Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits

Although recent studies provide evidence for a common genetic basis between complex traits and Mendelian disorders, a thorough quantification of their overlap in a phenotype-specific manner remains elusive. Here, we have quantified the overlap of genes identified through large-scale genome-wide association studies (GWASs) for 62 complex traits and diseases with genes containing mutations known to cause 20 broad categories of Mendelian disorders. We identified a significant enrichment of genes linked to phenotypically matched Mendelian disorders in GWAS gene sets; of the total 1,240 comparisons, a higher proportion of phenotypically matched or related pairs (n = 50 of 92 [54%]) than phenotypically unmatched pairs (n = 27 of 1,148 [2%]) demonstrated significant overlap, confirming a phenotype-specific enrichment pattern. Further, we observed elevated GWAS effect sizes near genes linked to phenotypically matched Mendelian disorders. Finally, we report examples of GWAS variants localized at the transcription start site or physically interacting with the promoters of genes linked to phenotypically matched Mendelian disorders. Our results are consistent with the hypothesis that genes that are disrupted in Mendelian disorders are dysregulated by non-coding variants in complex traits and demonstrate how leveraging findings from related Mendelian disorders and functional genomic datasets can prioritize genes that are putatively dysregulated by local and distal non-coding GWAS variants

Reverse gene–environment interaction approach to identify variants influencing body-mass index in humans

Identifying gene–environment (G×E) interactions contributing to human cardiometabolic disorders is challenging. Here we apply a reverse G×E candidate search by deriving candidate variants from promoter–enhancer interactions that respond to dietary fatty acid challenge through altered chromatin accessibility in primary human adipocytes. We then test all variants residing in lipid-responsive open chromatin sites in adipocyte promoter–enhancer contacts for interaction effects between genotype and dietary saturated fat intake on body-mass index (BMI) in the UK Biobank. We discover 14 new G×E variants in 12 lipid-responsive promoters, including in well-known lipid-related genes (LIPE, CARM1 and PLIN2) and newly associated genes, such as LDB3, for which we provide further functional and integrative genomic evidence. We further identify 24 G×E variants in enhancers, for a total of 38 new G×E variants for BMI in the UK Biobank, demonstrating that molecular genomics data produced in physiologically relevant contexts can be applied to discover new functional G×E mechanisms in humans

Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development. Here we perform promoter Capture Hi-C in human adipocytes to investigate interactions between gene promoters and distal elements as a transcription-regulating mechanism contributing to these phenotypes. We find that promoter-interacting elements in human adipocytes are enriched for adipose-related transcription factor motifs, such as PPARG and CEBPB, and contribute to heritability of cis-regulated gene expression. We further intersect these data with published genome-wide association studies for BMI and BMI-related metabolic traits to identify the genes that are under genetic cis regulation in human adipocytes via chromosomal interactions. This integrative genomics approach identifies four cis-eQTL-eGene relationships associated with BMI or obesity-related traits, including rs4776984 and MAP2K5, which we further confirm by EMSA, and highlights 38 additional candidate genes