Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease.

TitleAnalysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease.
Publication TypeJournal Article
Year of Publication2015
AuthorsLi, AH, Morrison, AC, Kovar, C, L Cupples, A, Brody, JA, Polfus, LM, Yu, B, Metcalf, G, Muzny, DM, Veeraraghavan, N, Liu, X, Lumley, T, Mosley, TH, Gibbs, RA, Boerwinkle, E
JournalNat Genet
Volume47
Issue6
Pagination640-2
Date Published2015 Jun
ISSN1546-1718
KeywordsAtherosclerosis, Chronic Disease, Exome, Gene Frequency, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Humans, Molecular Sequence Annotation, Phenotype, Polymorphism, Single Nucleotide, Risk Factors
Abstract

A typical human exome harbors dozens of loss-of-function (LOF) variants, which can lower disease risk factor levels and affect drug efficacy. We hypothesized that LOF variants are enriched in genes influencing risk factor levels and the onset of common chronic diseases, such as cardiovascular disease and diabetes. To test this hypothesis, we sequenced the exomes of 8,554 individuals and analyzed the effects of predicted LOF variants on 20 chronic disease risk factor phenotypes. Analysis of this sample as discovery and replication strata of equal size verified two relationships in well-studied genes (PCSK9 and APOC3) and identified eight new loci. Previously unknown relationships included elevated fasting glucose in carriers of heterozygous LOF variation in TXNDC5, which encodes a biomarker for type 1 diabetes progression, and apparent recessive effects of C1QTNF8 on serum magnesium levels. These data demonstrate the utility of functional-variant annotation within a large sample of deeply phenotyped individuals for gene discovery.

DOI10.1038/ng.3270
Alternate JournalNat. Genet.
PubMed ID25915599
PubMed Central IDPMC4470468
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100008 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100005 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
HHSN268201100011 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100009 / HL / NHLBI NIH HHS / United States
HHSN268201100006C / / PHS HHS / United States