Journal Article

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

Liu, Xiaoming, Cupples, L Adrienne, Mosley, Thomas H, Metcalf, Ginger, Polfus, Linda M, Yu, Bing, Veeraraghavan, Narayanan, Li, Alexander H, Muzny, Donna, Gibbs, Richard A, Boerwinkle, Eric, Kovar, Christie, Brody, Jennifer A, Morrison, Alanna C, Lumley, Thomas

2015

Overview

Eric Boerwinkle and colleagues carried out exome sequencing on 8,554 individuals and tested loss-of-function variants for association with 20 phenotypes related to common chronic diseases. They identified several new associations and illustrate the value of applying exome sequencing to a large sample of deeply phenotyped individuals. A typical human exome harbors dozens of loss-of-function (LOF) variants 1 , which can lower disease risk factor levels and affect drug efficacy 2 . 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 45/77 / 631/208/205/2138 / 631/208/514/1948 / 692/308/2056 / Agriculture / American Recovery & Reinvestment Act 2009-US / Animal Genetics and Genomics / Annotations / Atherosclerosis / Atherosclerosis - genetics / Biomedicine / Cancer Research / Cardiovascular disease / Cardiovascular diseases / Chronic Disease / Chronic diseases / Chronic illnesses / Diabetes / Exome / Gene Frequency / Gene Function / Gene loci / Genetic aspects / Genetic Association Studies / Genetic Loci / Genetic Predisposition to Disease / Genetic research / Genetic susceptibility / Genetic variation / Genome, Human / Genomes / Genotype & phenotype / Health risks / Human Genetics / Humans / Identification and classification / letter / Magnesium / Molecular Sequence Annotation / Mutation / Phenotype / Polymorphism, Single Nucleotide / Proteins / Ratios / Risk Factors / Studies