent with a previous report showing that SNPs associated with complex traits are more likely to be eQTLs 21 . In Figure 2 , we used a rank–rank plot to test for enrichment of small pvalues among airway eSNPs in the GABRIEL study ( Materials and Methods ). The rankrank plot showed an upward deviation from the diagonal line, indicating that airway epithelial eSNPs were enriched as hits in GABRIEL metaGWAS ( Figure 2 ).

In addition, we also interrogated welldocumented asthma candidate genes 21,53 (Table S3 ) and found that these genes were also significantly more likely to be airway eSNPs. In Figure S1A , the rankrank curve deviated above the diagonal line, indicating that airway epithelial eSNPs in asthma candidate genes were enriched for being significantly associated with asthma in the GWAS. The magnitude of deviation of the curve above the diagonal line in Figure S1A was larger than the deviation in Figure 2 , suggesting that the eSNPs in asthma candidate gene are more enriched for GWAS signal than airway eSNPs as a whole. Consistent with this notion, the rankrank plot curve in Figure S1B deviated above the diagonal line, suggesting the asthma GWAS associations for the airway epithelial eSNPs that influence asthma candidate genes harbor more GWAS signal than all airway epithelial eSNPs. Although the contribution of candidate genes from the pre GWAS era to today’s GWAS findings has been modest these results suggest that these candidate genes have relevance to the pathogenesis of asthma.

Importantly, many of the most significant hits in the GABRIEL study were airway eSNPs (Table 4 ). Chromosomes 2q12 and 17q21 both contained strong GWAS hits for asthma. However, these loci harbored a number of genes that could potentially explain these associations 911 . We identified genes in these GWAS regions that were regulated by

airway epithelial eQTLs and have biological plausibility. For example, rs10192157, which reached genomewide significance in the asthma GWAS (pvalue=8.12E12) 9, was associated with interleukin 1 receptor, type II (IL1R2) expression level in the airway epithelium (P =7.48E04). SNP rs10192157 was also associated with the expression level of cyclindependent kinase 12 (CDK12) (p value =1.95E03) and StARrelated lipid transfer (START) domain containing 3 (STARD3) (pvalue=4.22E04) in airway epithelia.

Beyond the GABRIEL asthma meta GWAS, we also surveyed four large GWAS data on nonairway diseases: Alzheimer's disease, schizophrenia, obesity, and type 2 diabetes (Materials and Methods ). We explored whether the airway eSNPs were enriched for association signal in these four diseases using rankrank plot methods (Figure S2). For all diseases a portion of the points were above the line of identity suggesting that there is enrichment for eSNPs among susceptibility alleles; this was especially so for schizophrenia and Alzheimer’s disease. This suggests there is pleiotropy for eSNPs since a percentage of them are likely to be eSNPs in multiple tissues. However, the extent of deviation was less than that shown in figure 2 for asthma indicating that the airway eSNPs are more likely to be susceptibility alleles for asthma than for nonairway diseases. We also noted that an eSNP might also exist in more than one tissue types (Table S1 and S2).

Airway eQTLs are enriched in regulatory elements A large fraction of GWAS hits do not change protein sequence, but affect regulatory elements. The ENCODE Project has mapped out open chromatin and protein binding regions for a large number of factors across many different cell types 33,53 . These data serve as powerful orthogonal evidence to complement GWAS and eQTL findings by demonstrating the potential functional consequences of variants, which are outside of the coding regions. We queried the regulomeDB databases 33 and intersected the asthma

GWAS and airway eQTL data together with; (1) ChIPseq information for a variety of important regulatory factors across a diverse set of cell types; and (2) chromatin state information across over 100 cell types. 372 (56.4%) of probesets influenced by the airway eQTLs were supported by regulatory element data. 55.9% of the airway eSNPs, which were on the “all GWAS hit” list were supported by regulatory element data (enrichment pvalue = 3.3E35). Further, we investigated the enrichment of ENCODE entries for eSNPs among GABRIEL top hits (Table S4). Notably, rs10192157 (GABRIEL meta GWAS pvalue=8.1E12) was an eSNP controlling IL1R2, and was supported by ENCODE data showing that this SNP spans a DNase hypersensitivity site in a number of cell types and also spans a transcription factor binding site for CEBPB and CTCF as determined by ChIPseq assays. In Table S5, we list the leading SNP for each 10% FDR eQTL that were annotated in RegulomeDB33 . In brief, we queried the RegulomeDB database by eQTL chromosome position, and identified the regulatory elements where at least one eQTL resided. The regulatory elements are small DNA regions that modulate expression through various mechanisms. Their detailed position information can be retrieved from http://regulomedb.org/ by searching for SNP position or using dbSNP ID. For example rs10954213 influences expression of IRF5, which has been linked to asthma 54 . Footprinting evidence showed that rs10954213 is located in the HOXD3 motif in several cell types (Helas3, Hsmmt and Huh7). The detailed location of the regulatory site can be found at http://regulomedb.org/snp/chr7/128589426.

BioProcess Enrichment of Asthma GWAS Genes Airway epithelial eQTLs serve as an empirical “bridge” between GWAS associated SNPs and the genes underlying these associations. Firstly, we summarized “asthma SNPs” with globally significant associations (e.g. NHGRI catalog) and suggestive association in GABRIEL. Secondly, we obtained a list of 88 genes that were controlled by “asthma SNPs” through eQTL in airway epithelium. Last, we tested the 88 genes for enrichment in biological processes using the BioProcess gene sets. A number of BioProcess gene sets were significantly enriched (Figure 3 ) including responses to interferongamma, immune response signaling, proliferation of various types of immune cells, IL4 signaling (noting IL4 or its receptor is not directly identified by GWAS SNPs), etc.

DISCUSSIONS In this paper, publically available data on genetic variation and gene expression in a collection of human small and large airway epithelial cell samples were used to explore the genetic influence on gene expression in this tissue. With a relatively small sample size, we discovered 660 and 1,066 eQTLs at a 10% and 20% FDR, respectively in the small airways. These eQTLs are genetic variants that directly or indirectly govern gene expression in the airway epithelium and represent a unique resource for respiratory diseases research. We provide a few examples of how this dataset can be used to elucidate new molecular drivers of asthma. Because of the relatively small sample size, we were only able to capture eQTLs that were strong. Weaker eQTLs may have been missed by this study. Larger sample sizes will be needed to fully characterize the genetic architecture of gene expression in airway epithelium.

Chromosome 17q21 is one of the most consistent loci associated with asthma 9,10,5562 . Based on an eQTL study performed in lymphoblastoid cell lines and lung tissue, ORMD3L, GSDMB, and GSDMA have been suggested to be prime candidates driving the GWAS signal 9,10,21,58 . In Table 4 , we showed that the GWAS hits at this locus controlled expression levels of additional genes: CDK12, PPP1R1B, TCAP and STARD3 in the airway epithelium. Interestingly, these genes were missed in a largescale lung tissue eQTL study most likely owing to the heterogeneity of cell types in the lung tissue 21 . The cyclindependent kinase (CDK) family, of which CDK12 is a member, is a group of serine/threonine kinases that regulate cell cycle events through phosphorylation of transcription factors and tumour suppressor proteins required for DNA replication and cell division 63 . CDKs are possible therapeutic targets to dampen inflammation 64 . The CDK inhibitor Rroscovitine has been shown to induce apoptosis of human eosinophils63 . However, little is known about a possible role for titincap (TCAP), and protein phosphatase 1 regulatory subunit 1B (PPP1R1B, also known as dopamine and cAMP regulated neuronal phosphoprotein (DARPP32) in asthma.

Chromosome 2q12 is another locus consistently associated with asthma 9. The previous study of eQTLs in whole lung tissues showed that the expression of IL1RL1 was

controlled by a GWAS hit (rs13431828) 21 . Herein, we showed that the GWAS hits at this locus also control expression levels of IL1R2 in airway epithelial cells, indicating that this is an airway eQTL. It is noteworthy that IL1R2 was detectable in microarrays of whole lung tissue (IL1R2 expression was “present” in 98.8% of subjects). IL1R2 has been shown to be associated with aspirininduced asthma, both at the level of gene expression in human nasal polyps and as SNP associations 65 . In another study, IL1R2 SNPs were associated with atopy, and showed interaction with early childhood virus infection 66 . IL1R2 encodes type II receptor, which acts as a soluble decoy receptor for IL1, and thus a negative regulator of the IL1 pathway. IL1 cytokine prolongs the in vitro survival of polymorphonuclear cells (PMN) through IL1R2. IL4 antagonizes the action of IL1 by inducing the expression and release of IL1R2 67,68 . Furthermore, dexamethasone promotes the expression and release of IL1R2 in PMN 67,69 . Beside corticosteroids and IL4, IL13 also induces the expression and release of IL1R2 70,71 , whereas bacterial lipopolysaccharide (LPS) causes rapid shedding, followed by inhibition of the transcripts’ expression 7274 . Interestingly, data from ENCODE suggest that the IL1R2 eSNP is located at a binding site for the transcription factor CCAAT/Enhancer Binding Protein Beta (CEBPB), a member of the CEBPs family of basic leucine zipper transcription factors that regulates inflammatory protein expression in several cell types, including lung epithelial cells 75 . These data on IL1R2 show the utility of airway epithelial eQTLs in explaining GWAS signals especially when this information is integrated with complementary resources such as ENCODE.

SNP rs16856186 resides in an intergenic region of chr1q32.1 and has been previously 50 associated with FEV 1 decline in asthmatics (pvalue=9E6) . In epithelial cells, it controls the expression levels of ARV1 Homolog (S. Cerevisiae) (ARV1) on chr1q42.2 and Cystatin SN (CST1) on chr20p11.21 both in trans with r2 values of 0.30. Recently, differential expression of CST1 was reported in airway cells when comparing asthmatics with exerciseinduced bronchoconstriction (EIB) relative to asthmatics without EIB 76 . In addition, CST1 expression was increased in patients with seasonal allergic rhinitis 77 . Importantly, these two eQTLs are transactivating and airway specific, and were not discovered by previous eQTL studies.

A recent GWAS for childhood asthma and severe exacerbations identified a nonsynonymous coding SNP in the cadherinrelated family member 3 gene (CDHR3), which is highly expressed in airway epithelium 78 . Using our airway epithelium eQTL dataset, we found that CDHR3 is measured by two probesets, and that both probesets have cis eQTLs controlling their expression levels. Specifically, probe 231582_at is influenced by rs75858860 (pvalue = 1.1e3 and r2=0.09) and probe 35650_at is influenced by rs2528883 (pvalue=8.8e4 and r2=0.10)). It is possible that this gene’s effect on asthma and exacerbations is driven by both coding and regulatory SNPs in airway epithelium.

In this study, we identified a number of genes for which the variation in expression was largely explained by airway eQTLs. For example, GSTT2 expression was strongly controlled by a cis eQTL (r 2= 0.72 and pvalue=5.8e30) in small airways but not in whole lungs. Glutathione Stransferases (GSTs) are a superfamily of enzymes that catalyze the conjugation of glutathione with electrophilic compounds. They are involved in detoxifying toxic components of tobacco smoke, and the epithelial lining fluid contains 140fold higher levels of glutathione than plasma, indicating its critical role in protecting airway epithelium from oxidant injury 79,80 . In one study, a missense (Met139Ile) coding SNP in GSTT2 was associated with nonsmall cell lung cancer in smokers 81 . Other genes for which eQTLs explained most of the variation in expression included Churchill Domain Containing 1 (CHURC1, r 2= 0.76 and pvalue 7.29E34), Hepatocellular CarcinomaAssociated Antigen 520 (CHP2, r 2= 0.75 and pvalue= 1.03E32) and Family with Sequence Similarity 118, Member A (FAM118A, r 2= 0.74 and pvalue= 8.11E32). Interestingly, the level of expression of CHURC1 and FAM118A were also identified as being strongly influenced by eQTLs in a study of the genetic control of gene expression in the sputum of COPD patients 82 .

Two additional genes under epithelial eQTL control were SPINK5 and SPATS2L. SPINK5 encodes for lymphoepithelial Kazaltyperelated inhibitor (LEKTI), a serine protease inhibitor 83 . The gene is located on 5q3132, a region repeatedly associated with asthma in linkage studies 8486 . Moreover, SNPs in the SPINK5 gene showed significant

associations with atopy, atopic dermatitis and asthma 8789 . SPATS2L (spermatogenesis associated, serinerich 2like) is located on 2q33.1. SNPs near this gene showed the strongest associations in a GWAS of bronchodilator response in individuals with asthma 90 . The authors followed up their studies of the association signal with in vitro study of the effect of knockeddown of SPATS2L in human airway smooth muscle cells using short interfering RNA (siRNA). The knockdown led to an increase in the beta 2 adrenergic receptor (β 2AR) protein expression, suggesting that SPATS2L may affect 90 BDR by directly modulating β 2AR protein expression .

The airway epithelium plays an essential role in the pathogenesis of asthma, and the eQTL data set allows interpretation of asthma GWAS hits in the context of the pathways and networks they alter by empirically linking association loci to the underlying genes. We identified a set of genes whose expression level is under the influence of asthma GWAS SNPs (GABRIEL and NHGRI database), and conducted BioProcess enrichment on this gene set. Results ( Figure 3 ) show strong overrepresentation of genes in response to interferongamma, immune response signaling, proliferation of various types of immune cells (Tcell, mononuclear cell, lymphocytes, leukocytes), and IL4 signaling. Such analyses reveal the functions of the GWAS loci at a higher level and are consistent with current knowledge of asthma pathogenesis. IL4 is a key cytokine in the development of allergic inflammation and the activity of IL4 promotes cellular inflammation in asthma 91 . SNPs on IL4 or its receptor genes are not identified in asthma GWAS with global significance, although reported in some candidate gene studies 91 , suggesting that these SNPs have smalltomoderate effect size (if any). However, SNPs regulating the expression of other genes of the IL4 pathway were captured by GWAS and these SNPs may influence the IL4 pathway and asthma susceptibility through regulation of gene networks.

In summary, this paper reports the results of a study of small airway epithelial eQTLs that complements previous large scale studies of lung eQTLs 21 and which can be used to shed light on GWAS findings in pulmonary diseases. With a moderate sample size, we only had statistical power to identify eQTLs which had substantial effect size (r 2=

>~0.33). Strikingly, a large fraction (48%) of these strong eQTLs were not discovered in the large scale lung tissue study, and are therefore, termed airway eQTLs. Using the results of the largest to date GWAS of asthma as an example we show how the airway eQTL dataset can be used to identify additional causal genes and pathways underlying asthma. Our results will also serve as a valuable tool to study the pathogenesis of other lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer.

Table 1. Intersecting NHGRI GWAS Results with Small Airway eQTLs* 10% FDR 20% FDR Number of # cis # trans Enrichment # cis # trans Enrichment SNP Sets GWAS Hits eQTLs eQTLs fold eQTLs eQTLs fold All Diseases 11,598 129 0 9.2 † 171 0 7.5 † Airway Diseases 538 6 0 9.2 ‡ 6 4 9.5 ‡ *At 10% and 20% eQTLs, we detected 660 and 1066 small airway eQTLs, respectively. † Significant level <0.005 based on resampling test; ‡ not statistical significant based on resamplingbased test.

Table 2. Pulmonary Diseases GWAS Results Informed by Small Airway eQTLs* Airway eQTL Statistics GWAS Reports Expression SNP location † SNP rsID eQTL regulated †† Probeset ID (hg19) Pvalue β r2 Proposed Gene GWAS Disease/Traits Gene

CiseQTLs rs13233571 †201428_at 7:72971231 3.2E05 0.400 0.155 CLDN4 BCL7B Creactive protein rs2658782 1554071_at 11:93166731 1.0E04 0.343 0.137 CCDC67 CCDC67 Pulmonary function decline rs412658 210697_at 19:22359440 1.1E04 0.089 0.136 ZNF257 ZNF676 Telomere length rs12188164 †226125_at 5:428236 1.1E04 0.505 0.136 LOC100288152 AHRR Cystic fibrosis severity rs9272346 209480_at 6:32604372 2.6E34 2.529 0.767 HLADQB1 HLADQA1 Asthma, Type 1 diabetes rs9272346 213831_at 6:32604372 1.1E27 2.516 0.686 HLADQA1 HLADQA1 Asthma, Type 1 diabetes

rs9272346 236203_at 6:32604372 9.9E14 0.910 0.417 HLADQA1 HLADQA1 Asthma, Type 1 diabetes rs9272346 212999_x_at 6:32604372 2.7E26 1.192 0.666 HLADQB1 HLADQA1 Asthma, Type 1 diabetes HLADRB1, HLA rs9268905 221491_x_at 6:32432077 7.8E14 1.248 0.420 DRB3, HLADRB4, HLADRA Cystic fibrosis severity HLADRB5 rs9268905 209728_at 6:32432077 2.5E26 2.515 0.667 HLADRB4 HLADRA Cystic fibrosis severity

TranseQTLs rs16856186 †238140_at 1:205678126 1.65E09 0.743 0.299 ARV1 SLC45A3,NUCKS1 Pulmonary function decline rs16856186 †206224_at 1:205678126 1.90E09 1.405 0.297 CST1 SLC45A3,NUCKS1 Pulmonary function decline rs7927044 233413_at 11:127761666 1.37E09 1.299 0.301 KIRREL3AS3,ETS1 Asthma (childhood onset)

rs4452212 232233_at 2:137015991 7.69E11 1.734 0.338 SLC22A16 CXCR4 Telomere length rs4452212 232232_s_at 2:137015991 4.93E10 1.926 0.314 SLC22A16 CXCR4 Telomere length rs4452212 205048_s_at 2:137015991 2.78E09 1.985 0.292 PSPH CXCR4 Telomere length rs17331332 †210170_at 4:106808107 4.41E11 0.606 0.345 PDLIM3 INTS12, GSTCD, Pulmonary function

NPNT *20% FDR was applied in eQTL discovery. In this analysis, eQTL discovery is carried out only in GWAS SNPs, which greatly reduced the number of tests and multiple testing penalty. Therefore, the pvalue threshold for 10% or 20% FDR is much relaxed compared to a genomewide eQTL search. † eQTL gene is the gene regulated by the airway epithelium eQTL. †† Proposed gene is the gene underlying GWAS hit, as proposed in the original publication.

Table 3. Intersecting Gabriel Asthma meta GWAS Results with Small Airway eQTLs* 10% FDR 20% FDR Pvalue Gabriel # cis # trans Enrichment Enrichment # cis # trans Enrichment Enrichment cutoff Hits eQTLs eQTLs fold pvalue eQTLs eQTLs fold pvalue 1E2 7,204 52 3 6.3 1.9e27 77 3 5.7 1.4e35 1E3 1,186 31 4 24.4 7.2e38 37 3 17.3 7.6e37 1E4 348 13 3 38.0 4.3e22 36 2 55.9 1.9e51 1E5 175 4 0 18.9 2.8e06 16 0 46.8 9.9e24 At 10% and 20% FDR we detected small airway 660 and 1066 eQTLs, respectively.

Table 4. GABRIEL meta GWAS Results Informed with eQTLs in Small Airway but not Lung Tissue* Small Airway eQTL Expression SNP location GWAS SNP rsID eQTL eQTL eQTL presents Probeset ID (hg19) pvalue Pvalue β r2 regulated Gene in other tissues ††† rs10192157 205403_at 2:102968356 8.12E12 7.48E04 0.509 0.105 IL1R2 NYY rs2596464 205905_s_at 6:31412961 5.05E06 7.12E05 0.167 0.143 MICA, MICB NNN, YYY rs2596464 205904_at 6:31412961 5.05E06 9.99E04 0.178 0.100 MICA NNN rs3939286 206426_at 9:6210099 4.53E14 7.19E04 0.060 0.106 MLANA NNN rs6485713 203409_at 11:46962474 9.24E06 2.31E03 0.124 0.087 DDB2 NYN rs7117590 203363_s_at 11:47005633 8.84E06 2.27E03 0.126 0.087 ATG13 NNN rs12453682 219226_at 17:37770005 3.32E07 4.04E04 0.166 0.115 CDK12 NNN rs4252627 225165_at 17:37868715 4.77E08 1.82E03 0.227 0.090 PPP1R1B NNY rs12150079 205766_at 17:38025417 2.04E09 1.52E03 0.194 0.093 TCAP NNN rs11557467 202991_at 17:38028634 2.49E17 4.22E04 0.157 0.114 STARD3 NNN rs11557467 225694_at 17:38028634 2.49E17 1.95E03 0.202 0.089 CDK12 NNN *20% FDR was applied in eQTL discovery. † Whether the small airway eQTL regulated gene presents in other tissue types: liver, LCL (lymphoblastoid cell lines) and whole blood, respectively. For example, NYN denotes a gene is regulated by eQTL in LCL, but not liver or whole blood.

Legend to Figure 1: Histogram of r2 values for eQTLs (fraction of gene expression level explained by the peak eSNP) for all small airway eQTLs (upper) and for small airway specific eQTLs (lower).

Legend to Figure 2: Rankrank plot (Materials and Methods ) were used to examine whether airway eSNPs were enriched for small pvalues in Gabriel meta GWAS. Among all SNPs surveyed by the GABRIEL meta GWAS, 1,458 were eSNPs in the airway epithelia at 10% FDR. Yaxis: observed standardized rank of airway eSNPs among all SNPs in Gabriel meta GWAS. Xaxis: expected standardized rank value if airway eSNPs were randomly distributed in ranked Gabriel SNPs.

Legend to Figure 3: BioProcess enrichment of genes transcriptionally regulated by asthma GWAS associated SNPs in airway epithelium

ACKNOWLEDGMENTS The authors would like to thank Dr. Ronald G. Crystal and colleagues for conducting the gene expression and genotype measurement 30,31 and contributing the results in GEO databases (accession: GSE5057 and GSE40364). Hao K is partially supported by National Natural Science Foundation of China (Grant No. 21477087). The following authors are partially supported by NIH grant R01HL118542: Obeidat M, Di Narzo A, Paré P and Hao K. Luo W is partially supported by Fujian Province Overseas Studying Fellowship. Ma’en Obeidat is a Postdoctoral Fellow of the Michael Smith Foundation for Health Research (MSFHR) and the Canadian Institute for Health Research (CIHR) Integrated and Mentored Pulmonary and Cardiovascular Training program (IMPACT).

