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: PMID:24006081   (View Abstract at PubMed)
PMCID: PMC3847770   (View Article at PubMed Central)
DOI: DOI:10.1101/gr.160283.113   (Journal Full-text)

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.

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased body weight  IMP 8662415; 8662415; 8662415as compared to the wild-typeRGD 
decreased heart weight  IMP 8662415as compared to the wild-typeRGD 
decreased mean systemic arterial blood pressure  IMP 8662415as compared to the wild-typeRGD 
decreased systemic arterial diastolic blood pressure  IMP 8662415as compared to the wild-typeRGD 
decreased urine creatinine level  IMP 8662415as compared to the wild-typeRGD 
decreased urine protein level  IMP 8662415as compared to the wild-typeRGD 
decreased urine sodium level  IMP 8662415as compared to the wild-typeRGD 
increased heart weight  IMP 8662415; 8662415as compared to the wild-typeRGD 
increased mean systemic arterial blood pressure  IMP 8662415as compared to the wild-typeRGD 
increased systemic arterial diastolic blood pressure  IMP 8662415as compared to the wild-typeRGD 
increased systemic arterial systolic blood pressure  IMP 8662415; 8662415as compared to the wild-typeRGD 
increased urine protein level  IMP 8662415; 8662415; 8662415as compared to the wild-typeRGD 

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