complex human disease; epistasis; essential genes; evolution; interchromosomal; linkage disequilibrium; long-range; pleiotropy; variable expressivity; Linkage Disequilibrium/genetics; Genotype; Biological Specimen Banks; United Kingdom; Polymorphism, Single Nucleotide/genetics; Genome-Wide Association Study; Epistasis, Genetic; Polymorphism, Single Nucleotide; Genetics; Genetics (clinical)
Abstract :
[en] Leveraging linkage disequilibrium (LD) patterns as representative of population substructure enables the discovery of additive association signals in genome-wide association studies (GWASs). Standard GWASs are well-powered to interrogate additive models; however, new approaches are required for invesigating other modes of inheritance such as dominance and epistasis. Epistasis, or non-additive interaction between genes, exists across the genome but often goes undetected because of a lack of statistical power. Furthermore, the adoption of LD pruning as customary in standard GWASs excludes detection of sites that are in LD but might 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's D statistics) in long-range LD (>0.25 cM). Across five disease phenotypes, we identified one significant and four near-significant associations 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) genes that were 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 LD under epistatic selection. Our work supports the hypothesis that epistatic interactions regulate diverse clinical mechanisms and might especially be driving factors in conditions with a wide range of phenotypic outcomes.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Singhal, Pankhuri; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Veturi, Yogasudha; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Dudek, Scott M; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Lucas, Anastasia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Frase, Alex; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Van Steen, Kristel ; Université de Liège - ULiège > Département d'électricité, électronique et informatique (Institut Montefiore) > Bioinformatique ; Department of Human Genetics, Katholieke Universiteit Leuven, ON4 Herestraat 49, 3000 Leuven, Belgium
Schrodi, Steven J; Laboratory of Genetics, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53706, USA
Fasel, David; Columbia University, New York, NY 10027, USA
Weng, Chunhua; Columbia University, New York, NY 10027, USA
Pendergrass, Rion; Genentech, San Francisco, CA 94080, USA
Schaid, Daniel J; Mayo Clinic, Rochester, MN 55902, USA
Kullo, Iftikhar J; Mayo Clinic, Rochester, MN 55902, USA
Dikilitas, Ozan; Mayo Clinic, Rochester, MN 55902, USA
Sleiman, Patrick M A; Children's Hospital of Pennsylvania, Philadelphia, PA 19104, USA
Hakonarson, Hakon; Children's Hospital of Pennsylvania, Philadelphia, PA 19104, USA
Moore, Jason H; Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Williams, Scott M; Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
Ritchie, Marylyn D; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: marylyn@pennmedicine.upenn.edu
Verma, Shefali S ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shefali.setiaverma@pennmedicine.upenn.edu
The authors would like to acknowledge their funding sources. M.D.R. is supported by R01 HG010067 and U01 AG066833. J.H.M. is supported by R01 LM010098 and U01 AG066833. P.S. is supported by F31 AG069441-01. eMERGE Network (phase III): This phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG8657 (Group Health Cooperative/University of Washington); U01HG8685 (Brigham and Women's Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children's Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children's Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center, serving as the coordinating center); U01HG8676 (Mass General Brigham and Broad Institute); and U01HG8664 (Baylor College of Medicine). The authors would also like to thank Stephen Schaeffer and the participants of the Epistasis Discovery in Genetics and Epidemiology (EDGE) meeting over the years for their insightful discussion and feedback that has guided this project. The authors declare no competing interests.The authors would like to acknowledge their funding sources. M.D.R . is supported by R01 HG010067 and U01 AG066833 . J.H.M . is supported by R01 LM010098 and U01 AG066833 . P.S . is supported by F31 AG069441-01 . eMERGE Network (phase III): This phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG8657 (Group Health Cooperative/ University of Washington ); U01HG8685 ( Brigham and Women's Hospital ); U01HG8672 ( Vanderbilt University Medical Center ); U01HG8666 ( Cincinnati Children's Hospital Medical Center ); U01HG6379 ( Mayo Clinic ); U01HG8679 ( Geisinger Clinic ); U01HG8680 ( Columbia University Health Sciences ); U01HG8684 ( Children's Hospital of Philadelphia ); U01HG8673 ( Northwestern University ); U01HG8701 ( Vanderbilt University Medical Center , serving as the coordinating center); U01HG8676 ( Mass General Brigham and Broad Institute ); and U01HG8664 ( Baylor College of Medicine ). The authors would also like to thank Stephen Schaeffer and the participants of the Epistasis Discovery in Genetics and Epidemiology (EDGE) meeting over the years for their insightful discussion and feedback that has guided this project.
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