REFERENCES 1. Choudhry S, Taub M, Mei R, et al. Genomewide screen for asthma in Puerto Ricans: evidence for association with 5q23 region. Hum Genet 2008;123:45568. 2. DeWan AT, Triche EW, Xu X, et al. PDE11A associations with asthma: results of a genomewide association scan. J Allergy Clin Immunol 2010;126:8713 e9. 3. Gudbjartsson DF, Bjornsdottir US, Halapi E, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009;41:3427. 4. Hancock DB, Romieu I, Shi M, et al. Genomewide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children. PLoS Genet 2009;5:e1000623. 5. Himes BE, Hunninghake GM, Baurley JW, et al. Genomewide association analysis identifies PDE4D as an asthmasusceptibility gene. Am J Hum Genet 2009;84:58193. 6. Hui J, Oka A, James A, et al. A genomewide association scan for asthma in a general Australian population. Hum Genet 2008;123:297306. 7. Kim SH, Cho BY, Park CS, et al. AlphaTcatenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanateinduced asthma by genomewide association analysis. Clin Exp Allergy 2009;39:20312. 8. Mathias RA, Grant AV, Rafaels N, et al. A genomewide association study on Africanancestry populations for asthma. J Allergy Clin Immunol 2010;125:33646 e4. 9. Moffatt MF, Gut IG, Demenais F, et al. A largescale, consortiumbased genomewide association study of asthma. The New England journal of medicine 2010;363:121121. 10. Moffatt MF, Kabesch M, Liang L, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007;448:4703. 11. Ober C, Tan Z, Sun Y, et al. Effect of variation in CHI3L1 on serum YKL40 level, risk of asthma, and lung function. The New England journal of medicine 2008;358:168291. 12. Sleiman PM, Flory J, Imielinski M, et al. Variants of DENND1B associated with asthma in children. N Engl J Med 2010;362:3644. 13. Weidinger S, Gieger C, Rodriguez E, et al. Genomewide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet 2008;4:e1000166. 14. Hirota T, Takahashi A, Kubo M, et al. Genomewide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet 2011. 15. Torgerson DG, Ampleford EJ, Chiu GY, et al. Metaanalysis of genomewide association studies of asthma in ethnically diverse North American populations. Nat Genet 2011. 16. Noguchi E, Sakamoto H, Hirota T, et al. GenomeWide Association Study Identifies HLADP as a Susceptibility Gene for Pediatric Asthma in Asian Populations. PLoS Genet 2011;7:e1002170. 17. Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases. Nature 2009;461:74753. 18. Emilsson V, Thorleifsson G, Zhang B, et al. Genetics of gene expression and its effect on disease. Nature 2008;452:4238.

19. Emilsson V, Thorleifsson G, Zhang B, et al. Genetics of gene expression and its effect on disease. Nature 2008;452:4238. 20. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:70713. 21. Hao K, Bosse Y, Nickle DC, et al. Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS genetics 2012;8:e1003029. 22. Obeidat M, Miller S, Probert K, et al. GSTCD and INTS12 regulation and expression in the human lung. PloS one 2013;8:e74630. 23. Lamontagne M, Couture C, Postma DS, et al. Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls. PloS one 2013;8:e70220. 24. Dimas AS, Deutsch S, Stranger BE, et al. Common regulatory variation impacts gene expression in a cell typedependent manner. Science 2009;325:124650. 25. Tam A, Wadsworth S, Dorscheid D, Man SF, Sin DD. The airway epithelium: more than just a structural barrier. Therapeutic advances in respiratory disease 2011;5:25573. 26. Holgate ST. The sentinel role of the airway epithelium in asthma pathogenesis. Immunological reviews 2011;242:20519. 27. Holgate ST, Roberts G, Arshad HS, Howarth PH, Davies DE. The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis. Proceedings of the American Thoracic Society 2009;6:6559. 28. Mercer BA, Lemaitre V, Powell CA, D'Armiento J. The Epithelial Cell in Lung Health and Emphysema Pathogenesis. Current respiratory medicine reviews 2006;2:101 42. 29. Thorley AJ, Tetley TD. Pulmonary epithelium, cigarette smoke, and chronic obstructive pulmonary disease. International journal of chronic obstructive pulmonary disease 2007;2:40928. 30. Carolan BJ, Heguy A, Harvey BG, Leopold PL, Ferris B, Crystal RG. Up regulation of expression of the ubiquitin carboxylterminal hydrolase L1 gene in human airway epithelium of cigarette smokers. Cancer research 2006;66:1072940. 31. Gao C, Tignor NL, Salit J, et al. HEFT: eQTL analysis of many thousands of expressed genes while simultaneously controlling for hidden factors. Bioinformatics 2014;30:36976. 32. Laurie CC, Doheny KF, Mirel DB, et al. Quality control and quality assurance in genotypic data for genomewide association studies. Genetic epidemiology 2010;34:591 602. 33. Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome research 2012;22:17907. 34. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genomewide association studies through prephasing. Nature genetics 2012;44:9559. 35. Schadt EE, Woo S, Hao K. Bayesian method to predict individual SNP genotypes from gene expression data. Nature genetics 2012;44:6038. 36. Kang HM, Sul JH, Service SK, et al. Variance component model to account for sample structure in genomewide association studies. Nature genetics 2010;42:34854. 37. Di Narzo A, Cheng H, Lu J, Hao K. MetaeQTL: a tool set for flexible eQTL metaanalysis. BMC bioinformatics 2014;15:392.

38. Lambert JC, IbrahimVerbaas CA, Harold D, et al. Metaanalysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature genetics 2013;45:14528. 39. Morris AP, Voight BF, Teslovich TM, et al. Largescale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nature genetics 2012;44:98190. 40. Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015;518:197206. 41. Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:74852. 42. Biological insights from 108 schizophreniaassociated genetic loci. Nature 2014;511:4217. 43. Ferreira MA, Matheson MC, Duffy DL, et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 2011;378:100614. 44. Schadt EE, Molony C, Chudin E, et al. Mapping the genetic architecture of gene expression in human liver. PLoS biology 2008;6:e107. 45. Westra HJ, Peters MJ, Esko T, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nature genetics 2013;45:123843. 46. Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etiologic and functional implications of genomewide association loci for human diseases and traits. Proc Natl Acad Sci U S A 2009;106:93627. 47. Flutre T, Wen X, Pritchard J, Stephens M. A statistical framework for joint eQTL analysis in multiple tissues. PLoS genetics 2013;9:e1003486. 48. Greenawalt DM, Dobrin R, Chudin E, et al. A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome research 2011;21:100816. 49. Dehghan A, Dupuis J, Barbalic M, et al. Metaanalysis of genomewide association studies in >80 000 subjects identifies multiple loci for Creactive protein levels. Circulation 2011;123:7318. 50. Imboden M, Bouzigon E, Curjuric I, et al. Genomewide association study of lung function decline in adults with and without asthma. The Journal of allergy and clinical immunology 2012;129:121828. 51. Hancock DB, Artigas MS, Gharib SA, et al. Genomewide joint metaanalysis of SNP and SNPbysmoking interaction identifies novel loci for pulmonary function. PLoS genetics 2012;8:e1003098. 52. Bosse Y, Hudson TJ. Toward a comprehensive set of asthma susceptibility genes. Annual review of medicine 2007;58:17184. 53. Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:5774. 54. Wang C, RoseZerilli MJ, Koppelman GH, et al. Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma. Gene 2012;504:2205. 55. Bisgaard H, Bonnelykke K, Sleiman PM, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med 2009;179:17985.

56. Ferreira MA, McRae AF, Medland SE, et al. Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. Eur J Hum Genet 2010. 57. Galanter J, Choudhry S, Eng C, et al. ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am J Respir Crit Care Med 2008;177:1194200. 58. Halapi E, Gudbjartsson DF, Jonsdottir GM, et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet 2010;18:9028. 59. Madore AM, Tremblay K, Hudson TJ, Laprise C. Replication of an association between 17q21 SNPs and asthma in a FrenchCanadian familial collection. Hum Genet 2008;123:935. 60. Sleiman PM, Annaiah K, Imielinski M, et al. ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. J Allergy Clin Immunol 2008;122:12257. 61. Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN. A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol 2008;121:8603. 62. Wu H, Romieu I, SienraMonge JJ, Li H, del RioNavarro BE, London SJ. Genetic variation in ORM1like 3 (ORMDL3) and gasderminlike (GSDML) and childhood asthma. Allergy 2009;64:62935. 63. Duffin R, Leitch AE, Sheldrake TA, et al. The CDK inhibitor, Rroscovitine, promotes eosinophil apoptosis by downregulation of Mcl1. FEBS letters 2009;583:25406. 64. Leitch AE, Haslett C, Rossi AG. Cyclindependent kinase inhibitor drugs as potential novel antiinflammatory and proresolution agents. British journal of pharmacology 2009;158:100416. 65. Sekigawa T, Tajima A, Hasegawa T, et al. Geneexpression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirinintolerant asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 2009;39:97281. 66. Daley D, Park JE, He JQ, et al. Associations and interactions of genetic polymorphisms in innate immunity genes with early viral infections and susceptibility to asthma and asthmarelated phenotypes. Journal of Allergy and Clinical Immunology 2012;130:128493. 67. Colotta F, Re F, Muzio M, et al. Interleukin1 type II receptor: a decoy target for IL1 that is regulated by IL4. Science 1993;261:4725. 68. Lang D, Knop J, Wesche H, et al. The Type II IL1 Receptor Interacts with the IL1 Receptor Accessory Protein: A Novel Mechanism of Regulation of IL1 Responsiveness. The Journal of Immunology 1998;161:68717. 69. Müller B, Peri G, Doni A, et al. High circulating levels of the IL1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration. Journal of Leukocyte Biology 2002;72:6439. 70. Re F, Muzio M, De Rossi M, et al. The type II "receptor" as a decoy target for interleukin 1 in polymorphonuclear leukocytes: characterization of induction by dexamethasone and ligand binding properties of the released decoy receptor. The Journal of Experimental Medicine 1994;179:73943.

71. Colotta F, Saccani S, Giri JG, et al. Regulated expression and release of the IL1 decoy receptor in human mononuclear phagocytes. The Journal of Immunology 1996;156:253441. 72. PentonRol G, Orlando S, Polentarutti N, et al. Bacterial Lipopolysaccharide Causes Rapid Shedding, Followed by Inhibition of mRNA Expression, of the IL1 Type II Receptor, with Concomitant UpRegulation of the Type I Receptor and Induction of Incompletely Spliced Transcripts. The Journal of Immunology 1999;162:29318. 73. Brown EA, Dare HA, Marsh CB, Wewers MD. The combination of endotoxin and dexamethasone induces type II interleukin 1 receptor (IL1r II) in monocytes: a comparison to interleukin 1 beta (IL1 beta) and interleukin 1 receptor antagonist (IL 1ra). Cytokine 1996;8:82836. 74. Yu PW, Schuler LA, Kehrli M, Mattocks L, Nonnecke BJ, Czuprynski CJ. Effects of dexamethasone treatment on IL1 receptor mRNA levels in vivo. Journal of Leukocyte Biology 1997;62:4014. 75. Lin CH, Nai PL, Bien MY, Yu CC, Chen BC. ThrombinInduced CCAAT/EnhancerBinding Protein β Activation and IL8/CXCL8 Expression via MEKK1, ERK, and p90 Ribosomal S6 Kinase 1 in Lung Epithelial Cells. The Journal of Immunology 2014;192:33848. 76. Hallstrand TS, Lai Y, Henderson WR, Jr., Altemeier WA, Gelb MH. Epithelial regulation of eicosanoid production in asthma. Pulmonary pharmacology & therapeutics 2012;25:4327. 77. Imoto Y, Tokunaga T, Matsumoto Y, et al. Cystatin SN Upregulation in Patients with Seasonal Allergic Rhinitis. PLoS ONE 2013;8:e67057. 78. Bonnelykke K, Sleiman P, Nielsen K, et al. A genomewide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 2014;46:515. 79. Cantin AM, North SL, Hubbard RC, Crystal RG. Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985) 1987;63:1527. 80. Harju T, Mazur W, Merikallio H, Soini Y, Kinnula VL. GlutathioneS transferases in lung and sputum specimens, effects of smoking and COPD severity. Respiratory research 2008;9:80. 81. Zienolddiny S, Campa D, Lind H, et al. A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of nonsmall cell lung cancer in smokers. Carcinogenesis 2008;29:11649. 82. Qiu W, Cho MH, Riley JH, et al. Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease. PLoS ONE 2011;6:e24395. 83. Magert HJ, Kreutzmann P, Drogemuller K, et al. The 15domain serine proteinase inhibitor LEKTI: biochemical properties, genomic organization, and pathophysiological role. European journal of medical research 2002;7:4956. 84. Postma DS, Bleecker ER, Amelung PJ, et al. Genetic Susceptibility to Asthma — Bronchial Hyperresponsiveness Coinherited with a Major Gene for Atopy. New England Journal of Medicine 1995;333:894900. 85. Noguchi E, Shibasaki M, Arinami T, et al. Evidence for Linkage Between Asthma/Atopy in Childhood and Chromosome 5q31q33 in a Japanese Population. American Journal of Respiratory and Critical Care Medicine 1997;156:13903.

86. Yokouchi Y, Nukaga Y, Shibasaki M, et al. Significant Evidence for Linkage of MiteSensitive Childhood Asthma to Chromosome 5q31–q33 near the Interleukin 12 B Locus by a Genomewide Search in Japanese Families. Genomics 2000;66:15260. 87. Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. British Journal of Dermatology 2003;148:6659. 88. Kabesch M, Carr D, Weiland SK, Von Mutius E. Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample. Clinical & Experimental Allergy 2004;34:3405. 89. Kusunoki T, Okafuji I, Yoshioka T, et al. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. The Journal of allergy and clinical immunology 2005;115:6368. 90. Himes BE, Jiang X, Hu R, et al. GenomeWide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene. PLoS Genet 2012;8:e1002824. 91. Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin4 receptor antagonists. Respiratory research 2001;2:6670.

Figure 2

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observed

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Figure 3

Supplementary Figure Legends

Legend to Figure S1: Rank-rank plot (Materials and Methods ) were used to examine whether eSNPs in asthma candidate genes were enriched for small pvalue in GABRIEL meta-GWAS (A); and whether eSNPs in asthma candidate genes were enriched for asthma-GWAS association pvalue even among all airway eSNPs ( B) The asthma candidate genes were previously proposed 21,52 and listed in Table S3.

Legend to Figure 2S: Rank-rank plot (Materials and Methods ) were used to compare GWAS pvalue of airway epithelium eSNPs vs. GWAS pvalue of all SNPs examined in a GWAS study. Enrichment of GWAS signal in airway epithelium eSNPs were assessed in four disease GWAS: A, Alzheimer's disease 38 ; B, schizophrenia 41,42 ; C, obesity 40 ; and D, type 2 diabetes 39 .

Figure S1A

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Figure S1B

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Figure S2A. Enrichment of Significant Pvalues among Airway eSNPs in Large

Alzheimer's Disease GWAS

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Figure S2B. Enrichment of Significant Pvalues among Airway eSNPs in Large Schizophrenia GWAS

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Figure S2C. Enrichment of Significant Pvalues among Airway eSNPs in Large Obesity

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Figure S2D. Enrichment of Significant Pvalues among Airway eSNPs in Large Type 2

Diabetes GWAS

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-log10(Standardized.Rankexpected)

Table S1a, small Airway cis eQTL 10% FDR reporterID Gene Snp(Chr:hg19‐Position) Pvalue beta Rsq T Liver LCL Whole.Blood 226736_at CHURC1 14:65399263 7.29E‐34 ‐1.135590632 0.761821003 ‐18.1506989 Y Y Y 206149_at CHP2 16:23788291 1.03E‐32 ‐1.976438678 0.74928776 ‐17.54507233 NA NA NA 219629_at FAM118A 22:45807538 8.11E‐32 ‐1.570091649 0.739078788 ‐17.08084251 Y Y Y 239412_at IRF5 7:128619415 6.10E‐31 ‐1.024841237 0.728685151 ‐16.63228011 Y Y Y 206777_s_at CRYBB2 22:25885353 7.44E‐31 ‐1.308830307 0.727642235 ‐16.58852156 Y Y NA 206777_s_at CRYBB2P1 22:25885353 7.44E‐31 ‐1.308830307 0.727642235 ‐16.58852156 NA Y NA 205439_at GSTT2 22:24312589 1.65E‐30 ‐1.412848385 0.723405095 ‐16.4129749 Y NA NA 209978_s_at LPA 6:161135313 2.01E‐29 ‐1.248207414 0.709707519 ‐15.86866611 Y NA NA 209978_s_at PLG 6:161135313 2.01E‐29 ‐1.248207414 0.709707519 ‐15.86866611 NA NA NA 219759_at ERAP2 5:96252589 2.29E‐29 ‐1.540975043 0.708978616 ‐15.84064021 NA Y NA 205542_at STEAP1 7:89801787 5.78E‐27 0.863579289 0.676128354 14.66380654 NA Y NA 201143_s_at EIF2S1 14:67836797 9.21E‐27 0.766110177 0.673198299 14.56625685 Y Y NA 1553992_s_at NBR2 17:41249094 1.97E‐26 0.485550136 0.668351854 14.40729351 NA Y NA 1552463_at SERPINB11 18:61382296 2.25E‐26 ‐2.035177492 0.66750809 ‐14.37991561 NA NA NA 238069_at LOC100506090 6:99888013 4.17E‐26 0.672694884 0.66351961 14.25166528 NA NA NA 220542_s_at BPIFA1 20:31839036 6.87E‐25 ‐2.633959017 0.644801661 ‐13.6740204 NA NA NA 227462_at ERAP2 5:96252589 7.97E‐24 ‐1.146717301 0.627579838 ‐13.17457188 NA Y NA 206010_at HABP2 10:115310563 2.41E‐23 ‐0.485013658 0.619537853 ‐12.9508063 NA NA NA 1554122_a_at HSD17B12 11:43773813 2.54E‐23 ‐0.599241752 0.619159232 ‐12.94041108 NA Y Y 231565_at C4orf22 4:81560988 4.27E‐23 ‐0.532337837 0.615305244 ‐12.835293 NA Y NA 209977_at PLG 6:161135313 5.34E‐23 ‐1.292946926 0.61364519 ‐12.79039973 NA NA NA 232382_s_at PCMTD1 8:52742230 1.78E‐22 1.000354416 0.604561694 12.54872369 Y NA NA 233675_s_at TPTE2P6 13:25180151 3.17E‐22 ‐1.160677181 0.60014377 ‐12.43352666 NA NA NA 214889_at FAM149A 4:187099089 4.09E‐22 ‐0.77623769 0.598170372 ‐12.38254981 NA Y NA 217753_s_at RPS26 12:56435929 4.79E‐22 ‐0.500682007 0.596931322 ‐12.35069141 Y Y NA 229497_at ANKDD1A 15:65198309 6.25E‐22 ‐0.434409899 0.594861759 ‐12.29773184 NA Y Y 237298_at FLJ26850 19:50586013 1.01E‐21 1.768149073 0.591058069 12.201209 NA Y NA 236473_at CC2D2A 4:15482322 1.88E‐20 1.022948545 0.567383619 11.62265989 NA NA NA 232315_at ZNF880 19:52880265 2.08E‐20 ‐0.872358976 0.566538057 ‐11.60266278 NA Y NA 235104_at ERAP2 5:96273032:TA_T 2.31E‐20 ‐0.673983643 0.565653622 ‐11.58179295 NA Y NA 212730_at SYNM 15:99655433 3.37E‐20 ‐0.702221648 0.562470348 ‐11.5070681 NA Y NA 240033_at PLG 6:161135313 3.60E‐20 ‐1.057122325 0.561925322 ‐11.49433469 NA NA NA 207022_s_at LDHC 11:18438770 9.95E‐20 ‐1.313069713 0.553255547 ‐11.29410747 NA Y Y 228058_at ZG16B 16:2880105 1.02E‐19 1.056809696 0.553017906 11.28867958 NA Y Y 208727_s_at CDC42 1:22388872 1.21E‐19 ‐1.555369793 0.551533734 ‐11.25485133 NA Y Y 213979_s_at CTBP1 4:1205667 1.64E‐19 1.425953002 0.54895168 11.19628994 NA NA Y 231828_at LOC253039 9:123516572 1.67E‐19 0.917726314 0.548793168 11.19270678 NA Y NA 210732_s_at LGALS8 1:236694662 2.10E‐19 1.547373829 0.546782283 11.14736932 NA Y Y 205319_at PSCA 8:143760256 2.49E‐19 ‐1.473958527 0.545292307 ‐11.11391694 NA NA NA 203096_s_at RAPGEF2 4:160292612 3.54E‐19 0.767576262 0.542183805 11.04450629 NA Y NA 1554820_at AGBL3 7:134719551 4.39E‐19 ‐0.314629741 0.540301908 ‐11.00273144 NA NA NA 218746_at TAPBPL 12:6569545 5.05E‐19 ‐0.493337543 0.539048607 ‐10.97501217 Y Y NA 226606_s_at GTPBP5 20:60776275 7.93E‐19 0.51629887 0.535026677 10.88660117 NA NA Y 219044_at THNSL2 2:88463155 9.05E‐19 0.844632947 0.533843571 10.86074912 NA Y Y 210096_at CYP4B1 1:47366050 1.23E‐18 1.100219156 0.531074189 10.80050695 NA NA NA 239302_s_at LOC100506922 2:128103801 1.31E‐18 1.118185311 0.530512063 10.78832511 NA NA NA 226475_at FAM118A 22:45731539 1.75E‐18 ‐0.728563589 0.527878698 ‐10.73146177 Y Y Y 219269_at HMBOX1 8:28909523 3.63E‐18 0.769597366 0.521214859 10.5890421 Y Y Y 213098_at RQCD1 2:219437018 4.49E‐18 ‐0.573821998 0.519241692 ‐10.54726825 NA Y Y 1559240_at LOC100507053 4:100027179 5.35E‐18 ‐0.758582672 0.517618121 ‐10.51302884 NA NA NA 1568843_at TTLL13 15:90785549 9.38E‐18 ‐0.409642157 0.512374241 ‐10.40324763 NA NA NA 231947_at MYCT1 6:152949109 9.61E‐18 ‐0.525938065 0.512152839 ‐10.39863929 NA NA NA 227910_at XPNPEP3 22:41295839:AAAG_ 2.20E‐17 0.764462828 0.504329941 10.23716364 Y NA NA 227083_at B3GALTL 13:31905641 2.81E‐17 ‐0.718562721 0.501985774 ‐10.18927873 Y Y NA 205730_s_at ABLIM3 5:148520184 3.90E‐17 ‐0.418027549 0.498814642 ‐10.12485988 NA NA Y 227474_at LOC654433 2:113993344 1.28E‐16 1.045704758 0.487223245 9.892782189 NA Y NA 239208_s_at YBEY 21:47716680 1.56E‐16 0.563349838 0.48526095 9.854003809 NA Y NA 208159_x_at DDX11 12:31230300 1.90E‐16 ‐0.631694025 0.483317733 ‐9.815743462 Y NA Y 226665_at AHSA2 2:61413092:AATAA 2.04E‐16 1.042912915 0.482599858 9.801644235 Y Y NA 221892_at H6PD 1:9331629 2.06E‐16 0.473023492 0.482540945 9.800488011 Y NA Y 213682_at NUP50 22:45544304 2.48E‐16 0.512877401 0.4806813 9.76405564 Y NA Y 242162_at WDR69 2:228776938 3.50E‐16 ‐0.445523409 0.477208661 ‐9.696356591 NA NA NA 218747_s_at TAPBPL 12:6569545 3.59E‐16 ‐0.551456173 0.47697333 ‐9.69178436 Y Y NA 201563_at SORD 15:45147368 4.68E‐16 1.216734781 0.474292994 9.639845754 Y Y Y 230931_at PLG 6:161135313 5.57E‐16 ‐0.495683541 0.472526532 ‐9.60575271 NA NA NA 1561759_at LOC100507322 4:120524283 5.66E‐16 ‐0.408759079 0.472363883 ‐9.602618972 NA NA NA 1561759_at LOC645513 4:120524283 5.66E‐16 ‐0.408759079 0.472363883 ‐9.602618972 NA NA NA 227067_x_at NOTCH2NL 1:145484698 6.90E‐16 ‐0.693675351 0.470351088 ‐9.56391366 NA Y NA 1555745_a_at LYZ 12:69774563 9.91E‐16 ‐1.794106718 0.466656989 ‐9.493234204 Y NA Y 212699_at SCAMP5 15:75147789 1.07E‐15 ‐0.922321822 0.465885191 ‐9.478524903 Y Y NA

