Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.
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ABSTRACT:
SUBMITTER: Hellwege JN
PROVIDER: S-EPMC6710266 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
Publications
Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.
Hellwege Jacklyn N JN Velez Edwards Digna R DR Giri Ayush A Qiu Chengxiang C Park Jihwan J Torstenson Eric S ES Keaton Jacob M JM Wilson O D OD Robinson-Cohen Cassianne C Chung Cecilia P CP Roumie Christianne L CL Klarin Derek D Damrauer Scott M SM DuVall Scott L SL Siew Edward E Akwo Elvis A EA Wuttke Matthias M Gorski Mathias M Li Man M Li Yong Y Gaziano J Michael JM Wilson Peter W F PWF Tsao Philip S PS O'Donnell Christopher J CJ Kovesdy Csaba P CP Pattaro Cristian C Köttgen Anna A Susztak Katalin K Edwards Todd L TL Hung Adriana M AM
Nature communications 20190826 1
Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickl ...[more]
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Project description:<p>MVP is an ongoing prospective cohort study and mega-biobank in the Department of Veterans Affairs Healthcare System designed to study genetic influences on health and disease among veterans.</p>
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Project description:PurposePrimary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS).DesignCross-sectional study.ParticipantsMVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls.MethodsWe tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS.Main outcome measuresPerformance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS.ResultsGRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases.ConclusionsVaried performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.
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