Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci Eilis Hannon, Mike Weedon, Nicholas Bray,

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Pleiotropic Effects of Trait-Associated Genetic Variation on DNA Methylation: Utility for Refining GWAS Loci Eilis Hannon, Mike Weedon, Nicholas Bray, Michael O’Donovan, Jonathan Mill The American Journal of Human Genetics Volume 100, Issue 6, Pages 954-959 (June 2017) DOI: 10.1016/j.ajhg.2017.04.013 Copyright © 2017 The Author(s) Terms and Conditions

Figure 1 SMR Analysis Using mQTLs and eQTLs Implicates a Role for RNASET2 in Crohn Disease Shown is a chromosome 6 genomic region (UCSC Genome Browser hg19: 167,243,095–167,565,882) identified in a recent Crohn disease GWAS performed by Liu et al.5 Genes located in this region are shown at the top; exons are indicated by thicker bars, and red arrows indicate the direction of transcription. DNA methylation sites interrogated by the Illumina 450K array are indicated by solid vertical lines underneath the genes. The four bottom panels depict the −log10 p value (y axis) against genomic location (x axis) from (A) SMR analysis (black squares represent Illumina 450K array DNA methylation sites, blue triangles represent gene expression probes, and green and red coloring highlight those with a non-significant HEIDI test for DNA methylation and gene expression, respectively), (B) blood mQTL (n = 639) results for the DNA methylation site cg25258033 (outlined in black in A), (C) blood eQTL (n = 5,311) results for ILMN1671565 (outlined in black in A), and (D) the Crohn disease GWAS performed by Liu et al.5 The American Journal of Human Genetics 2017 100, 954-959DOI: (10.1016/j.ajhg.2017.04.013) Copyright © 2017 The Author(s) Terms and Conditions

Figure 2 SMR Analysis Using Whole-Blood and Fetal Brain mQTL Data Implicates a Role for HEY2 in Migraine Shown is a chromosome 6 genomic region (UCSC Genome Browser hg19: 125,970,800–126,170,800) identified in a recent migraine GWAS performed by Gormley et al.25 Genes located in this region are shown at the top; exons are indicated by thicker bars, and red arrows indicate the direction of transcription. The four bottom panels depict the −log10 p value (y axis) against genomic location (x axis) from (A) SMR analysis (points represent DNA methylation sites interrogated by the Illumina 450K array, squares and diamonds indicate SMR tests from blood and fetal brain mQTLs, respectively, and green squares and blue diamonds highlight those with a non-significant HEIDI test for blood and fetal brain, respectively), mQTL results for the DNA methylation site cg05901451 (outlined in black in A) in (B) blood (n = 639) and (C) fetal brain (n = 166), and (D) the migraine GWAS performed by Gormley et al. (n = 59,674 case and 316,078 control samples).25 The American Journal of Human Genetics 2017 100, 954-959DOI: (10.1016/j.ajhg.2017.04.013) Copyright © 2017 The Author(s) Terms and Conditions

Figure 3 Heatmap of the SMR Results for 32 DNA Methylation Sites Associated with Crohn Disease across 38 GWAS Datasets Each square in the heatmap represents the t-statistic (b_SMR/se_SMR) of the GWAS trait (columns) for a DNA methylation site (row; n = 32) associated with Crohn disease. Only phenotypes (n = 38) tested against at least 20,000 DNA methylation sites were included in this comparison. SMR p < 1.38 × 10−6 and HEIDI p > 0.05. The American Journal of Human Genetics 2017 100, 954-959DOI: (10.1016/j.ajhg.2017.04.013) Copyright © 2017 The Author(s) Terms and Conditions