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Identifying multiple causative genes at a single GWAS locus. Genome Res 2013 Dec;23(12):1996-2002 PMID: 24006081 PMCID: PMC3847770

Pubmed ID

24006081

Abstract

Genome-wide association studies (GWAS) are useful for nominating candidate genes, but typically are unable to establish disease causality or differentiate between the effects of variants in linkage disequilibrium (LD). Additionally, some GWAS loci might contain multiple causative variants or genes that contribute to the overall disease susceptibility at a single locus. However, the majority of current GWAS lack the statistical power to test whether multiple causative genes underlie the same locus, prompting us to adopt an alternative approach to testing multiple GWAS genes empirically. We used gene targeting in a disease-susceptible rat model of genetic hypertension to test all six genes at the Agtrap-Plod1 locus (Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1) for blood pressure (BP) and renal phenotypes. This revealed that the majority of genes at this locus (five out of six) can impact hypertension by modifying BP and renal phenotypes. Mutations of Nppa, Plod1, and Mthfr increased disease susceptibility, whereas Agtrap and Clcn6 mutations decreased hypertension risk. Reanalysis of the human AGTRAP-PLOD1 locus also implied that disease-associated haplotype blocks with polygenic effects were not only possible, but rather were highly plausible. Combined, these data demonstrate for the first time that multiple modifiers of hypertension can cosegregate at a single GWAS locus.

Author List

Flister MJ, Tsaih SW, O'Meara CC, Endres B, Hoffman MJ, Geurts AM, Dwinell MR, Lazar J, Jacob HJ, Moreno C

Authors

Melinda R. Dwinell PhD Center Associate Director, Associate Professor in the Physiology department at Medical College of Wisconsin
Michael J. Flister PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
Aron Geurts PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Caitlin C. O'Meara PhD Assistant Professor in the Physiology department at Medical College of Wisconsin




Scopus

2-s2.0-84888132259   47 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Disease Models, Animal
Female
Gene Targeting
Genes, Modifier
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Haplotypes
Humans
Hypertension
Kidney
Linkage Disequilibrium
Male
Mutation
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Rats
Rats, Sprague-Dawley
Retrospective Studies
jenkins-FCD Prod-299 9ef562391eceb2b8f95265c767fbba1ce5a52fd6