Evidence of epistasis in regions of long-range linkage disequilibrium across five complex diseases in the UK Biobank and eMERGE datasets

Abstract

Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWAS). Standard GWAS are well-powered to interrogate additive models; however, new approaches are required to investigate other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected due to lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWAS excludes detection of sites in LD that may underlie the genetic architecture of complex traits. We hypothesize that uncovering long-range interactions between loci with strong LD due to epistatic selection can elucidate genetic mechanisms underlying common diseases. To investigate this hypothesis, we tested for associations between 23 common diseases and 5,625,845 epistatic SNP-SNP pairs (determined by Ohta’sDstatistics) in long-range LD (> 0.25cM). We identified five significant associations across five disease phenotypes that replicated in two large genotype-phenotype datasets (UK Biobank and eMERGE). The genes that were most likely involved in the replicated associations were 1) members of highly conserved gene families with complex roles in multiple pathways, 2) essential genes, and/or 3) associated in the literature with complex traits that display variable expressivity. These results support the highly pleiotropic and conserved nature of variants in long-range under epistatic selection. Our work supports the hypothesis that epistatic interactions regulate diverse clinical mechanisms and may especially be driving factors in conditions with a wide range of phenotypic outcomes.SignificanceCurrent knowledge of genotype-phenotype relationships is largely contingent on traditional univariate approaches to genomic analysis. Yet substantial evidence supports non-additive modes of inheritance and regulation, such as epistasis, as being abundant across the genome. In this genome-wide study, we probe the biomolecular mechanisms underlying complex human diseases by testing the association of pairwise genetic interactions with disease occurrence in large-scale biobank data. Specifically, we tested intrachromosomal and interchrosomal long-range interactions between regions of the genome in high linkage disequilibrium, these regions are typically excluded from genomic analyses. The results from this study suggest that essential gene, members of highly conserved gene families, and phenotypes with variable expressivity, are particularly enriched with epistatic and pleiotropic activity.

Learning gene networks under SNP perturbation using SNP and allele-specific expression data

“…Long-range linkage disequilibrium in eQTLs for global subnetworks was found only in the GTEx data, and thus, may have played a role in shaping tissue-specific gene regulation during evolution. Our results substantially elaborate the previous reports on the pleiotropic effects of eQTLs on clusters of locally co-expressed genes 15 , a hierarchy in gene expression and eQTL patterns across tissue types 16 , and long-range linkage disequilibrium that recent studies have begun to notice in genome-wide association studies 17,18,19 .…”

“…While Type I blocks have been previously reported as eQTLs for co-expressed local genes 15 , our analysis revealed previously unknown Type II blocks. Long-range linkage disequilibrium among SNPs has been known to arise from epistatic selection or population structure, and to be implicated in complex diseases 17,18,19 , but little has been known about their roles in gene regulation. Our results suggest that long-range linkage disequilibrium may have played a role in shaping tissue-specific gene regulation in global subnetworks.…”

Explainable artificial intelligence identifies an AQP4 polymorphism-based risk score associated with brain amyloid burden

“…Finally, 19 SNPs were used for the analysis. The decision to keep correlated SNPs up to an r 2 of 0.92 was based on evidence that SNP-SNP pairs in high linkage disequilibrium can be significantly associated with phenotypes due to epistatic effects (30), so that cases where two correlated SNPs differ from each other might contain valuable information. Details of the SNPs which were used, as well as previously reported associations, are shown in Table 1.…”

Bioinformatics pipeline to guide post‐GWAS studies in Alzheimer's: A new catalogue of disease candidate short structural variants

“…For haplotypes, the swept radius, 1/ɛ, estimates the distance in kb at which association falls to approximately one‐third of disease haplotypes, the swept radius is estimated to be between 300 and 500 kb, and for random haplotypes it is somewhat smaller than 300 kb 42 . More recently, LD at larger distances (1 centimorgan or approximately 1 Mb) has been characterized at the chromosome‐wide level, 43 and epistasis at distances of long‐range LD (>0.25 cM) have been reported for complex diseases including Alzheimer's disease (AD) 44 . It is noteworthy that LD is also influenced by factors including allele frequencies of the variants and is often ancestry‐specific.…”

“…42 More recently, LD at larger distances (1 centimorgan or approximately 1 Mb) has been characterized at the chromosome-wide level, 43 and epistasis at distances of long-range LD (>0.25 cM) have been reported for complex diseases including Alzheimer's disease (AD). 44 It is noteworthy that LD is also influenced by factors including allele frequencies of the variants and is often ancestry-specific.…”