Identifying multiple causative genes at a single GWAS locus
- Michael J Flister1,
- Shirng-Wern Tsaih2,
- Caitlin C O'Meara3,
- Bradley Endres2,
- Matthew J Hoffman2,
- Aron M Geurts2,
- Melinda R Dwinell2,
- Jozef Lazar2,
- Howard J Jacob2,4 and
- Carol Moreno2
- 1 Medical College Wisconsin;
- 2 Medical College of Wisconsin;
- 3 Brigham and Women's Hospital, Harvard Medical School
- ↵* Corresponding author; email: jacob{at}mcw.edu
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) in blood pressure (BP) and renal phenotypes. This revealed that the majority of genes at this locus (5 out of 6) 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. Re-analysis 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.
- Received May 11, 2013.
- Accepted September 3, 2013.
- © 2013, Published by Cold Spring Harbor Laboratory Press
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