200962_at RPL31 2:101634798:TTCAG 1.07E‐15 0.707971382 0.465880156 9.478429017 Y Y NA 231710_at CAPS 19:5915883 1.45E‐15 ‐0.614153239 0.462735235 ‐9.418694651 Y Y Y 220649_at AGBL3 7:134705373 1.49E‐15 ‐0.354593488 0.462484123 ‐9.413938952 NA NA NA 207249_s_at SLC28A2 15:45493122 1.51E‐15 ‐1.506507343 0.462318743 ‐9.41080801 NA NA NA 206306_at RYR3 15:34096531 1.58E‐15 2.205564466 0.461888542 9.402667674 NA NA NA 203502_at BPGM 7:134322829 1.68E‐15 ‐0.666076366 0.461238588 ‐9.390380455 Y NA NA 218948_at QRSL1 6:107102022 2.43E‐15 0.653039741 0.457402638 9.318137317 Y Y Y 223591_at RNF135 17:29315193 2.46E‐15 0.60813977 0.45728174 9.315867976 NA Y Y 1555497_a_at CYP4B1 1:47266064 4.01E‐15 1.867837012 0.452150924 9.219977409 NA NA NA 223592_s_at RNF135 17:29314784:TACAG 4.99E‐15 0.692163033 0.449844928 9.177142303 NA Y Y 229500_at SLC30A9 4:42098807 5.24E‐15 0.39723996 0.449327804 9.167558387 NA Y NA 220471_s_at MYCT1 6:152949109 5.77E‐15 ‐0.389901553 0.448303083 ‐9.148590663 NA NA NA 228160_at LOC339290 18:5240629:A_AT 6.10E‐15 ‐0.539698373 0.447724335 ‐9.137891749 NA Y NA 1565525_a_at TCP11L2 12:106708656 1.13E‐14 ‐0.52141281 0.441133709 ‐9.01674479 NA NA Y 236424_at CEP250 20:34049219:T_TCT 1.19E‐14 ‐0.285638975 0.440605219 ‐9.00708426 Y NA Y 219959_at MOCOS 18:33779276 1.56E‐14 ‐1.367578424 0.437686687 ‐8.953876467 Y Y NA 235080_at CLUAP1 16:3589846 1.63E‐14 ‐1.159385777 0.4371827 ‐8.944712321 NA NA Y 228619_x_at TIPRL 1:168171487 1.72E‐14 0.327645246 0.436611389 8.934332495 Y Y Y 218857_s_at ASRGL1 11:62098934:A_AGA 1.85E‐14 ‐0.714291881 0.435803985 ‐8.919678555 Y Y Y 1556064_at LOC284926 22:46652063 2.09E‐14 0.357702961 0.434523688 8.896478484 NA NA NA 1558484_s_at LRRC27 10:134164622 2.18E‐14 ‐0.605594084 0.434068798 ‐8.88824623 Y Y NA 239733_at DYDC2 10:82116602 2.31E‐14 ‐0.533793924 0.433428475 ‐8.876667653 NA NA NA 219870_at ATF7IP2 16:10425057 2.43E‐14 0.595332621 0.432876126 8.86668876 NA NA NA 212570_at ENDOD1 11:94863186 3.10E‐14 ‐0.555122968 0.430203434 ‐8.818518596 Y Y NA 220425_x_at ROPN1B 3:125684510:GATA_ 3.15E‐14 ‐0.554183088 0.430049403 ‐8.815748262 Y NA NA 223158_s_at NEK6 9:127029736 3.18E‐14 0.630436021 0.429938289 8.813750217 NA NA Y 210430_x_at RHD 1:25757996 4.14E‐14 ‐0.316248607 0.427054447 ‐8.762006278 NA NA Y 242660_at C10orf112 10:19506742 4.62E‐14 ‐0.437023422 0.425832616 ‐8.74014856 NA NA NA 212365_at MYO1B 2:192231088 4.81E‐14 0.763445541 0.425405489 8.732516618 NA Y NA 243680_at LOC100506476 14:74498829 7.35E‐14 ‐0.735907941 0.420703304 ‐8.648803858 NA NA NA 204855_at SERPINB5 18:61144034 8.13E‐14 ‐0.977795563 0.419586561 ‐8.629003935 NA NA NA 229068_at CCT5 5:10253537 1.12E‐13 0.43624067 0.415970056 8.565093135 Y NA Y 218609_s_at NUDT2 9:34172565:T_TAC 1.14E‐13 0.387767958 0.415785843 8.561846223 Y Y NA 1569582_at LOC201651 3:151487551 1.30E‐13 ‐1.165444669 0.414308014 ‐8.535827671 NA Y NA 236321_at FAM200B 4:15706466 1.59E‐13 0.440530975 0.41208549 8.496795867 NA Y NA 220592_at CCDC40 17:78018534 1.66E‐13 1.030891523 0.411616517 8.48857466 Y NA NA 1554273_a_at ERAP2 5:96252589 2.31E‐13 ‐0.375399539 0.407850215 ‐8.422735686 NA Y NA 210586_x_at RHD 1:25747399 2.47E‐13 ‐0.511361668 0.407085635 ‐8.409409759 NA NA Y 230936_at DNAJB13 11:73683507 2.95E‐13 0.399303185 0.405052775 8.3740432 NA NA NA 240436_at MIPEPP3 13:21904824 3.16E‐13 ‐0.568038633 0.404293504 ‐8.360857592 NA NA NA 222784_at SMOC1 14:70450179 3.44E‐13 ‐0.767061354 0.403301273 ‐8.343645678 NA NA NA 205412_at ACAT1 11:107985264 4.71E‐13 0.442313266 0.399712611 8.281574781 NA Y NA 227598_at C7orf29 7:150034184 4.87E‐13 0.334470127 0.399319582 8.274793772 NA Y NA 231996_at N4BP2 4:40091984 5.28E‐13 0.639281529 0.39840008 8.258942374 NA Y NA 230279_at LOC100507540 9:74927609 5.32E‐13 ‐0.44216863 0.398307714 ‐8.25735107 NA NA NA 1558649_at LOC145757 15:101398972 5.83E‐13 ‐0.6169489 0.397247468 ‐8.239097831 NA NA NA 1553269_at ZNF718 4:122874 6.84E‐13 ‐0.672935686 0.395415728 ‐8.20761847 Y Y NA 215483_at AKAP9 7:91592795:G_GTC 6.85E‐13 0.857879999 0.395390104 8.207178602 Y NA NA 239078_at BROX 1:222829302:TC_T 7.42E‐13 ‐1.334842563 0.394465464 ‐8.191315358 NA Y NA 56919_at WDR48 3:39125293 7.55E‐13 0.203058476 0.394266374 8.187902085 Y Y Y 218347_at TYW1 7:66560797 8.34E‐13 ‐0.57161052 0.393113692 ‐8.168156072 Y Y Y 218347_at TYW1B 7:66560797 8.34E‐13 ‐0.57161052 0.393113692 ‐8.168156072 NA Y NA 225324_at CRLS1 20:5987634 8.59E‐13 ‐0.364272576 0.392764223 ‐8.162174904 NA Y Y 202869_at OAS1 12:113357193 1.07E‐12 ‐0.5974408 0.390180067 ‐8.11802424 Y NA Y 232028_at ZNF678 1:227900908 1.08E‐12 ‐0.843071128 0.390055573 ‐8.115900653 NA NA NA 203243_s_at PDLIM5 4:95580462 1.25E‐12 1.003557997 0.388369597 8.087172227 Y Y NA 214890_s_at FAM149A 4:187099089 1.31E‐12 ‐0.510437811 0.387804178 ‐8.077550345 NA Y NA 201826_s_at SCCPDH 1:246922390 1.65E‐12 0.64967919 0.385143003 8.032348793 NA Y Y 222938_x_at ENPP3 6:132040562 1.66E‐12 ‐0.519450627 0.385031712 ‐8.030461459 NA NA Y 1553510_s_at RQCD1 2:219307744 1.71E‐12 ‐0.601916101 0.384686846 ‐8.024614541 NA Y Y 238258_at WBSCR28 7:73274384:AG_A 2.15E‐12 ‐0.525993646 0.382015047 ‐7.979393752 Y NA NA 216619_at GTPBP10 7:89969878 2.71E‐12 ‐0.247452778 0.379272344 ‐7.933113216 NA NA NA 226989_at RGMB 5:98135126 3.03E‐12 0.601503976 0.377931221 7.910533888 Y NA Y 227655_at LOC100505806 5:9541866 3.22E‐12 ‐0.382021334 0.377227455 ‐7.898698374 NA NA NA 1559171_at MGC57346 17:44182983 3.89E‐12 ‐1.453110843 0.374969433 ‐7.860784979 NA NA NA 237784_at SUB1 5:32592527 3.93E‐12 ‐0.264162131 0.374855873 ‐7.858880671 NA NA Y 222780_s_at BAALC 8:104222938 4.45E‐12 ‐0.979154374 0.373349328 ‐7.833638826 NA NA NA 203223_at RABEP1 17:5270414 5.20E‐12 ‐0.277862206 0.371477108 ‐7.802325958 Y NA NA 219683_at FZD3 8:28428104 5.67E‐12 0.480060916 0.37044417 7.785076225 NA NA Y 222048_at CRYBB2P1 22:25855629 7.31E‐12 0.233253755 0.367383264 7.734067494 NA Y NA 209685_s_at PRKCB 16:23788291 8.68E‐12 ‐0.990484795 0.36529441 ‐7.699348252 NA Y Y 228155_at FAM213A 10:82196061 8.96E‐12 0.441565456 0.364915916 7.693064978 NA NA NA

206577_at VIP 6:153059060 9.10E‐12 ‐0.362376311 0.36472521 ‐7.68990001 NA NA NA 239297_at KIAA1456 8:12827679 9.31E‐12 0.74426395 0.364446674 7.685278497 NA NA NA 218918_at MAN1C1 1:25928025:CTTCT 9.46E‐12 ‐0.869530512 0.364257767 ‐7.682144849 Y NA Y 229071_at C17orf100 17:6540354 1.15E‐11 ‐0.688459102 0.361930544 ‐7.643587684 NA Y NA 221057_at SPATA1 1:84943104 1.29E‐11 0.217544079 0.360494394 7.619837183 NA NA NA 211382_s_at TACC2 10:123872473 1.39E‐11 0.265776555 0.35959982 7.605059608 NA NA NA 217869_at HSD17B12 11:43878485 1.39E‐11 0.292298748 0.359538493 7.604047007 NA Y Y 222816_s_at ZCCHC2 18:60239967 1.45E‐11 ‐0.910275599 0.359039069 ‐7.59580292 NA NA NA 221735_at WDR48 3:39127345:C_CTA 1.95E‐11 ‐0.219488513 0.355423577 ‐7.536236541 Y Y Y 228381_at ATF7IP2 16:10415353 2.08E‐11 0.941331827 0.354630886 7.523203379 NA NA NA 228381_at LOC100287628 16:10415353 2.08E‐11 0.941331827 0.354630886 7.523203379 NA NA NA 220466_at CCDC15 11:124820428:G_GT 2.13E‐11 ‐0.340753267 0.35430599 ‐7.517864272 Y NA Y 229906_at ARMC7 17:73085662 2.39E‐11 0.374970298 0.352878731 7.494428432 NA NA Y 212818_s_at ASB1 2:239367057 2.42E‐11 ‐0.239996316 0.352765391 ‐7.492568661 NA NA Y 218210_at FN3KRP 17:80674839:CG_C 2.89E‐11 ‐0.383928328 0.350564938 ‐7.456499373 NA Y Y 218327_s_at SNAP29 22:21183881 3.01E‐11 ‐0.633804334 0.350063596 ‐7.448291335 Y Y Y 227113_at ADHFE1 8:67381619 3.03E‐11 0.346780068 0.349947579 7.44639241 Y NA Y 205700_at HSD17B6 12:57154489 3.44E‐11 ‐0.555661259 0.348373401 ‐7.420645844 NA NA NA 1569030_s_at NUB1 7:151057396:AC_A 3.44E‐11 ‐0.372038548 0.34837138 ‐7.4206128 NA Y Y 215785_s_at CYFIP2 5:156722486 3.44E‐11 0.351847287 0.348369906 7.420588718 Y Y Y 210219_at SP100 2:231380217 3.56E‐11 ‐0.87868681 0.347954632 ‐7.413802561 Y NA Y 206777_s_at CRYBB2 22:25287889 3.57E‐11 1.260636693 0.347907543 7.413033222 Y Y NA 206777_s_at CRYBB2P1 22:25287889 3.57E‐11 1.260636693 0.347907543 7.413033222 NA Y NA 219414_at CLSTN2 3:140053735 3.67E‐11 0.392090555 0.347564312 7.407426426 NA NA NA 201093_x_at SDHA 5:288408 3.76E‐11 ‐0.354338466 0.347264925 ‐7.402537176 NA Y Y 236098_at C17orf110 17:73708829 3.87E‐11 ‐0.728946908 0.346907118 ‐7.39669553 NA NA NA 203200_s_at MTRR 5:7933629 4.32E‐11 0.347253165 0.345558165 7.374688235 Y Y Y 212364_at MYO1B 2:192318241 4.66E‐11 0.722490915 0.344589097 7.358894005 NA Y NA 227421_at YBEY 21:47724648 6.25E‐11 ‐0.29579875 0.340921323 ‐7.299230259 NA Y NA 230737_s_at LOC387647 10:29719245 6.45E‐11 0.625218997 0.340523952 7.292776959 NA Y NA 238567_at SGPP2 2:223423804 6.89E‐11 0.45629446 0.339686035 7.279175954 NA Y NA 222030_at SIVA1 14:105225620 7.21E‐11 0.681148131 0.339121508 7.270017748 NA Y Y 201922_at NSA2 5:74048150 7.27E‐11 ‐0.43947826 0.339015051 ‐7.268291169 NA Y NA 218217_at SCPEP1 17:55037898:T_TA 7.59E‐11 ‐0.506952547 0.338473722 ‐7.2595139 NA NA Y 227340_s_at RGMB 5:98135084 8.34E‐11 0.734994681 0.337275439 7.240097876 Y NA Y 1556267_at C12orf28 12:70145471 8.90E‐11 ‐0.407463843 0.336461988 ‐7.226927733 Y NA Y 231081_at C2orf73 2:54568287 8.98E‐11 0.505258291 0.33634018 7.224956329 NA NA NA 213438_at NFASC 1:204884177 9.51E‐11 0.796156252 0.335616175 7.21324244 NA NA NA 228425_at LOC654433 2:113994417 1.14E‐10 ‐0.549174418 0.33326501 ‐7.175246873 NA Y NA 202581_at HSPA1A 6:31798593 1.15E‐10 0.961207543 0.333189319 7.174024804 NA Y Y 202581_at HSPA1B 6:31798593 1.15E‐10 0.961207543 0.333189319 7.174024804 NA Y Y 205905_s_at MICA 6:31409528 1.18E‐10 0.305724859 0.332835844 7.168318691 NA NA NA 205905_s_at MICB 6:31409528 1.18E‐10 0.305724859 0.332835844 7.168318691 Y Y Y 222060_at KRT8P12 3:160291866 1.25E‐10 ‐0.438543648 0.332099965 ‐7.15644428 NA NA NA 240391_at NDUFB2 7:140436764 1.30E‐10 ‐0.561329245 0.331694941 ‐7.149911434 NA Y Y 214136_at NUDT13 10:74853663:TATAC 1.42E‐10 0.642007396 0.330501486 7.130672852 Y Y NA 227808_at DNAJC15 13:43597706 1.46E‐10 0.765523568 0.330149644 7.125004334 Y Y Y 227005_at RPP14 3:58284189 1.49E‐10 ‐0.306705985 0.329882629 ‐7.12070342 NA NA NA 209939_x_at CFLAR 2:202017674 1.52E‐10 0.23379091 0.329657358 7.117075545 NA NA NA 222764_at ASRGL1 11:62083530 1.54E‐10 ‐0.608176374 0.32944821 ‐7.11370785 Y Y Y 225809_at PARM1 4:75971072 1.55E‐10 0.76842322 0.329366179 7.112387131 NA Y NA 1559171_at MGC57346 17:43682202 1.67E‐10 ‐1.412721771 0.328471934 ‐7.097994556 NA NA NA 230364_at CHPT1 12:102133685 1.68E‐10 ‐0.463594994 0.328398408 ‐7.09681159 NA Y Y 230552_at LOC100134317 19:36685690 1.71E‐10 ‐0.778440313 0.328117633 ‐7.092294736 NA NA NA 230552_at LOC284412 19:36685690 1.71E‐10 ‐0.778440313 0.328117633 ‐7.092294736 NA NA NA 213373_s_at CASP8 2:202198340 1.82E‐10 ‐0.392033724 0.327344125 ‐7.07985589 Y NA Y 238576_at MOCOS 18:33779276 2.02E‐10 ‐0.57832602 0.326013103 ‐7.058467409 Y Y NA 1555478_at C17orf82 17:59494574 2.06E‐10 0.209297428 0.325745112 7.054163383 Y NA NA 208063_s_at CAPN9 1:230913996 2.17E‐10 1.383707517 0.325075689 7.043415724 NA NA Y 237471_at LOC154822 7:158785095 2.21E‐10 0.311105764 0.324836737 7.039580516 NA NA NA 217932_at MRPS7 17:73257986 2.46E‐10 0.236675095 0.323462189 7.017530936 NA Y Y 232737_s_at ENPP3 6:132051181 2.52E‐10 ‐0.806671945 0.323147756 ‐7.012489884 NA NA Y 208733_at RAB2A 8:61473307:G_GT 2.61E‐10 ‐0.434049259 0.32270399 ‐7.005377143 NA Y NA 242446_at C6orf163 6:88070261:CTCA_ 2.66E‐10 0.459170417 0.322465979 7.001563135 Y NA Y 231133_at CCDC164 2:26650419 2.86E‐10 ‐0.291168204 0.321545679 ‐6.98682145 NA NA NA 205185_at SPINK5 5:147444785 2.88E‐10 ‐0.608037675 0.321456336 ‐6.985390796 Y NA NA 1552398_a_at CLEC12A 12:10118747 2.91E‐10 ‐0.585699675 0.321300583 ‐6.982896924 NA NA Y 208683_at CAPN2 1:223897012 3.08E‐10 0.181905245 0.320590456 6.971529749 NA Y NA 236107_at UBE2Z 17:47016837 3.08E‐10 ‐0.496892517 0.320570928 ‐6.971217239 NA Y Y 204359_at FLRT2 14:85604752 3.29E‐10 ‐0.782964969 0.319726558 ‐6.957708187 NA NA NA 204359_at LOC100506718 14:85604752 3.29E‐10 ‐0.782964969 0.319726558 ‐6.957708187 NA NA NA 210695_s_at WWOX 16:78306219 3.41E‐10 0.271566762 0.319234735 6.949842906 Y NA Y

