Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease.
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.
Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
Alexander H
AH
Li
Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
Alanna C
AC
Morrison
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Christie
C
Kovar
1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA. [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
L Adrienne
LA
Cupples
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Jennifer A
JA
Brody
Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
Linda M
LM
Polfus
Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
Bing
B
Yu
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Ginger
G
Metcalf
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Donna
D
Muzny
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Narayanan
N
Veeraraghavan
Human Genetics Center, University of Texas Health Science Center, Houston, Texas, USA.
Xiaoming
0000000182855528
X
Liu
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. [2] Department of Statistics, University of Auckland, Auckland, New Zealand.
Thomas
T
Lumley
Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, Mississippi, USA.
Thomas H
TH
Mosley
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
Richard A
RA
Gibbs
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.
Eric
E
Boerwinkle
D050197:Atherosclerosis / Q000235:genetics*; D002908:Chronic Disease; D059472:Exome; D005787:Gene Frequency; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D058977:Molecular Sequence Annotation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors