RGD Reference Report - Identifying multiple causative genes at a single GWAS locus. - Rat Genome Database

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Identifying multiple causative genes at a single GWAS locus.

Authors: Flister, MJ  Tsaih, SW  O'Meara, CC  Endres, B  Hoffman, MJ  Geurts, AM  Dwinell, MR  Lazar, J  Jacob, HJ  Moreno, C 
Citation: Flister MJ, etal., Genome Res. 2013 Dec;23(12):1996-2002. doi: 10.1101/gr.160283.113. Epub 2013 Sep 4.
RGD ID: 8662415
Pubmed: (View Article at PubMed) PMID:24006081
DOI: Full-text: DOI:10.1101/gr.160283.113

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.

Annotation

Phenotype Values via PhenoMiner

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Objects Annotated

Genes (Rattus norvegicus)
Agtrap  (angiotensin II receptor-associated protein)
Clcn6  (chloride voltage-gated channel 6)
Mthfr  (methylenetetrahydrofolate reductase)
Nppa  (natriuretic peptide A)
Plod1  (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1)

Objects referenced in this article
Strain SS-Agtrapem8Mcwi null Rattus norvegicus
Strain SS-Clcn6em2Mcwi null Rattus norvegicus
Strain SS-Mthfrem1Mcwi null Rattus norvegicus
Strain SS-Nppaem4Mcwi null Rattus norvegicus
Strain SS-Nppbem4Mcwi null Rattus norvegicus
Strain SS-Plod1em1Mcwi null Rattus norvegicus

Additional Information