214552_s_at RABEP1 17:5270414 3.72E‐10 ‐0.365429392 0.318126207 ‐6.932124215 Y NA NA 234341_x_at LOC91548 1:211854180 3.72E‐10 ‐0.217460624 0.318107943 ‐6.931832392 NA NA NA 214827_at PARD6B 20:49367817:T_TA 3.78E‐10 ‐0.416000156 0.317898859 ‐6.928491831 NA NA NA 202364_at MXI1 10:112018687:T_TCC 4.05E‐10 ‐0.237466629 0.317035025 ‐6.914694838 NA NA Y 37512_at HSD17B6 12:57166413 4.11E‐10 ‐0.450869413 0.316830967 ‐6.911436746 NA NA NA 201432_at CAT 11:34459717 4.15E‐10 0.29288913 0.316703368 6.90939965 NA Y Y 232111_at LINC00617 14:96341958 4.37E‐10 ‐0.601713885 0.31604091 ‐6.898826159 NA NA NA 239740_at ETV6 12:11797525 4.60E‐10 ‐0.708324103 0.315363302 ‐6.888015286 NA NA Y 228992_at MED28 4:17630242 4.61E‐10 0.293367877 0.315322206 6.887359756 NA Y NA 1570376_at LOC154822 7:158787168 4.89E‐10 ‐0.352701243 0.314567322 ‐6.875321515 NA NA NA 215229_at LOC100129973 15:52469476 5.50E‐10 0.409604014 0.313020829 6.850676287 NA NA NA 225214_at LOC100129034 9:127029736 5.54E‐10 0.403515796 0.312929998 6.849229475 NA NA NA 1562754_at LOC339260 17:20858920 5.58E‐10 ‐0.838263425 0.31283387 ‐6.84769839 NA NA NA 213423_x_at TUSC3 8:15400752:ATAT_ 6.33E‐10 0.366582024 0.311182981 6.821416962 Y NA NA 222783_s_at SMOC1 14:70450179 6.48E‐10 ‐0.302225685 0.310891311 ‐6.816776289 NA NA NA 208149_x_at DDX11 12:31228357 6.57E‐10 ‐0.475729961 0.310694466 ‐6.813644779 Y NA Y 220488_s_at BCAS3 17:59100246 7.15E‐10 0.36957569 0.309595365 6.796166154 NA Y NA 213170_at GPX7 1:53079133:TG_T 7.49E‐10 ‐0.38823304 0.30898662 ‐6.786490122 NA Y Y 207957_s_at PRKCB 16:23777883 8.15E‐10 ‐1.150060106 0.307868003 ‐6.76871809 NA Y Y 1553400_a_at C17orf69 17:43934736:TG_T 8.98E‐10 ‐0.478977011 0.306583823 ‐6.748328965 NA Y NA 213179_at RQCD1 2:219537993 9.12E‐10 ‐0.378038236 0.306381441 ‐6.74511699 NA Y Y 228141_at GPX8 5:54471439 9.71E‐10 0.519402763 0.305559331 6.732072962 NA NA NA 205469_s_at IRF5 7:128576086 1.03E‐09 ‐0.454838701 0.304782368 ‐6.71975041 Y Y Y 224449_at DDI2 1:15959886 1.14E‐09 ‐0.24133734 0.30339149 ‐6.697703569 NA NA Y 224449_at RSC1A1 1:15959886 1.14E‐09 ‐0.24133734 0.30339149 ‐6.697703569 NA NA Y 236105_at ZBTB10 8:81407651:T_TG 1.20E‐09 ‐0.444498365 0.302724492 ‐6.687136471 Y NA NA 205654_at C4BPA 1:207287187 1.27E‐09 ‐0.95213824 0.301965792 ‐6.675120844 NA NA Y 204089_x_at MAP3K4 6:161372852 1.34E‐09 0.233189579 0.301244525 6.663702215 NA Y Y 40687_at GJA4 1:35304501 1.48E‐09 ‐0.712773176 0.299993267 ‐6.643902602 NA NA NA 223638_at LOC100653178 1:21814668:C_CA 1.49E‐09 ‐0.622525305 0.299899799 ‐6.642424066 NA NA NA 223638_at NBPF3 1:21814668:C_CA 1.49E‐09 ‐0.622525305 0.299899799 ‐6.642424066 NA Y Y 203430_at HEBP2 6:138701873 1.51E‐09 0.287327764 0.299726991 6.639690649 Y Y Y 232798_at DNAJC5B 8:66960324 1.53E‐09 0.31897456 0.299552985 6.63693851 NA Y NA 1555550_at ZACN 17:74060168 1.59E‐09 ‐0.587299479 0.299048261 ‐6.628956889 NA NA NA 213547_at CAND2 3:12832853 1.65E‐09 0.497998653 0.298499015 6.620273344 Y NA Y 242316_at TMOD3 15:52253307 1.73E‐09 ‐0.272611465 0.297904433 ‐6.610875522 NA NA Y 238465_at SETD9 5:56193465 1.80E‐09 0.435461967 0.297355454 6.602200772 NA NA NA 206291_at NTS 12:86041527 1.81E‐09 1.281351074 0.297279198 6.600995977 NA Y NA 223159_s_at NEK6 9:127029736 1.83E‐09 0.596542609 0.297169302 6.599259765 NA NA Y 1568658_at C2orf74 2:61363196 1.85E‐09 ‐0.384038091 0.296962199 ‐6.595988037 NA Y NA 1568658_at KIAA1841 2:61363196 1.85E‐09 ‐0.384038091 0.296962199 ‐6.595988037 Y NA NA 235076_at CALCOCO2 17:47039541 2.02E‐09 ‐0.386497498 0.295822912 ‐6.577995492 NA Y Y 230837_at LOC100132057 1:147804327 2.17E‐09 ‐0.512257458 0.294859982 ‐6.562795156 NA NA NA 228879_at SNORD104 17:62258534 2.27E‐09 ‐0.29435519 0.294262862 ‐6.553372486 NA NA NA 218957_s_at PAAF1 11:73611349 2.27E‐09 0.484293776 0.294242889 6.55305736 NA Y Y 243900_at WDR38 9:127703351 2.32E‐09 0.885705589 0.293962907 6.548640048 NA NA NA 1556277_a_at PAPD4 5:78981369:TAACT 2.37E‐09 0.61206964 0.293677389 6.544135946 Y NA Y 225871_at STEAP2 7:89800241 2.58E‐09 0.460037205 0.292521853 6.525912632 NA Y NA 1562337_at OR7D2 19:9314803 2.67E‐09 ‐0.493359436 0.292061486 ‐6.518654865 Y Y Y 206765_at KCNJ2 17:68159947 2.84E‐09 ‐0.504096317 0.291263811 ‐6.50608258 NA Y Y 44617_at OGFOD2 12:123515172 3.29E‐09 0.339136497 0.289262076 6.474550421 NA Y NA 203243_s_at PDLIM5 4:94973737 3.32E‐09 0.444834523 0.28915435 6.472854161 Y Y NA 210697_at ZNF257 19:22350336:AAGAC 3.32E‐09 ‐0.145091723 0.289126776 ‐6.472420004 NA Y NA 242325_at YWHAH 22:32349543 3.33E‐09 0.494083473 0.28910825 6.472128304 Y NA Y 215175_at PCNX 14:71491218:T_TA 3.39E‐09 0.581250202 0.288864631 6.468292599 NA Y Y 243352_at ALPK1 4:113344431 3.40E‐09 0.446631003 0.288816293 6.467531585 NA NA Y 201563_at SORD 15:45710210 3.44E‐09 0.606512156 0.288660238 6.465074775 Y Y Y 226125_at LOC100288152 5:467977 3.46E‐09 ‐0.917110135 0.288590163 ‐6.463971621 NA NA NA 224971_at C2orf15 2:99584971:ATATG 3.47E‐09 0.231365956 0.288541972 6.463212998 NA NA NA 224971_at MRPL30 2:99584971:ATATG 3.47E‐09 0.231365956 0.288541972 6.463212998 NA NA NA 238673_at SAMD12 8:119287930 3.54E‐09 1.280610774 0.288283009 6.459136583 Y Y Y 217550_at ATF6 1:161923037 3.60E‐09 ‐0.443521931 0.288033058 ‐6.455202426 NA NA Y 1554480_a_at ARMC10 7:102742144 3.70E‐09 ‐0.335178477 0.287683138 ‐6.449695386 NA Y NA 222770_s_at GUF1 4:44616296 3.76E‐09 0.379975924 0.287466868 6.446292081 Y Y Y 209556_at NCDN 1:36021293 4.31E‐09 0.381069321 0.285601801 6.416953723 NA NA NA 206421_s_at SERPINB7 18:61370172:TC_T 4.39E‐09 ‐0.811049595 0.285372278 ‐6.413344572 NA NA NA 223471_at RAB3IP 12:70209475 4.59E‐09 0.309246645 0.284741119 6.403421297 Y Y NA 243761_at CLDN12 7:90068214 4.72E‐09 0.219701898 0.284384078 6.397808756 Y Y NA 215116_s_at DNM1 9:130971428 4.75E‐09 ‐0.984367641 0.28429631 ‐6.396429175 NA NA NA 218272_at TTC38 22:46686404 5.07E‐09 ‐0.319755801 0.283401956 ‐6.382373641 NA Y Y 211922_s_at CAT 11:34527436 5.40E‐09 0.594460116 0.282541412 6.368853354 NA Y Y 242251_at SPATA5 4:124174553 5.55E‐09 ‐0.238118618 0.282166718 ‐6.362967582 NA NA NA

231463_at CNTD1 17:40865647:G_GTC 5.87E‐09 1.099674009 0.281416871 6.351190939 NA NA NA 210993_s_at SMAD1 4:146502731 6.44E‐09 0.595613824 0.280135484 6.331072556 NA Y NA 240570_at INADL 1:62454724 6.60E‐09 ‐0.410111006 0.27981034 ‐6.325968882 Y NA Y 230736_at LOC387647 10:29717504 6.74E‐09 0.449368775 0.27951595 6.321348364 NA Y NA 224595_at SLC44A1 9:108141335 7.25E‐09 ‐0.731157598 0.278515109 ‐6.305642892 Y Y Y 230539_at FAM182A 20:25969265 7.36E‐09 ‐0.435601838 0.278309423 ‐6.302415769 NA NA NA 222904_s_at TMC5 16:19403894 7.51E‐09 0.248158525 0.278041182 6.298207467 NA NA NA 230175_s_at DCBLD2 3:98662518 7.53E‐09 ‐0.764867465 0.278004203 ‐6.297627349 NA NA Y 229430_at C8orf46 8:67378573 8.44E‐09 ‐0.31876585 0.276434473 ‐6.273007104 Y NA Y 236548_at GIPC2 1:78604387 8.66E‐09 ‐0.652122638 0.276088596 ‐6.267583628 Y NA NA 229290_at DAPL1 2:159707106 8.82E‐09 ‐0.740504872 0.275839094 ‐6.263671657 NA NA NA 225804_at CYB5D2 17:4203664 8.86E‐09 0.43016455 0.275766519 6.262533784 Y Y Y 222448_s_at CMPK1 1:47779259:CCTT_ 8.90E‐09 ‐0.290142609 0.275706282 ‐6.261589379 NA Y Y 201968_s_at PGM1 1:63906880 1.00E‐08 0.236854211 0.274057936 6.235751836 Y Y Y 1554258_a_at DNAJC5B 8:66955837 1.02E‐08 0.328658471 0.273868098 6.232776816 NA Y NA 229918_at CCDC40 17:78019345 1.04E‐08 ‐0.269465612 0.273520257 ‐6.227326058 Y NA NA 232428_at MOGAT2 11:75428766 1.05E‐08 ‐0.362458773 0.273387458 ‐6.225245189 NA NA NA 1568593_a_at NUDT16P1 3:131080505 1.09E‐08 0.319813877 0.272983252 6.218911923 NA NA NA 223833_at WDR55 5:140161604 1.13E‐08 ‐0.225929402 0.272424842 ‐6.210163518 Y NA Y 225540_at MAP2 2:210319745 1.15E‐08 0.654405857 0.272153786 6.205917371 NA NA NA 228461_at SH3RF3 2:109807719 1.15E‐08 0.587418073 0.272132012 6.205576293 NA NA NA 222735_at TMEM38B 9:108495704:T_TTT 1.22E‐08 ‐0.868813648 0.27139237 ‐6.193991019 Y Y NA 229835_s_at SLMO2 20:57597645 1.23E‐08 0.668236611 0.27129261 6.192428598 NA NA NA 222821_s_at GEMIN7 19:45602781 1.23E‐08 0.203764638 0.27127959 6.192224678 NA NA Y 230695_s_at RSPH9 6:43614513 1.23E‐08 0.432895167 0.271212077 6.191167324 NA NA NA 205904_at MICA 6:31330066 1.25E‐08 0.349935387 0.2710126 6.188043277 NA NA NA 219865_at LINC00339 1:22358457 1.32E‐08 0.696952523 0.270245053 6.176023857 NA NA NA 219388_at GRHL2 8:102698284 1.35E‐08 ‐0.284861701 0.269944809 ‐6.171322686 NA NA NA 203374_s_at TPP2 13:103315483:T_TA 1.37E‐08 ‐0.337970968 0.269799086 ‐6.169041092 Y Y Y 208358_s_at UGT8 4:115517933 1.38E‐08 ‐0.832937056 0.269695314 ‐6.167416369 NA Y NA 214180_at MAN1C1 1:25928855:GT_G 1.39E‐08 ‐0.660764245 0.269517308 ‐6.164629466 Y NA Y 210987_x_at TPM1 15:63376659 1.40E‐08 0.284931459 0.269451703 6.163602354 NA Y Y 205308_at ZC2HC1A 8:79657263 1.45E‐08 0.306570962 0.268951827 6.155776783 NA NA NA 209228_x_at TUSC3 8:15400752:ATAT_ 1.51E‐08 0.383274785 0.268421184 6.147470393 Y NA NA 239161_at FDX1 11:110340283 1.54E‐08 ‐0.399513123 0.268110204 ‐6.142602858 NA NA Y 1561096_at LOC285419 4:124775472 1.56E‐08 0.625796623 0.268000994 6.140893548 NA NA NA 1568987_at MGC57346 17:44018399 1.60E‐08 ‐0.285825145 0.267655757 ‐6.135490265 NA NA NA 204916_at RAMP1 2:238768160 1.97E‐08 ‐0.503871273 0.264719659 ‐6.089550449 Y Y Y 235141_at MARVELD2 5:68698766:C_CA 1.97E‐08 0.265526121 0.264693222 6.089136903 Y NA NA 243884_at TEX26 13:31553036 2.04E‐08 0.5192692 0.264251827 6.082232473 NA NA NA 231399_at RAB3IP 12:70209121:ATC_A 2.12E‐08 ‐0.57178578 0.263712782 ‐6.073801178 Y Y NA 238353_at RASL11A 13:28053011 2.15E‐08 ‐0.37773695 0.263510549 ‐6.070638194 NA Y Y 1560665_at SCPEP1 17:55037898:T_TA 2.24E‐08 ‐0.405807979 0.262924918 ‐6.061479231 NA NA Y 1556065_at LOC284926 22:46647388 2.35E‐08 0.097703086 0.262239564 6.050761546 NA NA NA 236999_at PPWD1 5:64925256 2.46E‐08 ‐0.199901411 0.261650124 ‐6.041544545 NA NA Y 229457_at ANKHD1 5:139807474 2.53E‐08 ‐0.934421459 0.261237637 ‐6.035094923 NA NA NA 229855_at RNF34 12:121863092:C_CAA 2.65E‐08 ‐0.202066696 0.26059795 ‐6.025093417 Y Y Y 201562_s_at SORD 15:45147368 2.66E‐08 0.690538004 0.260534775 6.02410571 Y Y Y 243746_at IGHMBP2 11:68678718 2.81E‐08 ‐0.193902491 0.259744427 ‐6.011749678 Y NA NA 221581_s_at LAT2 7:73779983:AT_A 2.89E‐08 ‐0.499055396 0.259388348 ‐6.006183185 NA NA Y 1560184_at TMCO5A 15:38122066:CCAA_ 2.91E‐08 ‐0.429073339 0.2592605 ‐6.004184614 NA NA NA 232816_s_at DDX11 12:31222178 2.94E‐08 ‐0.470558818 0.259120418 ‐6.001994833 Y NA Y 1560177_at CCDC66 3:56706329 2.96E‐08 ‐0.259697445 0.259035344 ‐6.000664948 NA Y NA 205382_s_at CFD 19:886257 2.98E‐08 ‐0.932053673 0.258957407 ‐5.99944665 Y NA Y 219750_at TMEM144 4:159175475 3.02E‐08 ‐1.00236263 0.258761029 ‐5.996376933 NA NA Y 243426_at LOC339290 18:5247942 3.05E‐08 0.321440118 0.258598048 5.993829305 NA Y NA 201617_x_at CALD1 7:134191457 3.10E‐08 ‐0.551986997 0.258406129 ‐5.990829391 Y NA Y 205467_at CASP10 2:201714728 3.14E‐08 0.188784222 0.258206419 5.987707731 NA NA Y 236983_at TMC5 16:19418840 3.21E‐08 0.408516755 0.257891012 5.982777748 NA NA NA 1561106_at LINC00271 6:136059423 3.26E‐08 0.32869534 0.257688435 5.979611429 NA NA NA 222801_s_at STAG3L4 7:66786384 3.33E‐08 0.341111368 0.257376818 5.974740878 NA Y NA 214136_at NUDT13 10:75380256:TTC_T 3.43E‐08 0.607337379 0.256968276 5.968355582 Y Y NA 219587_at TTC12 11:113238223 3.45E‐08 ‐0.337590064 0.256900353 ‐5.967293998 Y Y Y 1559105_at LEKR1 3:156570521:T_TA 3.61E‐08 0.277089728 0.256235384 5.95690133 NA NA NA 240898_at SPAG16 2:214802636 3.62E‐08 ‐0.534995271 0.25619264 ‐5.956233307 NA NA NA 208934_s_at LGALS8 1:236397249 3.73E‐08 0.457162978 0.255767617 5.949590968 NA Y Y 206754_s_at CYP2B6 19:41469850 3.74E‐08 ‐0.706997937 0.255752149 ‐5.949349232 NA NA NA 206754_s_at CYP2B7P1 19:41469850 3.74E‐08 ‐0.706997937 0.255752149 ‐5.949349232 NA NA NA 225862_at SLC25A26 3:66491822 3.79E‐08 0.190532377 0.255567843 5.946468931 Y NA Y 209137_s_at USP10 16:84742355 3.79E‐08 0.738950809 0.255561928 5.946376489 NA NA NA 242884_at LOC440570 1:17460994 3.83E‐08 ‐0.257330337 0.255409299 ‐5.943991248 NA NA NA 239713_at CASC2 10:119934302 3.93E‐08 ‐0.650471953 0.255053248 ‐5.938427058 NA NA NA

201143_s_at EIF2S1 14:67332377 4.10E‐08 0.410184638 0.254466717 5.929261271 Y Y NA 232395_x_at AGBL3 7:134706143 4.33E‐08 ‐0.25661133 0.253680291 ‐5.916972081 NA NA NA 1552575_a_at C6orf141 6:49627343 4.42E‐08 ‐0.529541336 0.253380791 ‐5.912292021 NA NA NA 227560_at SFXN2 10:104509064 4.46E‐08 ‐0.195190909 0.253267526 ‐5.910522126 Y Y Y 226342_at SPTBN1 2:54889136 4.57E‐08 ‐0.256164033 0.252907 ‐5.904888524 NA Y Y 229128_s_at ANP32E 1:150560296 4.62E‐08 1.487811525 0.252762074 5.902623935 NA NA NA 224926_at EXOC4 7:133541625 4.70E‐08 0.269928843 0.252526635 5.898945007 Y Y Y 236471_at NFE2L3 7:26150279 4.73E‐08 ‐0.293014484 0.252437026 ‐5.897544802 NA Y NA 217870_s_at CMPK1 1:47828442 4.86E‐08 0.288130601 0.252055323 5.891580432 NA Y Y 223095_at MARVELD1 10:99487376 4.87E‐08 0.335310123 0.252011488 5.890895489 NA NA NA 220364_at FLJ11235 5:111755690 5.22E‐08 0.237622168 0.251047712 5.875836059 NA NA NA 229280_s_at LINC00340 6:21819216 5.45E‐08 0.306727513 0.250425561 5.86611477 NA NA NA 221690_s_at NLRP2 19:55474502 5.51E‐08 ‐1.185213392 0.250271604 ‐5.86370915 NA Y Y 235361_at STAMBP 2:74067880 5.56E‐08 ‐0.180158017 0.250137948 ‐5.861620752 NA Y Y 204082_at PBX3 9:128620887 5.67E‐08 0.330595713 0.249864504 5.857348122 NA Y Y 211726_s_at FMO2 1:171158797:TC_T 5.81E‐08 0.629206484 0.249523709 5.852023107 Y NA NA 214059_at IFI44 1:79128569:T_TG 5.90E‐08 0.4291278 0.249308931 5.848667148 NA Y Y 235878_at TAF1B 2:9960111 5.95E‐08 0.317942607 0.249188404 5.846783879 Y Y Y 235602_at TP53INP1 8:95684778:TG_T 6.09E‐08 ‐0.302013865 0.248860094 ‐5.841653926 NA Y NA 204904_at GJA4 1:35304501 6.18E‐08 ‐0.650718252 0.248635256 ‐5.838140754 NA NA NA 219060_at WDYHV1 8:124439743 6.54E‐08 ‐0.288814472 0.247851059 ‐5.825887275 NA Y NA 210272_at CYP2B7P1 19:41469850 6.71E‐08 ‐0.730335839 0.247479199 ‐5.820076707 NA NA NA 225187_at KIAA1967 8:22491622 6.77E‐08 0.562367478 0.247355596 5.818145314 Y NA Y 240771_at C1orf101 1:244773129 6.96E‐08 0.583054815 0.246955672 5.811896129 Y NA NA 227737_at SRPRB 3:133539541:GTCT_ 7.15E‐08 ‐0.361169396 0.246568958 ‐5.805853296 NA Y Y 218899_s_at BAALC 8:104222938 7.21E‐08 ‐0.948157885 0.246455123 ‐5.804074485 NA NA NA 210641_at CAPN9 1:230924451 7.37E‐08 1.138922385 0.246146821 5.799256835 NA NA Y 1552851_at ZSCAN4 19:58241715 7.56E‐08 ‐0.606229735 0.245779483 ‐5.793516585 NA NA NA 1552594_at TMEM190 19:55905237 7.69E‐08 1.115051802 0.245528866 5.789600231 NA Y NA 1558541_at KIAA1456 8:12827679 8.41E‐08 0.398263983 0.244258644 5.76974991 NA NA NA 231779_at IRAK2 3:10086954 8.44E‐08 ‐0.726037897 0.244213879 ‐5.769050321 NA NA Y 204758_s_at C2CD2L 11:118995729:T_TTG 8.48E‐08 ‐0.248552376 0.244132731 ‐5.767782132 NA NA Y 1554121_at HSD17B12 11:43773813 8.63E‐08 ‐0.119843555 0.243889353 ‐5.763978549 NA Y Y 222597_at SNAP29 22:21127335 8.80E‐08 0.589014584 0.24361371 5.759670653 Y Y Y 229457_at ANKHD1 5:140402915 9.05E‐08 ‐0.939052149 0.24321422 ‐5.753427068 NA NA NA 237753_at IL21R 16:26981919:A_AT 9.16E‐08 ‐0.379192529 0.243041849 ‐5.750733051 NA Y Y 211471_s_at RAB36 22:23522810 9.17E‐08 0.360077844 0.243023718 5.750449666 NA NA Y 237919_at RFFL 17:33357522 9.47E‐08 ‐0.585482496 0.242569028 ‐5.743343035 NA NA NA 242462_at LOC100506930 19:38000548 9.62E‐08 0.290906997 0.242342414 5.73980105 NA NA NA 231642_at C6orf201 6:4067046 9.62E‐08 0.236694462 0.242335644 5.739695228 NA Y NA 241709_s_at DOCK1 10:128892214 9.71E‐08 ‐0.290317728 0.242202536 ‐5.737614709 Y NA NA 227776_at ACER3 11:76747625 9.73E‐08 ‐0.384157555 0.242174144 ‐5.737170941 NA Y Y 214428_x_at C4A 6:31799393 9.74E‐08 ‐1.149781308 0.242165517 ‐5.737036091 Y NA NA 214428_x_at C4B 6:31799393 9.74E‐08 ‐1.149781308 0.242165517 ‐5.737036091 Y NA NA 214428_x_at LOC100293534 6:31799393 9.74E‐08 ‐1.149781308 0.242165517 ‐5.737036091 NA NA NA 221069_s_at TACO1 17:62136276 1.01E‐07 0.224329061 0.241649799 5.728975023 NA NA NA 232620_at WDR93 15:90248819 1.02E‐07 ‐0.297355596 0.241565132 ‐5.727651568 NA NA NA 225255_at MRPL35 2:86427615 1.03E‐07 0.271216013 0.241302547 5.723546979 Y Y Y 209227_at TUSC3 8:15575645 1.04E‐07 0.396288759 0.241285842 5.723285852 Y NA NA 202584_at NFX1 9:33387224 1.04E‐07 ‐0.380388461 0.241241871 ‐5.722598517 NA Y Y 207181_s_at CASP7 10:115097614 1.06E‐07 0.557976386 0.240949861 5.718033823 Y NA Y 219201_s_at TWSG1 18:9390346 1.06E‐07 0.60338702 0.240941994 5.717910847 NA Y Y 219077_s_at WWOX 16:78280176 1.08E‐07 ‐0.314937156 0.240741291 ‐5.714773384 Y NA Y 1563458_at PARVA 11:12529004 1.08E‐07 ‐1.042077508 0.240671464 ‐5.713681808 NA NA NA 1560172_at INTS10 8:19681647 1.10E‐07 0.338387161 0.240368502 5.708945654 NA NA NA 1554742_at PMS1 2:190721425 1.14E‐07 ‐0.193270268 0.239911645 ‐5.701803382 NA Y NA 1557051_s_at HOTAIRM1 7:27138829 1.14E‐07 ‐0.536682494 0.239893454 ‐5.701518983 NA NA NA 205945_at IL6R 1:154522248 1.18E‐07 0.310280558 0.239426214 5.694213998 NA Y Y 1556588_at C15orf37 15:80212150 1.23E‐07 ‐0.267268503 0.238791123 ‐5.684284149 NA NA NA 240857_at DNAH9 17:11815688 1.24E‐07 0.563217132 0.238644845 5.681996935 NA NA NA 209560_s_at DLK1 14:101135876 1.28E‐07 ‐2.08377491 0.238294794 ‐5.676523336 Y NA Y 228707_at CLDN23 8:8548877 1.29E‐07 0.556533606 0.238139356 5.674092749 NA NA NA 1564010_at CAST 5:96114493 1.32E‐07 0.38951973 0.237850081 5.669569198 Y Y Y 219245_s_at OGFOD2 12:123452618 1.32E‐07 0.446315118 0.237827207 5.669211497 NA Y NA 222446_s_at BACE2 21:42619749 1.32E‐07 ‐0.307337213 0.23776326 ‐5.668211492 NA Y Y 205571_at LIPT1 2:99706817 1.38E‐07 0.300005268 0.237205573 5.659490059 Y Y NA 205969_at AADAC 3:151527484 1.42E‐07 0.532984292 0.236742022 5.652240232 Y NA NA 200870_at STRAP 12:16009289:C_CTA 1.46E‐07 ‐0.236039396 0.236377422 ‐5.646537643 NA NA NA 222163_s_at SPATA5L1 15:45615036:C_CAT 1.46E‐07 ‐0.30733189 0.236307288 ‐5.645440673 Y Y Y 205209_at ACVR1B 12:52352449 1.49E‐07 ‐0.260353798 0.236062625 ‐5.641613751 NA NA Y 227566_at LOC100653217 11:131708549 1.50E‐07 ‐1.005640447 0.235928523 ‐5.63951613 NA NA NA 227566_at NTM 11:131708549 1.50E‐07 ‐1.005640447 0.235928523 ‐5.63951613 NA NA NA

202745_at USP8 15:50534676 1.51E‐07 0.456098574 0.235845541 5.638218094 Y NA NA 235059_at RAB12 18:9093635 1.51E‐07 ‐1.590370013 0.23583227 ‐5.638010515 NA NA Y 217867_x_at BACE2 21:42619749 1.53E‐07 ‐0.368035686 0.235681286 ‐5.635648729 NA Y Y 244771_at KBTBD12 3:128049764 1.53E‐07 ‐0.820953867 0.235666265 ‐5.635413751 NA NA NA 218322_s_at ACSL5 10:114138672 1.55E‐07 ‐0.236356482 0.235508921 ‐5.632952414 NA NA Y 223169_s_at RHOU 1:229196226:G_GTG 1.56E‐07 0.456023187 0.235389655 5.631086691 NA NA NA 221786_at C6orf120 6:169725749 1.58E‐07 0.889575789 0.235218304 5.62840612 NA NA NA 205363_at BBOX1 11:27093635 1.58E‐07 0.571897734 0.235216215 5.62837344 NA NA NA 211052_s_at TBCD 17:80871644 1.60E‐07 ‐0.404441684 0.235059201 ‐5.625917091 NA Y Y 238853_at RAB3IP 12:70157582 1.61E‐07 ‐0.551660626 0.234955637 ‐5.624296879 Y Y NA 213556_at LOC390940 19:44077507 1.62E‐07 0.42421679 0.234875448 5.623042352 NA NA NA 226604_at TMTC3 12:88615335 1.64E‐07 0.374495857 0.234661848 5.619700537 Y NA NA 1556711_at FAM216B 13:43367981 1.64E‐07 ‐0.343149975 0.234653639 ‐5.619572113 NA NA NA 228268_at FMO2 1:171158797:TC_T 1.72E‐07 0.607848096 0.233985448 5.609117364 Y NA NA 230992_at BTNL9 5:180350167 1.75E‐07 ‐0.377793756 0.233730371 ‐5.605126012 NA Y NA 204440_at CD83 6:14004741 1.75E‐07 ‐0.482410253 0.233705375 ‐5.60473487 NA Y Y 224758_at C7orf73 7:135306609 1.78E‐07 ‐0.370909855 0.233470856 ‐5.601065015 NA NA NA 220087_at BCMO1 16:81309670 1.80E‐07 0.18248251 0.233348684 5.599153162 NA Y NA 201214_s_at PPP1R7 2:242197225 1.83E‐07 0.318252303 0.233101223 5.595280537 NA Y Y 229764_at LOC100505861 3:188971324 1.85E‐07 ‐0.330876254 0.232891359 ‐5.591996137 NA NA NA 229764_at TPRG1 3:188971324 1.85E‐07 ‐0.330876254 0.232891359 ‐5.591996137 NA Y NA 226235_at LOC339290 18:5248582:G_GGA 1.90E‐07 ‐0.214162249 0.232556222 ‐5.586750926 NA Y NA 209212_s_at KLF5 13:73655521 1.90E‐07 0.769103569 0.232538554 5.586474388 NA Y NA 219198_at GTF3C4 9:135571115:AAC_A 1.92E‐07 0.224968337 0.232402016 5.584337341 Y Y NA 228300_at CCDC103 17:42977073 1.92E‐07 0.279290207 0.232399481 5.584297654 NA Y NA 228300_at FAM187A 17:42977073 1.92E‐07 0.279290207 0.232399481 5.584297654 NA NA NA 210233_at IL1RAP 3:190348810 1.92E‐07 ‐0.310411722 0.232365786 ‐5.583770271 Y NA NA 235990_at LOC100130987 11:67135856 1.97E‐07 ‐0.320353521 0.232050322 ‐5.57883246 NA NA NA 222735_at TMEM38B 9:109035995:G_GA 1.97E‐07 ‐0.564565734 0.232012331 ‐5.578237786 Y Y NA 219419_at RBFA 18:77911100 1.99E‐07 ‐0.161320591 0.231873779 ‐5.576068979 NA NA NA 208451_s_at C4A 6:31799393 2.01E‐07 ‐1.376698231 0.231753546 ‐5.574186877 Y NA NA 208451_s_at C4B 6:31799393 2.01E‐07 ‐1.376698231 0.231753546 ‐5.574186877 Y NA NA 208451_s_at LOC100293534 6:31799393 2.01E‐07 ‐1.376698231 0.231753546 ‐5.574186877 NA NA NA 227614_at HKDC1 10:71015180 2.04E‐07 ‐0.656701892 0.231520523 ‐5.570539051 Y NA Y 222089_s_at C16orf71 16:4795245 2.13E‐07 ‐0.336849918 0.230909669 ‐5.560975688 NA NA NA 1557311_at LOC100131354 1:205647155 2.16E‐07 0.246850567 0.230713722 5.557907721 NA NA NA 202787_s_at MAPKAPK3 3:50217234 2.26E‐07 0.28815918 0.230048018 5.547483759 NA Y Y 1559479_at LOC285540 4:25152346 2.26E‐07 0.325473312 0.230011066 5.5469051 NA NA NA 205750_at BPHL 6:3229477 2.27E‐07 0.234864175 0.229968193 5.546233714 NA Y Y 238914_at DCC 18:50763049 2.30E‐07 ‐0.104117861 0.22979694 ‐5.543551836 NA NA NA 232692_at TDRD6 6:46648129 2.31E‐07 0.391468608 0.229686076 5.541815625 NA NA NA 203131_at PDGFRA 4:55128084 2.32E‐07 ‐0.439443629 0.229667032 ‐5.541517379 NA NA NA 205547_s_at TAGLN 11:117069061 2.33E‐07 0.423673313 0.229615243 5.540706301 NA NA Y 205826_at MYOM2 8:2100796 2.34E‐07 0.34389881 0.229546144 5.539624101 Y Y Y 223523_at TMEM108 3:133063071 2.39E‐07 ‐0.369746757 0.229220422 ‐5.534522616 NA NA NA 225326_at RBM27 5:146110880 2.41E‐07 0.366364737 0.229122685 5.532991771 NA NA NA 223272_s_at NTPCR 1:233105001 2.44E‐07 0.419890058 0.22893622 5.530071097 NA Y NA 228720_at SORCS2 4:7219907 2.44E‐07 ‐0.264371456 0.228922338 ‐5.529853655 Y NA NA 209388_at PAPOLA 14:96504116 2.46E‐07 0.599571087 0.228816912 5.528202254 Y NA NA 201570_at SAMM50 22:44343009 2.56E‐07 0.253675145 0.228223992 5.518913972 NA NA Y 213304_at FAM179B 14:45473982:ATG_A 2.57E‐07 0.397049826 0.228136052 5.517536247 NA NA NA 206572_x_at ZNF85 19:20969680 2.66E‐07 0.288232246 0.227644187 5.509829815 NA Y NA 1570121_at ZNF365 10:64599839 2.71E‐07 ‐0.18086717 0.22740177 ‐5.506031333 NA NA Y 220999_s_at CYFIP2 5:156722486 2.74E‐07 0.316600973 0.227235313 5.50342294 Y Y Y 226456_at RMI2 16:11360607:GA_G 2.77E‐07 0.242336522 0.227093918 5.50120719 NA NA NA 1554743_x_at PMS1 2:190965293 2.79E‐07 ‐0.260335725 0.226949914 ‐5.498950459 NA Y NA 219840_s_at TCL6 14:96071874 2.94E‐07 ‐0.581671174 0.226218902 ‐5.487493259 Y Y NA 243495_s_at ZNF652 17:47357966 2.96E‐07 1.386083517 0.22612857 5.48607731 Y NA NA 203814_s_at NQO2 6:3480368 2.96E‐07 0.759490504 0.226115466 5.485871916 Y Y Y 212183_at NUDT4 12:93814983 2.96E‐07 0.694056016 0.226115018 5.485864887 Y Y NA 209978_s_at LPA 6:161644584 2.96E‐07 ‐0.777383323 0.226086865 ‐5.485423584 Y NA NA 209978_s_at PLG 6:161644584 2.96E‐07 ‐0.777383323 0.226086865 ‐5.485423584 NA NA NA 219235_s_at PHACTR4 1:28780915 3.07E‐07 ‐0.580230553 0.225569707 ‐5.477316465 NA Y NA 212932_at RAB3GAP1 2:135898794:A_ACT 3.08E‐07 0.360184631 0.22551619 5.476477439 NA NA NA 232961_at SPATS2L 2:201277512 3.19E‐07 0.516311147 0.22499057 5.468236342 NA Y NA 1555892_s_at LOC253039 9:123572038 3.20E‐07 0.525199222 0.224945885 5.46753568 NA Y NA 220444_at ZNF557 19:7090337 3.21E‐07 0.327676837 0.224942041 5.467475399 Y Y NA 229266_at SHISA6 17:11149073:GGT_G 3.23E‐07 ‐0.44309422 0.224834057 ‐5.465782166 NA NA NA 226464_at C3orf58 3:143982472 3.39E‐07 0.695118686 0.224143894 5.454958826 NA NA Y 235874_at PRSS35 6:84709832 3.41E‐07 ‐0.227864773 0.224027959 ‐5.453140494 Y Y NA 231565_at C4orf22 4:82126316 3.43E‐07 0.407024609 0.223966926 5.452183219 NA Y NA 202948_at IL1R1 2:102759381 3.50E‐07 0.409409975 0.22366733 5.447483936 NA Y NA

214877_at CDKAL1 6:21233431 3.71E‐07 0.640588355 0.22280672 5.433982514 Y NA Y 224668_at SYS1 20:44025692 3.71E‐07 ‐0.250919759 0.22278788 ‐5.433686915 NA NA Y 232382_s_at PCMTD1 8:52236426 3.73E‐07 1.012726211 0.22272922 5.432766506 Y NA NA 239065_at DNAJC22 12:49766870 3.74E‐07 0.217683074 0.222681589 5.432019137 NA NA NA 213467_at RND2 17:41408054 3.89E‐07 0.322111993 0.222121161 5.423224724 NA NA NA 209036_s_at MDH2 7:75324899:T_TTG 3.90E‐07 0.176650268 0.222067416 5.422381268 Y NA Y 239989_at CNTLN 9:17177401 3.96E‐07 ‐0.279280847 0.221849072 ‐5.418954459 NA NA NA 231491_at LINC00113 21:29577921 4.07E‐07 ‐0.530556841 0.221460913 ‐5.412861876 NA NA NA 214450_at CTSW 11:65663547 4.09E‐07 0.351394775 0.221384403 5.411660869 NA Y Y 220361_at IQCH 15:68177714 4.16E‐07 0.487413278 0.221137407 5.407783497 NA NA NA 243261_at LOC154822 7:158762612 4.18E‐07 ‐0.424785813 0.221073057 ‐5.406773269 NA NA NA 219298_at ECHDC3 10:11804197 4.33E‐07 0.451965434 0.22055287 5.398606066 NA Y Y 244619_at LOC646626 1:85675627 4.44E‐07 ‐0.149951666 0.22018136 ‐5.392772279 NA NA NA 221675_s_at CHPT1 12:102116656 4.45E‐07 ‐0.466200512 0.22013798 ‐5.392091029 NA Y Y 227209_at CNTN1 12:41101186 4.47E‐07 0.139801326 0.220082939 5.391226656 NA NA NA 1555007_s_at WDR66 12:122635353 4.47E‐07 0.801110366 0.22007922 5.391168246 NA NA NA 239647_at CHST13 3:126289091 4.58E‐07 0.195008898 0.219707891 5.385336336 NA NA Y 218643_s_at CRIPT 2:46843631 4.60E‐07 ‐0.311598005 0.219661168 ‐5.384602485 Y Y Y 226755_at MIR205HG 1:209604536 4.61E‐07 ‐0.824757147 0.219631456 ‐5.384135795 NA NA NA 242540_at DNHD1 11:6876227:AT_A 4.64E‐07 0.107109719 0.219530397 5.382548441 NA NA NA 222889_at DCLRE1B 1:114462810 4.82E‐07 ‐0.407712216 0.218962548 ‐5.373628036 Y Y NA 223591_at RNF135 17:29818545 4.83E‐07 0.530739056 0.218925264 5.373042282 NA Y Y 220249_at HYAL4 7:123518178 4.84E‐07 ‐0.312959377 0.218914191 ‐5.37286831 NA Y NA 243324_x_at TNPO1 5:72186905 4.88E‐07 ‐0.115773128 0.218792995 ‐5.370964164 NA NA NA 213924_at GNAL 18:11695920 4.96E‐07 ‐0.287235383 0.21853286 ‐5.366876811 Y NA Y 219567_s_at DEM1 1:41020054 5.02E‐07 0.174609591 0.218360169 5.364163203 NA NA NA 221992_at NPIPL2 16:74860758 5.16E‐07 0.832367243 0.217964214 5.357940629 NA NA NA 228947_x_at TMEM204 16:2010615 5.17E‐07 ‐0.553645228 0.217939278 ‐5.357548714 NA Y NA 233210_at FLJ12120 17:34352232 5.20E‐07 ‐0.230353985 0.217842061 ‐5.356020766 NA NA NA 206527_at ABAT 16:8875531 5.23E‐07 ‐0.312457889 0.217761338 ‐5.354752003 Y Y Y 205854_at TULP3 12:2971973 5.33E‐07 0.288123837 0.217495129 5.350567591 Y NA NA 1552370_at C4orf33 4:130124876 5.52E‐07 1.013125452 0.21697401 5.342375145 Y Y NA 205443_at SNAPC1 14:62224716 5.53E‐07 0.383132775 0.216935214 5.341765168 NA NA NA 208696_at CCT5 5:10561110 5.56E‐07 0.307816079 0.216857809 5.340548143 Y NA Y 210986_s_at TPM1 15:63374256 5.69E‐07 0.357865163 0.216536823 5.335500911 NA Y Y 1555022_at RGS12 4:3300083 5.73E‐07 0.17411859 0.216420188 5.333666764 NA NA Y 212355_at KHNYN 14:24917052 5.79E‐07 0.339285919 0.216258254 5.331120125 NA NA NA 209582_s_at CD200 3:111937299:TTTTT 5.80E‐07 0.231040661 0.21624817 5.330961531 NA NA NA 227733_at TMEM63C 14:77668695 5.86E‐07 ‐0.288499274 0.216082154 ‐5.328350518 NA NA Y 242565_x_at YBEY 21:47632580 6.07E‐07 0.390933833 0.215581646 5.320477741 NA Y NA 225170_at WDR5 9:137369200 6.26E‐07 0.539312564 0.215126999 5.313324944 NA NA NA 206405_x_at USP6 17:5287946 6.36E‐07 ‐1.315424386 0.214883875 ‐5.309499416 Y NA NA 231824_at LARP1B 4:128961402 6.40E‐07 ‐0.257485388 0.21478698 ‐5.307974674 NA NA NA 235077_at MEG3 14:101135878 6.44E‐07 ‐0.908219876 0.214694895 ‐5.30652557 Y NA NA 203400_s_at TF 3:133465283 6.47E‐07 ‐0.679744472 0.21464152 ‐5.305685599 Y NA NA 219315_s_at TMEM204 16:1547999 6.50E‐07 ‐0.492306613 0.214552091 ‐5.304278205 NA Y NA 213272_s_at TMEM159 16:21169828 6.63E‐07 ‐0.350249211 0.214279968 ‐5.299995317 NA Y Y 218585_s_at DTL 1:212015067 6.65E‐07 ‐0.616533931 0.214216241 ‐5.298992268 NA NA NA 236517_at MEGF10 5:126700140 6.72E‐07 ‐0.269351807 0.21407036 ‐5.296696003 NA NA NA 217552_x_at CR1 1:207372291 6.74E‐07 ‐0.158314666 0.214019307 ‐5.295892374 NA NA Y 202451_at GTF2H1 11:18309700 6.92E‐07 0.297108637 0.213629527 5.289756165 Y Y Y 205505_at GCNT1 9:79134180 7.11E‐07 0.266309413 0.213230809 5.283478165 NA Y Y 222635_s_at MED28 4:17617208 7.14E‐07 0.169656268 0.21316498 5.28244155 NA Y NA 237002_at NCDN 1:36335862 7.18E‐07 0.1519099 0.213101571 5.281443025 NA NA NA 213822_s_at UBE3B 12:109918867 7.18E‐07 ‐0.714635827 0.213084438 ‐5.281173216 NA NA Y 214063_s_at TF 3:133457514 7.26E‐07 ‐0.612243923 0.212934313 ‐5.278808998 Y NA NA 227099_s_at C11orf96 11:44373965 7.37E‐07 ‐0.50785487 0.21269588 ‐5.27505375 NA NA NA 227624_at TET2 4:106029469 7.45E‐07 0.648816269 0.212542585 5.27263919 NA NA NA 1559050_at HCG27 6:31168865:ATG_A 7.63E‐07 ‐0.287351897 0.212184392 ‐5.266996611 NA Y Y 218139_s_at AP5M1 14:57904666:G_GA 7.66E‐07 0.620636485 0.212129119 5.266125825 NA NA NA 1559025_at 9‐Sep 17:75811381 7.85E‐07 ‐0.392448895 0.211766865 ‐5.26041821 NA Y Y 228148_at ZNF584 19:58912384 8.01E‐07 0.213969519 0.211475029 5.255819394 Y Y NA 1553623_at MGC15705 22:31248289 8.02E‐07 ‐0.256143965 0.211457004 ‐5.255535342 NA NA NA 219734_at SIDT1 3:113254987 8.10E‐07 0.398050387 0.211310258 5.25322263 NA NA Y 214799_at NFASC 1:204884836 8.21E‐07 0.327861089 0.211098608 5.24988677 NA NA NA 219196_at SCG3 15:51654147 8.33E‐07 ‐0.494999912 0.210896799 ‐5.246705689 NA NA NA 227939_s_at TRA2A 7:23283399 8.35E‐07 ‐0.533982091 0.210850368 ‐5.245973769 NA Y NA 228468_at MASTL 10:27464600 8.40E‐07 ‐0.310945598 0.210773181 ‐5.244756988 NA Y Y 1558658_at ZNF391 6:27367824 8.44E‐07 ‐0.132019857 0.210700327 ‐5.243608461 NA Y NA 206247_at MICB 6:31525105 8.64E‐07 ‐0.549628537 0.210347961 ‐5.238052966 Y Y Y 209544_at RIPK2 8:90923026 8.72E‐07 ‐0.686538171 0.210209329 ‐5.235866992 NA NA Y 232239_at LOC643529 10:91919662 8.73E‐07 ‐0.560368044 0.210204933 ‐5.235797669 NA NA NA

235993_at PSMF1 20:1153143 8.84E‐07 ‐0.579342608 0.210011212 ‐5.232742811 Y NA Y 232318_s_at LINC00284 13:44380846 8.89E‐07 0.563308975 0.209926219 5.23140242 NA NA NA 230477_at LOC100130522 18:77486912 8.99E‐07 ‐0.386812063 0.209762507 ‐5.228820456 NA NA NA 201053_s_at PSMF1 20:1153143 9.06E‐07 0.681077201 0.209645504 5.226975028 Y NA Y 231829_at MAVS 20:3849289:A_AG 9.13E‐07 0.424578967 0.209528973 5.225136933 NA Y NA 1557646_at LOC100507240 13:42578316 9.28E‐07 0.218444873 0.209294938 5.22144509 NA NA NA 235377_at MLIP 6:53977495 9.43E‐07 0.239858316 0.209059315 5.217727765 NA NA NA 228956_at UGT8 4:115517933 9.45E‐07 ‐1.198466129 0.209017336 ‐5.217065437 NA Y NA 1566764_at MACC1 7:20170669 9.57E‐07 0.99662218 0.208824929 5.214029529 NA NA NA 202797_at SACM1L 3:45726095 9.58E‐07 0.528556109 0.208819899 5.213950163 NA Y Y 1569378_at LOC100292680 12:1218302 9.72E‐07 ‐0.802242856 0.208595899 ‐5.210415376 NA Y NA 218195_at C6orf211 6:151573527 9.80E‐07 1.172450274 0.208475163 5.208509975 NA NA Y 208814_at HSPA4 5:132688031:T_TAC 9.84E‐07 0.556731373 0.208421436 5.207662034 Y NA Y 208268_at ADAM28 8:24022989 9.94E‐07 ‐0.657314326 0.208273532 ‐5.205327642 NA NA Y 230782_at SORD 15:45204954 1.01E‐06 0.547637227 0.207997822 5.200975613 Y Y Y 226200_at VARS2 6:31128552 1.02E‐06 ‐0.225388167 0.207940735 ‐5.200074431 NA Y NA 228542_at MRS2 6:24416482 1.02E‐06 0.289421833 0.207866356 5.198900238 NA Y NA 224785_at FAM100B 17:74412056 1.02E‐06 ‐0.934005826 0.207819075 ‐5.198153806 NA NA NA 222361_at TUBBP5 9:141017343 1.04E‐06 0.824282926 0.207656204 5.195582394 NA NA NA 203199_s_at MTRR 5:8003528:GAT_G 1.04E‐06 0.426549631 0.207572901 5.194267123 Y Y Y 228119_at LRCH3 3:197599919 1.05E‐06 ‐0.589096855 0.207494773 ‐5.193033505 NA NA Y 226351_at NSUN4 1:46815003 1.05E‐06 0.310274049 0.207431541 5.192035056 NA Y Y 217067_s_at DMP1 4:88881864 1.05E‐06 ‐0.336706402 0.207430901 ‐5.192024948 NA NA NA 201919_at SLC25A36 3:140630934 1.05E‐06 0.307998788 0.207385102 5.191301765 NA NA NA 224477_s_at NUDT16L1 16:4965930 1.07E‐06 0.428280552 0.207114761 5.187032535 NA NA NA 206305_s_at C8A 1:57773089 1.08E‐06 ‐0.358513206 0.207100774 ‐5.186811638 NA NA NA 230063_at ZNF264 19:57752670 1.08E‐06 0.321778794 0.206996914 5.185171303 NA Y Y 1555716_a_at CXADR 21:19314396 1.09E‐06 0.411484831 0.206944291 5.184340162 NA NA NA 209849_s_at RAD51C 17:56488063 1.09E‐06 ‐0.337173383 0.206882557 ‐5.183365093 Y Y Y 231872_at LRRCC1 8:86055093:GAA_G 1.10E‐06 0.291619633 0.206759063 5.181414431 NA NA NA 212819_at ASB1 2:239442688 1.11E‐06 ‐0.238763067 0.206661391 ‐5.179871556 NA NA Y 243803_at LOC643037 11:94092983 1.11E‐06 0.366746667 0.206600645 5.178911944 NA NA NA 1557647_a_at LOC100507240 13:42579985 1.11E‐06 ‐0.392114308 0.206585617 ‐5.178674552 NA NA NA 204033_at TRIP13 5:952827 1.14E‐06 0.292721457 0.206187394 5.172382957 NA NA NA 220744_s_at IFT122 3:129140738 1.16E‐06 0.215779599 0.206018496 5.169714094 NA NA Y 1561761_x_at LOC100507322 4:120279532:AAG_A 1.16E‐06 ‐0.197512744 0.205920912 ‐5.168172013 NA NA NA 1561761_x_at LOC645513 4:120279532:AAG_A 1.16E‐06 ‐0.197512744 0.205920912 ‐5.168172013 NA NA NA 240390_at GALNT5 2:158212849 1.16E‐06 ‐0.538613275 0.205920841 ‐5.168170891 NA Y NA 231341_at SLC35D3 6:137500385 1.18E‐06 ‐0.975269256 0.205736986 ‐5.165265264 Y NA Y 1553636_at TMCO5A 15:38268244 1.18E‐06 ‐0.387622406 0.205718393 ‐5.164971401 NA NA NA 1561633_at HMGA2 12:66382329 1.19E‐06 ‐0.103535384 0.205558193 ‐5.162439351 NA NA NA 205841_at JAK2 9:5271598 1.20E‐06 ‐0.383890178 0.205481434 ‐5.161226052 NA NA Y 206658_at UPK3B 7:76008973 1.21E‐06 ‐0.358377151 0.205316455 ‐5.158618134 NA Y Y 1559672_a_at CCDC171 9:15533820 1.21E‐06 ‐0.243832923 0.205315489 ‐5.158602871 NA NA NA 214113_s_at RBM8A 1:145522421:C_CTT 1.22E‐06 0.235854239 0.205253399 5.157621309 NA NA NA 226992_at NOSTRIN 2:169405927 1.22E‐06 ‐0.452394088 0.205179474 ‐5.156452624 Y NA NA 208454_s_at CPQ 8:98051434 1.23E‐06 ‐0.247518648 0.20509416 ‐5.155103811 NA NA NA 217113_at AMACR 5:34028619 1.23E‐06 ‐0.379643543 0.205092051 ‐5.155070471 Y Y Y 231026_at EFHC1 6:52365402 1.25E‐06 0.210186058 0.204895912 5.151969289 NA Y NA 231379_at LOC100507560 12:5001593 1.25E‐06 ‐0.844059096 0.204832744 ‐5.150970468 NA NA NA 243382_at CCDC85A 2:56543482 1.26E‐06 ‐0.446324158 0.204731798 ‐5.149374215 NA NA NA 231124_x_at LY9 1:161231962 1.27E‐06 ‐0.310156609 0.204610007 ‐5.147448216 Y NA Y 1557430_at LOC147670 19:57120534 1.28E‐06 ‐0.232822559 0.204473759 ‐5.145293437 NA NA NA 214071_at GNAL 18:11695920 1.28E‐06 ‐0.451342208 0.204466289 ‐5.145175303 Y NA Y 232039_at KIAA1383 1:232918606 1.28E‐06 0.088064123 0.204465158 5.145157402 NA NA Y 213184_at SENP5 3:196339915 1.31E‐06 0.122527019 0.204098877 5.139363801 NA NA NA 227628_at GPX8 5:54467882 1.32E‐06 ‐0.463085689 0.204011763 ‐5.1379857 NA NA NA 203126_at IMPA2 18:11934294 1.34E‐06 ‐0.496553174 0.203818245 ‐5.134924121 NA NA Y 235171_at LOC100505501 8:59847927 1.34E‐06 ‐0.226505109 0.203789006 ‐5.134461519 NA NA NA 240033_at PLG 6:161654829 1.34E‐06 ‐0.586389282 0.203778835 ‐5.134300588 NA NA NA 206541_at KLKB1 4:187182660 1.34E‐06 0.352594464 0.203765716 5.134093027 NA NA Y 222775_s_at MRPL35 2:86523440 1.36E‐06 ‐0.246103725 0.203579587 ‐5.131147928 Y Y Y 218435_at DNAJC15 13:43608939 1.38E‐06 0.40609717 0.203415394 5.128549661 Y Y Y 239246_at FARP1 13:99151447 1.38E‐06 0.696688654 0.20340469 5.128380269 NA Y NA 216624_s_at MLL 11:117845195 1.39E‐06 ‐0.485328344 0.203245162 ‐5.125855575 NA NA NA 229395_at STX4 16:31039376 1.40E‐06 0.153992446 0.203119246 5.123862672 NA Y Y *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present whether it is observed in other tissues (ie., liver, LCL and whole blood).

Table S1b, small Airway trans eQTL 10% FDR reporterID Gene Snp(Chr:hg19‐Position) Pvalue beta Rsq T Liver LCL Whole.Blood 230026_at MRPL43 10:102733779 9.49E‐49 ‐1.57292946 0.877411983 ‐27.15165976 Y Y NA 1554663_a_at NUMA1 11:71754338 6.98E‐43 ‐2.225904456 0.840709474 ‐23.31560071 Y NA Y 239591_at ‐‐‐ 17:43659663 4.96E‐42 ‐2.588071088 0.83454087 ‐22.79276693 NA NA NA 225155_at SNHG5 6:86283777:TATA_ 2.06E‐41 ‐1.055147229 0.829915565 ‐22.41833121 NA Y NA 225155_at SNORD50A 6:86283777:TATA_ 2.06E‐41 ‐1.055147229 0.829915565 ‐22.41833121 NA NA NA 225155_at SNORD50B 6:86283777:TATA_ 2.06E‐41 ‐1.055147229 0.829915565 ‐22.41833121 NA NA NA 239591_at ‐‐‐ 17:44782224:A_AGT 1.53E‐37 ‐2.453294112 0.797846706 ‐20.16220053 NA NA NA 1555989_at ‐‐‐ 14:59827968 3.36E‐35 ‐1.86984186 0.775597704 ‐18.86788505 NA NA NA 1560263_at ‐‐‐ 1:46112218 2.23E‐34 ‐1.147141784 0.767228444 ‐18.42536096 NA NA NA 209480_at HLA‐DQB1 6:32604372 2.55E‐34 ‐2.529364127 0.766612819 ‐18.39365988 Y Y NA 203290_at HLA‐DQA1 6:32603007 4.87E‐33 ‐3.727325436 0.752900663 ‐17.71542852 Y Y NA 232233_at SLC22A16 6:110792782 8.91E‐33 ‐1.93374255 0.749997381 ‐17.57827307 NA NA Y 238632_at LOC100505946 4:76005174 3.36E‐32 1.267976067 0.743485786 17.27822916 NA NA NA 230937_at LOC285835 6:31362340:GT_G 1.17E‐31 1.198596132 0.737206471 16.99831404 NA NA NA 239591_at ‐‐‐ 17:44192590 1.20E‐31 ‐2.355626827 0.737099258 ‐16.99361183 NA NA NA 209728_at HLA‐DRB4 6:32604108 2.88E‐31 ‐3.97630967 0.732591662 ‐16.79817593 NA NA NA 209728_at LOC100509582 6:32604108 2.88E‐31 ‐3.97630967 0.732591662 ‐16.79817593 NA NA NA 232232_s_at SLC22A16 6:110792782 5.09E‐31 ‐2.197315598 0.729636925 ‐16.67240786 NA NA Y 202565_s_at SVIL 10:29725799 2.29E‐30 ‐0.86869538 0.721644087 ‐16.34104836 Y Y NA 224364_s_at PPIL3 2:201730687 3.21E‐29 0.769217785 0.70706221 15.76738693 Y Y Y 1553296_at GPR128 3:77486911 1.94E‐28 ‐2.292881523 0.696711918 ‐15.38216834 NA NA Y 223434_at GBP3 1:89481583 5.87E‐28 1.368417301 0.690131912 15.1459403 Y Y NA 238835_at AVPR1A 12:63478727:AG_A 7.95E‐28 ‐2.359281631 0.68831329 ‐15.08177814 NA NA NA 213831_at HLA‐DQA1 6:32604000 9.08E‐28 ‐2.951380518 0.687512439 ‐15.05367465 Y Y NA 213831_at LOC100507718 6:32604000 9.08E‐28 ‐2.951380518 0.687512439 ‐15.05367465 NA NA NA 213831_at LOC100509457 6:32604000 9.08E‐28 ‐2.951380518 0.687512439 ‐15.05367465 NA NA NA 229843_at FAM82B 8:87358677 1.46E‐27 ‐0.798836503 0.684617551 ‐14.95284619 NA NA NA 205048_s_at PSPH 7:55885610 1.55E‐27 3.488943735 0.684252507 14.94021528 Y Y NA 241841_at ‐‐‐ 22:51021763 7.74E‐27 ‐1.099759959 0.674289243 ‐14.60244828 NA NA NA 212999_x_at HLA‐DQB1 6:32604000 1.69E‐26 ‐1.40057217 0.669335368 ‐14.43931619 Y Y NA 212999_x_at LOC100293977 6:32604000 1.69E‐26 ‐1.40057217 0.669335368 ‐14.43931619 NA NA NA 204148_s_at POMZP3 7:76135403 5.61E‐26 ‐1.036352548 0.661583494 ‐14.19009079 Y Y NA 204148_s_at ZP3 7:76135403 5.61E‐26 ‐1.036352548 0.661583494 ‐14.19009079 Y Y NA 232602_at WFDC3 20:44402869 7.61E‐26 0.549770485 0.659584745 14.12698249 NA NA NA 229604_at CMAHP 6:25106783 1.22E‐25 0.630633386 0.656483289 14.02996266 NA NA NA 227446_s_at DHRS4‐AS1 14:24422946:A_ACT 1.73E‐25 0.715525214 0.654133683 13.95718176 NA NA NA 242680_at AVPR1A 12:63478727:AG_A 2.65E‐25 ‐2.362336589 0.651287146 ‐13.869822 NA NA NA 207584_at LPA 6:161146634 4.27E‐25 ‐0.785750457 0.648043346 ‐13.77133522 Y NA NA 212777_at SOS1 2:39225171 4.87E‐25 ‐0.829837042 0.647146461 ‐13.74430121 NA Y Y 243943_x_at C6orf52 6:10689301 6.57E‐25 1.142513321 0.645104997 13.68308022 NA Y NA 222722_at OGN 13:90043112 9.12E‐25 ‐2.088603142 0.642846651 ‐13.61585575 NA NA NA 215432_at ACSM1 16:20674116 1.24E‐24 ‐0.735786955 0.640737417 ‐13.55353748 Y NA NA 236712_at ‐‐‐ 1:223180953 1.35E‐24 ‐0.621033239 0.64013044 ‐13.53568678 NA NA NA 217761_at ADI1 2:3515708 3.16E‐24 1.060602971 0.634166176 13.36220781 Y Y Y 242557_at ZNRD1‐AS1 6:30002881 5.16E‐24 0.667115236 0.630692919 13.26275578 NA NA NA 235126_at FLVCR1‐AS1 1:213016565 1.44E‐23 ‐0.53527511 0.623299244 ‐13.05475321 NA NA NA 206007_at PRG4 13:90043112 4.30E‐23 ‐2.157442936 0.615253259 ‐12.83388369 Y NA NA 211715_s_at BDH1 3:197246689 5.05E‐23 1.14151602 0.614065256 12.80173805 NA NA NA 239417_x_at C6orf52 6:10689301 5.76E‐23 1.090317623 0.613088408 12.77539373 NA Y NA 231181_at ‐‐‐ 13:90043112 8.09E‐23 ‐1.466570797 0.610537391 ‐12.7069658 NA NA NA 242594_at BOD1L1 4:13609674 9.79E‐23 0.448995183 0.609098598 12.6686051 NA NA NA *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present whether it is observed in other tissues (ie., liver, LCL and whole blood).

Table S1c, large Airway cis eQTL 10% FDR reporterID Gene Snp(Chr:hg19‐Position) Pvalue beta Rsq T Liver LCL Whole.Blood 206777_s_at CRYBB2 22:25872592 9.17E‐19 ‐1.708837002 0.882115845 ‐16.63933466 Y Y NA 206777_s_at CRYBB2P1 22:25872592 9.17E‐19 ‐1.708837002 0.882115845 ‐16.63933466 NA Y NA 219629_at FAM118A 22:45731050 1.85E‐15 ‐1.591988149 0.822475527 ‐13.09282123 Y Y Y 205439_at GSTT2 22:24312589 2.02E‐10 ‐1.192468447 0.669317636 ‐8.653892163 Y NA NA 226475_at FAM118A 22:45731050 2.31E‐10 ‐0.889478222 0.666976141 ‐8.608318702 Y Y Y *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present whether it is observed in other tissues (ie., liver, LCL and whole blood).

Table S1d, large Airway trans eQTL 10% FDR reporterID Gene Snp(Chr:hg19‐Position) Pvalue beta Rsq T Liver LCL Whole.Blood 214038_at CCL8 21:16690492 8.48E‐31 ‐7.291536844 0.973572935 ‐36.91991062 NA NA NA 210163_at CXCL11 21:16690492 7.24E‐29 ‐8.719174536 0.966398594 ‐32.62122634 NA NA NA 211122_s_at CXCL11 21:16690492 2.30E‐28 ‐9.1040422 0.964237414 ‐31.5848192 NA NA NA *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present whether it is observed in other tissues (ie., liver, LCL and whole blood).

Table S2A*, Airway epithelia specific cis eQTL (exist in airway epithelia but not in lung) in small airway 10% FDR Average Present Call Liver Whole Blood reporterID SNP Chr:Position (hg19) Pvalue beta Rsq T N Gene in Lung Expression LCL eQTL eQTLs eQTL Study 226736_at 14:65399263 7.29E-34 -1.1356 0.7618 -18.1507 105 CHURC1 NA Yes Yes Yes 219629_at 22:45807538 8.11E-32 -1.5701 0.7391 -17.0808 105 FAM118A NA Yes Yes Yes 206777_s_at 22:25885353 7.44E-31 -1.3088 0.7276 -16.5885 105 CRYBB2 0.067457376 Yes Yes NA 206777_s_at 22:25885353 7.44E-31 -1.3088 0.7276 -16.5885 105 CRYBB2P1 NA NA Yes NA 205439_at 22:24312589 1.65E-30 -1.4128 0.7234 -16.4130 105 GSTT2 NA Yes NA NA 205542_at 7:89801787 5.78E-27 0.8636 0.6761 14.6638 105 STEAP1 1 NA Yes NA 1553992_s_at 17:41249094 1.97E-26 0.4856 0.6684 14.4073 105 NBR2 NA NA Yes NA 238069_at 6:99888013 4.17E-26 0.6727 0.6635 14.2517 105 LOC100506090 NA NA NA NA 220542_s_at 20:31839036 6.87E-25 -2.6340 0.6448 -13.6740 105 BPIFA1 NA NA NA NA 232382_s_at 8:52742230 1.78E-22 1.0004 0.6046 12.5487 105 PCMTD1 1 Yes NA NA 233675_s_at 13:25180151 3.17E-22 -1.1607 0.6001 -12.4335 105 TPTE2P6 NA NA NA NA 217753_s_at 12:56435929 4.79E-22 -0.5007 0.5969 -12.3507 105 RPS26 0.971830986 Yes Yes NA 237298_at 19:50586013 1.01E-21 1.7681 0.5911 12.2012 105 FLJ26850 NA NA Yes NA 232315_at 19:52880265 2.08E-20 -0.8724 0.5665 -11.6027 105 ZNF880 NA NA Yes NA 212730_at 15:99655433 3.37E-20 -0.7022 0.5625 -11.5071 105 SYNM NA NA Yes NA 228058_at 16:2880105 1.02E-19 1.0568 0.5530 11.2887 105 ZG16B NA NA Yes Yes 208727_s_at 1:22388872 1.21E-19 -1.5554 0.5515 -11.2549 105 CDC42 0.122312824 NA Yes Yes 231828_at 9:123516572 1.67E-19 0.9177 0.5488 11.1927 105 LOC253039 NA NA Yes NA 1554820_at 7:134719551 4.39E-19 -0.3146 0.5403 -11.0027 105 AGBL3 NA NA NA NA 218746_at 12:6569545 5.05E-19 -0.4933 0.5390 -10.9750 105 TAPBPL NA Yes Yes NA 239302_s_at 2:128103801 1.31E-18 1.1182 0.5305 10.7883 105 LOC100506922 NA NA NA NA 226475_at 22:45731539 1.75E-18 -0.7286 0.5279 -10.7315 105 FAM118A NA Yes Yes Yes 1559240_at 4:100027179 5.35E-18 -0.7586 0.5176 -10.5130 105 LOC100507053 NA NA NA NA 1568843_at 15:90785549 9.38E-18 -0.4096 0.5124 -10.4032 105 TTLL13 0.109710897 NA NA NA 205730_s_at 5:148520184 3.90E-17 -0.4180 0.4988 -10.1249 105 ABLIM3 0.969607116 NA NA Yes 227474_at 2:113993344 1.28E-16 1.0457 0.4872 9.8928 105 LOC654433 NA NA Yes NA 239208_s_at 21:47716680 1.56E-16 0.5633 0.4853 9.8540 105 YBEY NA NA Yes NA 208159_x_at 12:31230300 1.90E-16 -0.6317 0.4833 -9.8157 105 DDX11 NA Yes NA Yes 242162_at 2:228776938 3.50E-16 -0.4455 0.4772 -9.6964 105 WDR69 0.990363232 NA NA NA 218747_s_at 12:6569545 3.59E-16 -0.5515 0.4770 -9.6918 105 TAPBPL NA Yes Yes NA 1561759_at 4:120524283 5.66E-16 -0.4088 0.4724 -9.6026 105 LOC100507322 NA NA NA NA 1561759_at 4:120524283 5.66E-16 -0.4088 0.4724 -9.6026 105 LOC645513 NA NA NA NA 212699_at 15:75147789 1.07E-15 -0.9223 0.4659 -9.4785 105 SCAMP5 0.980726464 Yes Yes NA 200962_at 2:101634798:TTCAG 1.07E-15 0.7080 0.4659 9.4784 105 RPL31 1 Yes Yes NA 231710_at 19:5915883 1.45E-15 -0.6142 0.4627 -9.4187 105 CAPS 0.966641957 Yes Yes Yes

220649_at 7:134705373 1.49E-15 -0.3546 0.4625 -9.4139 105 AGBL3 NA NA NA NA 228160_at 18:5240629:A_AT 6.10E-15 -0.5397 0.4477 -9.1379 105 LOC339290 NA NA Yes NA 1565525_a_at 12:106708656 1.13E-14 -0.5214 0.4411 -9.0167 105 TCP11L2 0.995552261 NA NA Yes 236424_at 20:34049219:T_TCT 1.19E-14 -0.2856 0.4406 -9.0071 105 CEP250 NA Yes NA Yes 1556064_at 22:46652063 2.09E-14 0.3577 0.4345 8.8965 105 LOC284926 NA NA NA NA 212570_at 11:94863186 3.10E-14 -0.5551 0.4302 -8.8185 105 ENDOD1 NA Yes Yes NA 220425_x_at 3:125684510:GATA_ 3.15E-14 -0.5542 0.4300 -8.8157 105 ROPN1B NA Yes NA NA 212365_at 2:192231088 4.81E-14 0.7634 0.4254 8.7325 105 MYO1B 1 NA Yes NA 243680_at 14:74498829 7.35E-14 -0.7359 0.4207 -8.6488 105 LOC100506476 NA NA NA NA 204855_at 18:61144034 8.13E-14 -0.9778 0.4196 -8.6290 105 SERPINB5 0.352853966 NA NA NA 1569582_at 3:151487551 1.30E-13 -1.1654 0.4143 -8.5358 105 LOC201651 NA NA Yes NA 236321_at 4:15706466 1.59E-13 0.4405 0.4121 8.4968 105 FAM200B NA NA Yes NA 240436_at 13:21904824 3.16E-13 -0.5680 0.4043 -8.3609 105 MIPEPP3 NA NA NA NA 222784_at 14:70450179 3.44E-13 -0.7671 0.4033 -8.3436 105 SMOC1 0.888806523 NA NA NA 230279_at 9:74927609 5.32E-13 -0.4422 0.3983 -8.2574 105 LOC100507540 NA NA NA NA 1558649_at 15:101398972 5.83E-13 -0.6169 0.3972 -8.2391 105 LOC145757 NA NA NA NA 215483_at 7:91592795:G_GTC 6.85E-13 0.8579 0.3954 8.2072 105 AKAP9 0.52409192 Yes NA NA 239078_at 1:222829302:TC_T 7.42E-13 -1.3348 0.3945 -8.1913 105 BROX NA NA Yes NA 218347_at 7:66560797 8.34E-13 -0.5716 0.3931 -8.1682 105 TYW1 NA Yes Yes Yes 218347_at 7:66560797 8.34E-13 -0.5716 0.3931 -8.1682 105 TYW1B NA NA Yes NA 202869_at 12:113357193 1.07E-12 -0.5974 0.3902 -8.1180 105 OAS1 NA Yes NA Yes 232028_at 1:227900908 1.08E-12 -0.8431 0.3901 -8.1159 105 ZNF678 0.162342476 NA NA NA 227655_at 5:9541866 3.22E-12 -0.3820 0.3772 -7.8987 105 LOC100505806 NA NA NA NA 1559171_at 17:44182983 3.89E-12 -1.4531 0.3750 -7.8608 105 MGC57346 NA NA NA NA 222780_s_at 8:104222938 4.45E-12 -0.9792 0.3733 -7.8336 105 BAALC 0.979985174 NA NA NA 222048_at 22:25855629 7.31E-12 0.2333 0.3674 7.7341 105 CRYBB2P1 NA NA Yes NA 209685_s_at 16:23788291 8.68E-12 -0.9905 0.3653 -7.6993 105 PRKCB NA NA Yes Yes 228155_at 10:82196061 8.96E-12 0.4416 0.3649 7.6931 105 FAM213A NA NA NA NA 239297_at 8:12827679 9.31E-12 0.7443 0.3644 7.6853 105 KIAA1456 NA NA NA NA 218918_at 1:25928025:CTTCT 9.46E-12 -0.8695 0.3643 -7.6821 105 MAN1C1 1 Yes NA Yes 229071_at 17:6540354 1.15E-11 -0.6885 0.3619 -7.6436 105 C17orf100 NA NA Yes NA 228381_at 16:10415353 2.08E-11 0.9413 0.3546 7.5232 105 ATF7IP2 0.928094885 NA NA NA 228381_at 16:10415353 2.08E-11 0.9413 0.3546 7.5232 105 LOC100287628 NA NA NA NA 229906_at 17:73085662 2.39E-11 0.3750 0.3529 7.4944 105 ARMC7 0.997034841 NA NA Yes 227113_at 8:67381619 3.03E-11 0.3468 0.3499 7.4464 105 ADHFE1 NA Yes NA Yes 205700_at 12:57154489 3.44E-11 -0.5557 0.3484 -7.4206 105 HSD17B6 NA NA NA NA 210219_at 2:231380217 3.56E-11 -0.8787 0.3480 -7.4138 105 SP100 NA Yes NA Yes 206777_s_at 22:25287889 3.57E-11 1.2606 0.3479 7.4130 105 CRYBB2 0.067457376 Yes Yes NA 206777_s_at 22:25287889 3.57E-11 1.2606 0.3479 7.4130 105 CRYBB2P1 NA NA Yes NA

201093_x_at 5:288408 3.76E-11 -0.3543 0.3473 -7.4025 105 SDHA 0.99925871 NA Yes Yes 236098_at 17:73708829 3.87E-11 -0.7289 0.3469 -7.3967 105 C17orf110 NA NA NA NA 212364_at 2:192318241 4.66E-11 0.7225 0.3446 7.3589 105 MYO1B 1 NA Yes NA 227421_at 21:47724648 6.25E-11 -0.2958 0.3409 -7.2992 105 YBEY NA NA Yes NA 230737_s_at 10:29719245 6.45E-11 0.6252 0.3405 7.2928 105 LOC387647 NA NA Yes NA 222030_at 14:105225620 7.21E-11 0.6811 0.3391 7.2700 105 SIVA1 NA NA Yes Yes 201922_at 5:74048150 7.27E-11 -0.4395 0.3390 -7.2683 105 NSA2 NA NA Yes NA 231081_at 2:54568287 8.98E-11 0.5053 0.3363 7.2250 105 C2orf73 NA NA NA NA 228425_at 2:113994417 1.14E-10 -0.5492 0.3333 -7.1752 105 LOC654433 NA NA Yes NA 202581_at 6:31798593 1.15E-10 0.9612 0.3332 7.1740 105 HSPA1A NA NA Yes Yes 202581_at 6:31798593 1.15E-10 0.9612 0.3332 7.1740 105 HSPA1B NA NA Yes Yes 222060_at 3:160291866 1.25E-10 -0.4385 0.3321 -7.1564 105 KRT8P12 NA NA NA NA 225809_at 4:75971072 1.55E-10 0.7684 0.3294 7.1124 105 PARM1 NA NA Yes NA 1559171_at 17:43682202 1.67E-10 -1.4127 0.3285 -7.0980 105 MGC57346 NA NA NA NA 230552_at 19:36685690 1.71E-10 -0.7784 0.3281 -7.0923 105 LOC100134317 NA NA NA NA 230552_at 19:36685690 1.71E-10 -0.7784 0.3281 -7.0923 105 LOC284412 NA NA NA NA 217932_at 17:73257986 2.46E-10 0.2367 0.3235 7.0175 105 MRPS7 NA NA Yes Yes 208733_at 8:61473307:G_GT 2.61E-10 -0.4340 0.3227 -7.0054 105 RAB2A NA NA Yes NA 231133_at 2:26650419 2.86E-10 -0.2912 0.3215 -6.9868 105 CCDC164 NA NA NA NA 208683_at 1:223897012 3.08E-10 0.1819 0.3206 6.9715 105 CAPN2 NA NA Yes NA 204359_at 14:85604752 3.29E-10 -0.7830 0.3197 -6.9577 105 FLRT2 1 NA NA NA 204359_at 14:85604752 3.29E-10 -0.7830 0.3197 -6.9577 105 LOC100506718 NA NA NA NA 234341_x_at 1:211854180 3.72E-10 -0.2175 0.3181 -6.9318 105 LOC91548 NA NA NA NA 214827_at 20:49367817:T_TA 3.78E-10 -0.4160 0.3179 -6.9285 105 PARD6B 0.99851742 NA NA NA 37512_at 12:57166413 4.11E-10 -0.4509 0.3168 -6.9114 105 HSD17B6 NA NA NA NA 232111_at 14:96341958 4.37E-10 -0.6017 0.3160 -6.8988 105 LINC00617 NA NA NA NA 215229_at 15:52469476 5.50E-10 0.4096 0.3130 6.8507 105 LOC100129973 NA NA NA NA 225214_at 9:127029736 5.54E-10 0.4035 0.3129 6.8492 105 LOC100129034 NA NA NA NA 1562754_at 17:20858920 5.58E-10 -0.8383 0.3128 -6.8477 105 LOC339260 NA NA NA NA 222783_s_at 14:70450179 6.48E-10 -0.3022 0.3109 -6.8168 105 SMOC1 0.888806523 NA NA NA 208149_x_at 12:31228357 6.57E-10 -0.4757 0.3107 -6.8136 105 DDX11 NA Yes NA Yes 220488_s_at 17:59100246 7.15E-10 0.3696 0.3096 6.7962 105 BCAS3 0.99925871 NA Yes NA 207957_s_at 16:23777883 8.15E-10 -1.1501 0.3079 -6.7687 105 PRKCB NA NA Yes Yes 1553400_a_at 17:43934736:TG_T 8.98E-10 -0.4790 0.3066 -6.7483 105 C17orf69 NA NA Yes NA 228141_at 5:54471439 9.71E-10 0.5194 0.3056 6.7321 105 GPX8 NA NA NA NA 40687_at 1:35304501 1.48E-09 -0.7128 0.3000 -6.6439 105 GJA4 0.696071164 NA NA NA 232798_at 8:66960324 1.53E-09 0.3190 0.2996 6.6369 105 DNAJC5B 0.966641957 NA Yes NA 1555550_at 17:74060168 1.59E-09 -0.5873 0.2990 -6.6290 105 ZACN NA NA NA NA 238465_at 5:56193465 1.80E-09 0.4355 0.2974 6.6022 105 SETD9 NA NA NA NA

206291_at 12:86041527 1.81E-09 1.2814 0.2973 6.6010 105 NTS 0.47739066 NA Yes NA 230837_at 1:147804327 2.17E-09 -0.5123 0.2949 -6.5628 105 LOC100132057 NA NA NA NA 228879_at 17:62258534 2.27E-09 -0.2944 0.2943 -6.5534 105 SNORD104 NA NA NA NA 218957_s_at 11:73611349 2.27E-09 0.4843 0.2942 6.5531 105 PAAF1 NA NA Yes Yes 243900_at 9:127703351 2.32E-09 0.8857 0.2940 6.5486 105 WDR38 0.853965901 NA NA NA 1556277_a_at 5:78981369:TAACT 2.37E-09 0.6121 0.2937 6.5441 105 PAPD4 1 Yes NA Yes 206765_at 17:68159947 2.84E-09 -0.5041 0.2913 -6.5061 105 KCNJ2 0.079318013 NA Yes Yes 242325_at 22:32349543 3.33E-09 0.4941 0.2891 6.4721 105 YWHAH 1 Yes NA Yes 226125_at 5:467977 3.46E-09 -0.9171 0.2886 -6.4640 105 LOC100288152 NA NA NA NA 224971_at 2:99584971:ATATG 3.47E-09 0.2314 0.2885 6.4632 105 C2orf15 0.95033358 NA NA NA 224971_at 2:99584971:ATATG 3.47E-09 0.2314 0.2885 6.4632 105 MRPL30 NA NA NA NA 238673_at 8:119287930 3.54E-09 1.2806 0.2883 6.4591 105 SAMD12 0.99925871 Yes Yes Yes 209556_at 1:36021293 4.31E-09 0.3811 0.2856 6.4170 105 NCDN 0.992587102 NA NA NA 206421_s_at 18:61370172:TC_T 4.39E-09 -0.8110 0.2854 -6.4133 105 SERPINB7 0.228317272 NA NA NA 243761_at 7:90068214 4.72E-09 0.2197 0.2844 6.3978 105 CLDN12 0.054855448 Yes Yes NA 218272_at 22:46686404 5.07E-09 -0.3198 0.2834 -6.3824 105 TTC38 NA NA Yes Yes 242251_at 4:124174553 5.55E-09 -0.2381 0.2822 -6.3630 105 SPATA5 NA NA NA NA 230736_at 10:29717504 6.74E-09 0.4494 0.2795 6.3213 105 LOC387647 NA NA Yes NA 224595_at 9:108141335 7.25E-09 -0.7312 0.2785 -6.3056 105 SLC44A1 NA Yes Yes Yes 230539_at 20:25969265 7.36E-09 -0.4356 0.2783 -6.3024 105 FAM182A NA NA NA NA 222904_s_at 16:19403894 7.51E-09 0.2482 0.2780 6.2982 105 TMC5 NA NA NA NA 222448_s_at 1:47779259:CCTT_ 8.90E-09 -0.2901 0.2757 -6.2616 105 CMPK1 NA NA Yes Yes 201968_s_at 1:63906880 1.00E-08 0.2369 0.2741 6.2358 105 PGM1 1 Yes Yes Yes 1554258_a_at 8:66955837 1.02E-08 0.3287 0.2739 6.2328 105 DNAJC5B 0.966641957 NA Yes NA 232428_at 11:75428766 1.05E-08 -0.3625 0.2734 -6.2252 105 MOGAT2 0.017049666 NA NA NA 1568593_a_at 3:131080505 1.09E-08 0.3198 0.2730 6.2189 105 NUDT16P1 NA NA NA NA 225540_at 2:210319745 1.15E-08 0.6544 0.2722 6.2059 105 MAP2 0.988880652 NA NA NA 228461_at 2:109807719 1.15E-08 0.5874 0.2721 6.2056 105 SH3RF3 NA NA NA NA 229835_s_at 20:57597645 1.23E-08 0.6682 0.2713 6.1924 105 SLMO2 NA NA NA NA 230695_s_at 6:43614513 1.23E-08 0.4329 0.2712 6.1912 105 RSPH9 NA NA NA NA 205904_at 6:31330066 1.25E-08 0.3499 0.2710 6.1880 105 MICA NA NA NA NA 219865_at 1:22358457 1.32E-08 0.6970 0.2702 6.1760 105 LINC00339 NA NA NA NA 219388_at 8:102698284 1.35E-08 -0.2849 0.2699 -6.1713 105 GRHL2 NA NA NA NA 208358_s_at 4:115517933 1.38E-08 -0.8329 0.2697 -6.1674 105 UGT8 NA NA Yes NA 214180_at 1:25928855:GT_G 1.39E-08 -0.6608 0.2695 -6.1646 105 MAN1C1 1 Yes NA Yes 205308_at 8:79657263 1.45E-08 0.3066 0.2690 6.1558 105 ZC2HC1A NA NA NA NA 1561096_at 4:124775472 1.56E-08 0.6258 0.2680 6.1409 105 LOC285419 NA NA NA NA 1568987_at 17:44018399 1.60E-08 -0.2858 0.2677 -6.1355 105 MGC57346 NA NA NA NA 243884_at 13:31553036 2.04E-08 0.5193 0.2643 6.0822 105 TEX26 NA NA NA NA 1556065_at 22:46647388 2.35E-08 0.0977 0.2622 6.0508 105 LOC284926 NA NA NA NA

236999_at 5:64925256 2.46E-08 -0.1999 0.2617 -6.0415 105 PPWD1 NA NA NA Yes 229457_at 5:139807474 2.53E-08 -0.9344 0.2612 -6.0351 105 ANKHD1 NA NA NA NA 221581_s_at 7:73779983:AT_A 2.89E-08 -0.4991 0.2594 -6.0062 105 LAT2 1 NA NA Yes 1560184_at 15:38122066:CCAA_ 2.91E-08 -0.4291 0.2593 -6.0042 105 TMCO5A NA NA NA NA 232816_s_at 12:31222178 2.94E-08 -0.4706 0.2591 -6.0020 105 DDX11 NA Yes NA Yes 243426_at 18:5247942 3.05E-08 0.3214 0.2586 5.9938 105 LOC339290 NA NA Yes NA 236983_at 16:19418840 3.21E-08 0.4085 0.2579 5.9828 105 TMC5 NA NA NA NA 1561106_at 6:136059423 3.26E-08 0.3287 0.2577 5.9796 105 LINC00271 NA NA NA NA 222801_s_at 7:66786384 3.33E-08 0.3411 0.2574 5.9747 105 STAG3L4 NA NA Yes NA 1559105_at 3:156570521:T_TA 3.61E-08 0.2771 0.2562 5.9569 105 LEKR1 0.014825797 NA NA NA 240898_at 2:214802636 3.62E-08 -0.5350 0.2562 -5.9562 105 SPAG16 0.979985174 NA NA NA 206754_s_at 19:41469850 3.74E-08 -0.7070 0.2558 -5.9493 105 CYP2B6 1 NA NA NA 206754_s_at 19:41469850 3.74E-08 -0.7070 0.2558 -5.9493 105 CYP2B7P1 NA NA NA NA 209137_s_at 16:84742355 3.79E-08 0.7390 0.2556 5.9464 105 USP10 0.99851742 NA NA NA 242884_at 1:17460994 3.83E-08 -0.2573 0.2554 -5.9440 105 LOC440570 NA NA NA NA 239713_at 10:119934302 3.93E-08 -0.6505 0.2551 -5.9384 105 CASC2 NA NA NA NA 232395_x_at 7:134706143 4.33E-08 -0.2566 0.2537 -5.9170 105 AGBL3 NA NA NA NA 1552575_a_at 6:49627343 4.42E-08 -0.5295 0.2534 -5.9123 105 C6orf141 NA NA NA NA 229128_s_at 1:150560296 4.62E-08 1.4878 0.2528 5.9026 105 ANP32E 1 NA NA NA 224926_at 7:133541625 4.70E-08 0.2699 0.2525 5.8989 105 EXOC4 NA Yes Yes Yes 217870_s_at 1:47828442 4.86E-08 0.2881 0.2521 5.8916 105 CMPK1 NA NA Yes Yes 223095_at 10:99487376 4.87E-08 0.3353 0.2520 5.8909 105 MARVELD1 NA NA NA NA 220364_at 5:111755690 5.22E-08 0.2376 0.2510 5.8758 105 FLJ11235 NA NA NA NA 229280_s_at 6:21819216 5.45E-08 0.3067 0.2504 5.8661 105 LINC00340 NA NA NA NA 235361_at 2:74067880 5.56E-08 -0.1802 0.2501 -5.8616 105 STAMBP NA NA Yes Yes 204082_at 9:128620887 5.67E-08 0.3306 0.2499 5.8573 105 PBX3 NA NA Yes Yes 214059_at 1:79128569:T_TG 5.90E-08 0.4291 0.2493 5.8487 105 IFI44 NA NA Yes Yes 204904_at 1:35304501 6.18E-08 -0.6507 0.2486 -5.8381 105 GJA4 0.696071164 NA NA NA 219060_at 8:124439743 6.54E-08 -0.2888 0.2479 -5.8259 105 WDYHV1 NA NA Yes NA 210272_at 19:41469850 6.71E-08 -0.7303 0.2475 -5.8201 105 CYP2B7P1 NA NA NA NA 240771_at 1:244773129 6.96E-08 0.5831 0.2470 5.8119 105 C1orf101 NA Yes NA NA 227737_at 3:133539541:GTCT_ 7.15E-08 -0.3612 0.2466 -5.8059 105 SRPRB NA NA Yes Yes 218899_s_at 8:104222938 7.21E-08 -0.9482 0.2465 -5.8041 105 BAALC 0.979985174 NA NA NA 1552851_at 19:58241715 7.56E-08 -0.6062 0.2458 -5.7935 105 ZSCAN4 0.215715345 NA NA NA 1558541_at 8:12827679 8.41E-08 0.3983 0.2443 5.7697 105 KIAA1456 NA NA NA NA 231779_at 3:10086954 8.44E-08 -0.7260 0.2442 -5.7691 105 IRAK2 1 NA NA Yes 204758_s_at 11:118995729:T_TTG 8.48E-08 -0.2486 0.2441 -5.7678 105 C2CD2L NA NA NA Yes 229457_at 5:140402915 9.05E-08 -0.9391 0.2432 -5.7534 105 ANKHD1 NA NA NA NA 242462_at 19:38000548 9.62E-08 0.2909 0.2423 5.7398 105 LOC100506930 NA NA NA NA 241709_s_at 10:128892214 9.71E-08 -0.2903 0.2422 -5.7376 105 DOCK1 0.879911045 Yes NA NA 227776_at 11:76747625 9.73E-08 -0.3842 0.2422 -5.7372 105 ACER3 NA NA Yes Yes

214428_x_at 6:31799393 9.74E-08 -1.1498 0.2422 -5.7370 105 C4A NA Yes NA NA 214428_x_at 6:31799393 9.74E-08 -1.1498 0.2422 -5.7370 105 C4B NA Yes NA NA 214428_x_at 6:31799393 9.74E-08 -1.1498 0.2422 -5.7370 105 LOC100293534 NA NA NA NA 221069_s_at 17:62136276 1.01E-07 0.2243 0.2416 5.7290 105 TACO1 NA NA NA NA 225255_at 2:86427615 1.03E-07 0.2712 0.2413 5.7235 105 MRPL35 NA Yes Yes Yes 1560172_at 8:19681647 1.10E-07 0.3384 0.2404 5.7089 105 INTS10 1 NA NA NA 1557051_s_at 7:27138829 1.14E-07 -0.5367 0.2399 -5.7015 105 HOTAIRM1 NA NA NA NA 205945_at 1:154522248 1.18E-07 0.3103 0.2394 5.6942 105 IL6R 0.948851001 NA Yes Yes 240857_at 17:11815688 1.24E-07 0.5632 0.2386 5.6820 105 DNAH9 0.19051149 NA NA NA 209560_s_at 14:101135876 1.28E-07 -2.0838 0.2383 -5.6765 105 DLK1 0.00222387 Yes NA Yes 200870_at 12:16009289:C_CTA 1.46E-07 -0.2360 0.2364 -5.6465 105 STRAP NA NA NA NA 227566_at 11:131708549 1.50E-07 -1.0056 0.2359 -5.6395 105 LOC100653217 NA NA NA NA 227566_at 11:131708549 1.50E-07 -1.0056 0.2359 -5.6395 105 NTM NA NA NA NA 202745_at 15:50534676 1.51E-07 0.4561 0.2358 5.6382 105 USP8 1 Yes NA NA 244771_at 3:128049764 1.53E-07 -0.8210 0.2357 -5.6354 105 KBTBD12 NA NA NA NA 223169_s_at 1:229196226:G_GTG 1.56E-07 0.4560 0.2354 5.6311 105 RHOU 0.76056338 NA NA NA 205363_at 11:27093635 1.58E-07 0.5719 0.2352 5.6284 105 BBOX1 0.034840623 NA NA NA 1556711_at 13:43367981 1.64E-07 -0.3431 0.2347 -5.6196 105 FAM216B NA NA NA NA 204440_at 6:14004741 1.75E-07 -0.4824 0.2337 -5.6047 105 CD83 1 NA Yes Yes 224758_at 7:135306609 1.78E-07 -0.3709 0.2335 -5.6011 105 C7orf73 NA NA NA NA 229764_at 3:188971324 1.85E-07 -0.3309 0.2329 -5.5920 105 LOC100505861 NA NA NA NA 229764_at 3:188971324 1.85E-07 -0.3309 0.2329 -5.5920 105 TPRG1 0.354336546 NA Yes NA 226235_at 18:5248582:G_GGA 1.90E-07 -0.2142 0.2326 -5.5868 105 LOC339290 NA NA Yes NA 219198_at 9:135571115:AAC_A 1.92E-07 0.2250 0.2324 5.5843 105 GTF3C4 0.99777613 Yes Yes NA 228300_at 17:42977073 1.92E-07 0.2793 0.2324 5.5843 105 CCDC103 0.632320237 NA Yes NA 228300_at 17:42977073 1.92E-07 0.2793 0.2324 5.5843 105 FAM187A NA NA NA NA 235990_at 11:67135856 1.97E-07 -0.3204 0.2321 -5.5788 105 LOC100130987 NA NA NA NA 219419_at 18:77911100 1.99E-07 -0.1613 0.2319 -5.5761 105 RBFA NA NA NA NA 208451_s_at 6:31799393 2.01E-07 -1.3767 0.2318 -5.5742 105 C4A NA Yes NA NA 208451_s_at 6:31799393 2.01E-07 -1.3767 0.2318 -5.5742 105 C4B NA Yes NA NA 208451_s_at 6:31799393 2.01E-07 -1.3767 0.2318 -5.5742 105 LOC100293534 NA NA NA NA 1557311_at 1:205647155 2.16E-07 0.2469 0.2307 5.5579 105 LOC100131354 NA NA NA NA 1559479_at 4:25152346 2.26E-07 0.3255 0.2300 5.5469 105 LOC285540 NA NA NA NA 225326_at 5:146110880 2.41E-07 0.3664 0.2291 5.5330 105 RBM27 1 NA NA NA 223272_s_at 1:233105001 2.44E-07 0.4199 0.2289 5.5301 105 NTPCR NA NA Yes NA 213304_at 14:45473982:ATG_A 2.57E-07 0.3970 0.2281 5.5175 105 FAM179B NA NA NA NA 226456_at 16:11360607:GA_G 2.77E-07 0.2423 0.2271 5.5012 105 RMI2 NA NA NA NA 243495_s_at 17:47357966 2.96E-07 1.3861 0.2261 5.4861 105 ZNF652 0.99925871 Yes NA NA 232961_at 2:201277512 3.19E-07 0.5163 0.2250 5.4682 105 SPATS2L NA NA Yes NA 1555892_s_at 9:123572038 3.20E-07 0.5252 0.2249 5.4675 105 LOC253039 NA NA Yes NA 229266_at 17:11149073:GGT_G 3.23E-07 -0.4431 0.2248 -5.4658 105 SHISA6 NA NA NA NA

226464_at 3:143982472 3.39E-07 0.6951 0.2241 5.4550 105 C3orf58 0 NA NA Yes 202948_at 2:102759381 3.50E-07 0.4094 0.2237 5.4475 105 IL1R1 1 NA Yes NA 224668_at 20:44025692 3.71E-07 -0.2509 0.2228 -5.4337 105 SYS1 NA NA NA Yes 232382_s_at 8:52236426 3.73E-07 1.0127 0.2227 5.4328 105 PCMTD1 1 Yes NA NA 239065_at 12:49766870 3.74E-07 0.2177 0.2227 5.4320 105 DNAJC22 NA NA NA NA 213467_at 17:41408054 3.89E-07 0.3221 0.2221 5.4232 105 RND2 NA NA NA NA 209036_s_at 7:75324899:T_TTG 3.90E-07 0.1767 0.2221 5.4224 105 MDH2 1 Yes NA Yes 239989_at 9:17177401 3.96E-07 -0.2793 0.2218 -5.4190 105 CNTLN NA NA NA NA 231491_at 21:29577921 4.07E-07 -0.5306 0.2215 -5.4129 105 LINC00113 NA NA NA NA 244619_at 1:85675627 4.44E-07 -0.1500 0.2202 -5.3928 105 LOC646626 NA NA NA NA 1555007_s_at 12:122635353 4.47E-07 0.8011 0.2201 5.3912 105 WDR66 0.967383247 NA NA NA 226755_at 1:209604536 4.61E-07 -0.8248 0.2196 -5.3841 105 MIR205HG NA NA NA NA 243324_x_at 5:72186905 4.88E-07 -0.1158 0.2188 -5.3710 105 TNPO1 1 NA NA NA 219567_s_at 1:41020054 5.02E-07 0.1746 0.2184 5.3642 105 DEM1 NA NA NA NA 221992_at 16:74860758 5.16E-07 0.8324 0.2180 5.3579 105 NPIPL2 NA NA NA NA 228947_x_at 16:2010615 5.17E-07 -0.5536 0.2179 -5.3575 105 TMEM204 NA NA Yes NA 233210_at 17:34352232 5.20E-07 -0.2304 0.2178 -5.3560 105 FLJ12120 NA NA NA NA 212355_at 14:24917052 5.79E-07 0.3393 0.2163 5.3311 105 KHNYN NA NA NA NA 242565_x_at 21:47632580 6.07E-07 0.3909 0.2156 5.3205 105 YBEY NA NA Yes NA 231824_at 4:128961402 6.40E-07 -0.2575 0.2148 -5.3080 105 LARP1B NA NA NA NA 235077_at 14:101135878 6.44E-07 -0.9082 0.2147 -5.3065 105 MEG3 NA Yes NA NA 203400_s_at 3:133465283 6.47E-07 -0.6797 0.2146 -5.3057 105 TF NA Yes NA NA 219315_s_at 16:1547999 6.50E-07 -0.4923 0.2146 -5.3043 105 TMEM204 NA NA Yes NA 218585_s_at 1:212015067 6.65E-07 -0.6165 0.2142 -5.2990 105 DTL 0.625648629 NA NA NA 236517_at 5:126700140 6.72E-07 -0.2694 0.2141 -5.2967 105 MEGF10 0.090437361 NA NA NA 237002_at 1:36335862 7.18E-07 0.1519 0.2131 5.2814 105 NCDN 0.992587102 NA NA NA 214063_s_at 3:133457514 7.26E-07 -0.6122 0.2129 -5.2788 105 TF NA Yes NA NA 227099_s_at 11:44373965 7.37E-07 -0.5079 0.2127 -5.2751 105 C11orf96 NA NA NA NA 218139_s_at 14:57904666:G_GA 7.66E-07 0.6206 0.2121 5.2661 105 AP5M1 NA NA NA NA 1559025_at 17:75811381 7.85E-07 -0.3924 0.2118 -5.2604 105 9-Sep NA NA Yes Yes 1553623_at 22:31248289 8.02E-07 -0.2561 0.2115 -5.2555 105 MGC15705 NA NA NA NA 219196_at 15:51654147 8.33E-07 -0.4950 0.2109 -5.2467 105 SCG3 0.742031134 NA NA NA 209544_at 8:90923026 8.72E-07 -0.6865 0.2102 -5.2359 105 RIPK2 1 NA NA Yes 232239_at 10:91919662 8.73E-07 -0.5604 0.2102 -5.2358 105 LOC643529 NA NA NA NA 232318_s_at 13:44380846 8.89E-07 0.5633 0.2099 5.2314 105 LINC00284 NA NA NA NA 230477_at 18:77486912 8.99E-07 -0.3868 0.2098 -5.2288 105 LOC100130522 NA NA NA NA 231829_at 20:3849289:A_AG 9.13E-07 0.4246 0.2095 5.2251 105 MAVS NA NA Yes NA 1557646_at 13:42578316 9.28E-07 0.2184 0.2093 5.2214 105 LOC100507240 NA NA NA NA 235377_at 6:53977495 9.43E-07 0.2399 0.2091 5.2177 105 MLIP NA NA NA NA 228956_at 4:115517933 9.45E-07 -1.1985 0.2090 -5.2171 105 UGT8 NA NA Yes NA 1566764_at 7:20170669 9.57E-07 0.9966 0.2088 5.2140 105 MACC1 NA NA NA NA

1569378_at 12:1218302 9.72E-07 -0.8022 0.2086 -5.2104 105 LOC100292680 NA NA Yes NA 218195_at 6:151573527 9.80E-07 1.1725 0.2085 5.2085 105 C6orf211 1 NA NA Yes 208268_at 8:24022989 9.94E-07 -0.6573 0.2083 -5.2053 105 ADAM28 1 NA NA Yes 226200_at 6:31128552 1.02E-06 -0.2254 0.2079 -5.2001 105 VARS2 NA NA Yes NA 228542_at 6:24416482 1.02E-06 0.2894 0.2079 5.1989 105 MRS2 NA NA Yes NA 224785_at 17:74412056 1.02E-06 -0.9340 0.2078 -5.1982 105 FAM100B 1 NA NA NA 222361_at 9:141017343 1.04E-06 0.8243 0.2077 5.1956 105 TUBBP5 NA NA NA NA 217067_s_at 4:88881864 1.05E-06 -0.3367 0.2074 -5.1920 105 DMP1 0.063009637 NA NA NA 224477_s_at 16:4965930 1.07E-06 0.4283 0.2071 5.1870 105 NUDT16L1 1 NA NA NA 243803_at 11:94092983 1.11E-06 0.3667 0.2066 5.1789 105 LOC643037 NA NA NA NA 1557647_a_at 13:42579985 1.11E-06 -0.3921 0.2066 -5.1787 105 LOC100507240 NA NA NA NA 204033_at 5:952827 1.14E-06 0.2927 0.2062 5.1724 105 TRIP13 0.989621942 NA NA NA 220744_s_at 3:129140738 1.16E-06 0.2158 0.2060 5.1697 105 IFT122 NA NA NA Yes 1561761_x_at 4:120279532:AAG_A 1.16E-06 -0.1975 0.2059 -5.1682 105 LOC100507322 NA NA NA NA 1561761_x_at 4:120279532:AAG_A 1.16E-06 -0.1975 0.2059 -5.1682 105 LOC645513 NA NA NA NA 240390_at 2:158212849 1.16E-06 -0.5386 0.2059 -5.1682 105 GALNT5 0.99777613 NA Yes NA 231341_at 6:137500385 1.18E-06 -0.9753 0.2057 -5.1653 105 SLC35D3 0.297998517 Yes NA Yes 1553636_at 15:38268244 1.18E-06 -0.3876 0.2057 -5.1650 105 TMCO5A NA NA NA NA 1561633_at 12:66382329 1.19E-06 -0.1035 0.2056 -5.1624 105 HMGA2 0.421793921 NA NA NA 1559672_a_at 9:15533820 1.21E-06 -0.2438 0.2053 -5.1586 105 CCDC171 NA NA NA NA 214113_s_at 1:145522421:C_CTT 1.22E-06 0.2359 0.2053 5.1576 105 RBM8A 1 NA NA NA 208454_s_at 8:98051434 1.23E-06 -0.2475 0.2051 -5.1551 105 CPQ NA NA NA NA 217113_at 5:34028619 1.23E-06 -0.3796 0.2051 -5.1551 105 AMACR NA Yes Yes Yes 231379_at 12:5001593 1.25E-06 -0.8441 0.2048 -5.1510 105 LOC100507560 NA NA NA NA 243382_at 2:56543482 1.26E-06 -0.4463 0.2047 -5.1494 105 CCDC85A 0.99925871 NA NA NA 231124_x_at 1:161231962 1.27E-06 -0.3102 0.2046 -5.1474 105 LY9 0.137879911 Yes NA Yes 1557430_at 19:57120534 1.28E-06 -0.2328 0.2045 -5.1453 105 LOC147670 NA NA NA NA 213184_at 3:196339915 1.31E-06 0.1225 0.2041 5.1394 105 SENP5 1 NA NA NA 227628_at 5:54467882 1.32E-06 -0.4631 0.2040 -5.1380 105 GPX8 NA NA NA NA 203126_at 18:11934294 1.34E-06 -0.4966 0.2038 -5.1349 105 IMPA2 1 NA NA Yes 235171_at 8:59847927 1.34E-06 -0.2265 0.2038 -5.1345 105 LOC100505501 NA NA NA NA 222775_s_at 2:86523440 1.36E-06 -0.2461 0.2036 -5.1311 105 MRPL35 NA Yes Yes Yes 216624_s_at 11:117845195 1.39E-06 -0.4853 0.2032 -5.1259 105 MLL NA NA NA NA *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present its lung expression status.

Table S2B*, Airway epithelia specific trans eQTL (exist in airway epithelia but not in lung) in small airway 10% FDR Average Present Liver Whole Blood reporterID SNP Chr:Position (hg19) Pvalue beta Rsq T N Gene Call in Lung LCL eQTL eQTLs eQTL Expression Study 1554663_a_at 11:71754338 6.98E-43 -2.2259 0.8407 -23.3156 105 NUMA1 NA NA NA NA 225155_at 6:86283777:TATA_ 2.06E-41 -1.0551 0.8299 -22.4183 105 SNHG5 NA NA NA NA 225155_at 6:86283777:TATA_ 2.06E-41 -1.0551 0.8299 -22.4183 105 SNORD50A NA NA Yes NA 225155_at 6:86283777:TATA_ 2.06E-41 -1.0551 0.8299 -22.4183 105 SNORD50B NA NA Yes NA 209480_at 6:32604372 2.55E-34 -2.5294 0.7666 -18.3937 105 HLA-DQB1 NA NA Yes NA 203290_at 6:32603007 4.87E-33 -3.7273 0.7529 -17.7154 105 HLA-DQA1 NA NA NA NA 238632_at 4:76005174 3.36E-32 1.2680 0.7435 17.2782 105 LOC100505946 NA NA NA NA 230937_at 6:31362340:GT_G 1.17E-31 1.1986 0.7372 16.9983 105 LOC285835 NA NA NA NA 209728_at 6:32604108 2.88E-31 -3.9763 0.7326 -16.7982 105 HLA-DRB4 0.897702001 NA NA NA 209728_at 6:32604108 2.88E-31 -3.9763 0.7326 -16.7982 105 LOC100509582 NA NA NA NA 213831_at 6:32604000 9.08E-28 -2.9514 0.6875 -15.0537 105 HLA-DQA1 NA NA NA NA 213831_at 6:32604000 9.08E-28 -2.9514 0.6875 -15.0537 105 LOC100507718 NA NA NA NA 213831_at 6:32604000 9.08E-28 -2.9514 0.6875 -15.0537 105 LOC100509457 NA NA NA NA 212999_x_at 6:32604000 1.69E-26 -1.4006 0.6693 -14.4393 105 HLA-DQB1 NA NA Yes NA 212999_x_at 6:32604000 1.69E-26 -1.4006 0.6693 -14.4393 105 LOC100293977 NA NA NA NA 204148_s_at 7:76135403 5.61E-26 -1.0364 0.6616 -14.1901 105 POMZP3 NA NA Yes NA 204148_s_at 7:76135403 5.61E-26 -1.0364 0.6616 -14.1901 105 ZP3 NA NA NA NA 229604_at 6:25106783 1.22E-25 0.6306 0.6565 14.0300 105 CMAHP NA NA NA NA 227446_s_at 14:24422946:A_ACT 1.73E-25 0.7155 0.6541 13.9572 105 DHRS4-AS1 NA NA NA NA 207584_at 6:161146634 4.27E-25 -0.7858 0.6480 -13.7713 105 LPA 0.176426983 NA NA NA 243943_x_at 6:10689301 6.57E-25 1.1425 0.6451 13.6831 105 C6orf52 0.880652335 NA Yes NA 222722_at 13:90043112 9.12E-25 -2.0886 0.6428 -13.6159 105 OGN NA NA NA NA 242557_at 6:30002881 5.16E-24 0.6671 0.6307 13.2628 105 ZNRD1-AS1 NA NA NA NA 235126_at 1:213016565 1.44E-23 -0.5353 0.6233 -13.0548 105 FLVCR1-AS1 NA NA NA NA 239417_x_at 6:10689301 5.76E-23 1.0903 0.6131 12.7754 105 C6orf52 0.880652335 NA Yes NA 242594_at 4:13609674 9.79E-23 0.4490 0.6091 12.6686 105 BOD1L1 NA NA NA NA *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present its lung expression status.

Table S2C*, Airway epithelia specific cis eQTL (exist in airway epithelia but not in lung) in large airway 10% FDR SNP Chr:Position Average Present Call in Liver LCL Whole reporterID Pvalue beta Rsq T N Gene (hg19) Lung Expression Study eQTLs eQTL Blood eQTL 214038_at 21:16690492 8.48E-31 -7.292 0.974 -36.920 39 CCL8 0.999 NA NA NA 210163_at 21:16690492 7.24E-29 -8.719 0.966 -32.621 39 CXCL11 NA NA NA NA 1559258_a_at 21:20437826 2.02E-28 -4.814 0.964 -31.699 39 CXorf61 0.505 NA Yes NA 211122_s_at 21:16690492 2.30E-28 -9.104 0.964 -31.585 39 CXCL11 NA NA NA NA 1559258_a_at 21:41286231 5.41E-28 -5.091 0.963 -30.834 39 CXorf61 0.505 NA Yes NA *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present its lung expression status.

Table S2D*, Airway epithelia specific trans eQTL (exist in airway epithelia but not in lung) in large airway 10% FDR SNP Chr:Position Average Present Call in Liver LCL Whole Blood reporterID Pvalue beta Rsq T N Gene (hg19) Lung Expression Study eQTLs eQTL eQTL 214038_at 21:16690492 8.48E-31 -7.292 0.974 -36.920 39 CCL8 0.999 NA NA NA 210163_at 21:16690492 7.24E-29 -8.719 0.966 -32.621 39 CXCL11 NA NA NA NA 1559258_a_at 21:20437826 2.02E-28 -4.814 0.964 -31.699 39 CXorf61 0.505 NA Yes NA 211122_s_at 21:16690492 2.30E-28 -9.104 0.964 -31.585 39 CXCL11 NA NA NA NA 1559258_a_at 21:41286231 5.41E-28 -5.091 0.963 -30.834 39 CXorf61 0.505 NA Yes NA *When a probeset is mapped to multiple genes, we devote one row in the table for every gene and present its lung expression status.

Table S3

Asthma candidate genes ABO ACE ACP1 ACVR1 ADA ADAM33 ADAM8 ADCY9 ADH5 AGT AICDA AKR1C3 ALDH2 ALOX15 ALOX5AP ANXA2 AOAH ARG1 ARG2 BAT1 BCL2 BCL2L1 BDKRB1 BDKRB2 BDNF BMP2 BMP4 BMP7 BMPR1A BMPR1B C3 C3AR1 C5 C5orf20 CAMP CAT CCL11 CCL2 CCL28 CCR1 CCR3

CCR5 CCR9 CD14 CD28 CD40 CD69 CD86 CDH1 CDKN1A CFL1 CFTR CHI3L1 CHIA CHIT1 CHML CHRM1 CHRM2 CHRM3 CLCA1 CMA1 COL1A1 COMT CREB1 CRHR1 CRHR2 CRP CSF2RB CTLA4 CTNNA1 CTNNA3 CX3CR1 CXCL10 CYBA CYP1A1 CYP1A2 CYP2C9 CYP2J2 CYP2R1 CYP4F3 CYSLTR1 CYSLTR2 DAP3

DEFB1 DPP10 EDNRA EDNRB EFNA1 EGFR EHF ELAC2 ELF5 EPHX2 F2RL1 FCAR FCER1G FCGR2A FGF2 FGFBP2 FLG FLT3LG FMR1 FOXP3 FUT2 FUT3 FYN GATA3 GC GCLC GHRL GIF GNAS GNB1 GPR44 GPX1 GSTA1 GSTM3 GSTO2 GSTP1 GSTT1 HAVCR1 HAVCR2 HEXB HLA-A HLA-B

HLA-C HLA-DRB3 HLA-G HNMT HRH2 IFNA1 IFNAR1 IFNGR1 IFNGR2 IKBKAP IL10 IL10RA IL12A IL12RB1 IL12RB2 IL13RA1 IL15 IL16 IL17F IL18 IL18R1 IL18RAP IL19 IL1A IL1R1 IL1RL1 IL1RN IL21 IL27 IL31 IL8 IL9R INHA INPP4A ITGA4 ITGA6 ITGB3 ITGB7 ITK ITLN1 JUND KCNMB1

KCNS3 KDR LAMA5 LELP1 LEP LEPR LGALS3 LTA4H LTB LTB4R LTC4S MBL2 MICB MIF MMP1 MMP21 MMP28 MPO MS4A1 MS4A3 MTHFR MUC5AC MUC7 MYH11 MYLK NAT1 NAT2 NFKB2 NFKBIL1 NOD2 NOS1 NOS3 NOX4 NPSR1 NQO1 NR3C1 NRIP2 NTF3 ORMDL3 PAFAH1B1 PDGFA PDGFRA

PHF11 PLA2G4A PLA2G7 PLAUR PMCH PPARG PTAFR PTGDR PTGER1 PTGER2 PTGER3 PTGER4 PTGFR PTGIR PTGS1 PTGS2 PTPRD RASGRP4 RIPK2 RNASE3 ROM1 RUNX1 SCGB1A1 SCGB3A2 SELP SERBP1 SERPINA3 SERPINB3 SFRP1 SIGIRR SIGLEC8 SLC11A1 SLC26A4 SMAD2 SOCS1 SOD2 SPINK5 SPP1 STAT2 STAT3 STAT4 TAC1

TAGLN TBX21 TBXA2R TGFB1 TGFB2 TGFBR1 TIMD4 TJP1 TLR1 TLR10 TLR2 TLR3 TLR6 TLR7 TLR8 TLR9 TNC TNFRSF10A TNFRSF10B TNFRSF14 TNXB TPSD1 TPSG1 TPT1 TSLP VDR VEGFA WDR36 XDH

Table S4. Gabriel Asthma meta GWAS eSNPs Supported by Regulatory Elements 10% FDR 20% FDR # # ENCODE Pvalue Gabriel # cis ENCODE Enrichment # cis Enrichment

cutoff Hits eQTLs pvalue eQTLs pvalue Support Support * 1E-2 7,204 52 23 9.5e-12 77 32 1.9e-14 1E-3 1,186 31 13 2.8e-07 37 15 8.5e-08 1E-4 348 13 5 7.2e-04 36 10 3.7e-04 1E-5 175 4 2 3.2e-03 16 5 2.6e-03 At 10% and 20% eQTLs, we detected small airway 660 and 1066 eQTLs, respectively. *GABRIEL meta GWAS hits that are cis- eSNPs and also supported by regulatory evidence from ENCODE.