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

Pubmed ID: 25915599

Pubmed Central ID: PMC4470468

Journal: Nature genetics

Publication Date: June 1, 2015

Affiliation: 1] Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA. [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

MeSH Terms: Humans, Risk Factors, Gene Frequency, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Chronic Disease, Atherosclerosis, Phenotype, Genome, Human, Genetic Association Studies, Genetic Loci, Exome, Molecular Sequence Annotation

Grants: HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, RC2 HL102419, 5RC2HL102419, U54 HG003273, HHSN268201100009I, HHSN268201100005G, HHSN268201100008I, HHSN268201100011I, HHSN268201100005I, HHSN268201100007I

Authors: Polfus LM, Yu B, Boerwinkle E, Mosley TH, Li AH, Morrison AC, Kovar C, Cupples LA, Brody JA, Metcalf G, Muzny D, Veeraraghavan N, Liu X, Lumley T, Gibbs RA

Cite As: Li AH, Morrison AC, Kovar C, Cupples LA, Brody JA, Polfus LM, Yu B, Metcalf G, Muzny D, Veeraraghavan N, Liu X, Lumley T, Mosley TH, Gibbs RA, Boerwinkle E. Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease. Nat Genet 2015 Jun;47(6):640-2. Epub 2015 Apr 27.

Studies:

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.