Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

The NHLBI Grand Opportunity Exome Sequencing Project

doi:10.1016/j.ajhg.2014.01.010

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

The NHLBI Grand Opportunity Exome Sequencing Project

School of Life Science and Technology (SLST)

University of North Carolina at Chapel Hill
University of Michigan, Ann Arbor
Renaissance Computing Institute
University of Washington
Massachusetts General Hospital
Broad Institute
Fred Hutchinson Cancer Research Center
University of Wisconsin-Milwaukee
University of Oxford
Harvard University
Norwegian University of Science and Technology
Icahn School of Medicine at Mount Sinai
University of Vermont
Erasmus University Rotterdam
University of Mississippi
Icelandic Heart Association
University of Iceland
University of Minnesota Twin Cities
Washington University St. Louis
University of Edinburgh
University of Texas Health Science Center at Houston
University of Pittsburgh
George Washington University
University of Iowa
Stanford University
The University of Auckland
Ohio State University
National Institutes of Health
University of California at Los Angeles
Tougaloo College
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Lund University
University of Copenhagen
Helmholtz Zentrum München - German Research Center for Environmental Health
Technical University of Munich
Baylor College of Medicine
Houston Methodist
Johns Hopkins University
Group Health Cooperative
Boston University
University of Virginia

Research output: Contribution to journal › Article › peer-review

193 Scopus citations

Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98^th or <2^nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

Original language	English
Pages (from-to)	233-245
Number of pages	13
Journal	American Journal of Human Genetics
Volume	94
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2014.01.010
State	Published - 6 Feb 2014

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10.1016/j.ajhg.2014.01.010

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@article{677637bc402b4b0ebcc13f2d33263cac,

title = "Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol",

abstract = "Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.",

author = "\{The NHLBI Grand Opportunity Exome Sequencing Project\} and Lange, \{Leslie A.\} and Youna Hu and He Zhang and Chenyi Xue and Schmidt, \{Ellen M.\} and Tang, \{Zheng Zheng\} and Chris Bizon and Lange, \{Ethan M.\} and Smith, \{Joshua D.\} and Turner, \{Emily H.\} and Goo Jun and Kang, \{Hyun Min\} and Gina Peloso and Paul Auer and Li, \{Kuo Ping\} and Jason Flannick and Ji Zhang and Christian Fuchsberger and Kyle Gaulton and Cecilia Lindgren and Adam Locke and Alisa Manning and Xueling Sim and Rivas, \{Manuel A.\} and Holmen, \{Oddgeir L.\} and Omri Gottesman and Yingchang Lu and Douglas Ruderfer and Stahl, \{Eli A.\} and Qing Duan and Yun Li and Peter Durda and Shuo Jiao and Aaron Isaacs and Albert Hofman and Bis, \{Joshua C.\} and Adolfo Correa and Griswold, \{Michael E.\} and Johanna Jakobsdottir and Smith, \{Albert V.\} and Schreiner, \{Pamela J.\} and Feitosa, \{Mary F.\} and Qunyuan Zhang and Huffman, \{Jennifer E.\} and Jacy Crosby and Wassel, \{Christina L.\} and Ron Do and Nora Franceschini and Martin, \{Lisa W.\} and Jiankang Liu",

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doi = "10.1016/j.ajhg.2014.01.010",

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AU - The NHLBI Grand Opportunity Exome Sequencing Project

AU - Lange, Leslie A.

AU - Hu, Youna

AU - Zhang, He

AU - Xue, Chenyi

AU - Schmidt, Ellen M.

AU - Tang, Zheng Zheng

AU - Bizon, Chris

AU - Lange, Ethan M.

AU - Smith, Joshua D.

AU - Turner, Emily H.

AU - Jun, Goo

AU - Kang, Hyun Min

AU - Peloso, Gina

AU - Auer, Paul

AU - Li, Kuo Ping

AU - Flannick, Jason

AU - Zhang, Ji

AU - Fuchsberger, Christian

AU - Gaulton, Kyle

AU - Lindgren, Cecilia

AU - Locke, Adam

AU - Manning, Alisa

AU - Sim, Xueling

AU - Rivas, Manuel A.

AU - Holmen, Oddgeir L.

AU - Gottesman, Omri

AU - Lu, Yingchang

AU - Ruderfer, Douglas

AU - Stahl, Eli A.

AU - Duan, Qing

AU - Li, Yun

AU - Durda, Peter

AU - Jiao, Shuo

AU - Isaacs, Aaron

AU - Hofman, Albert

AU - Bis, Joshua C.

AU - Correa, Adolfo

AU - Griswold, Michael E.

AU - Jakobsdottir, Johanna

AU - Smith, Albert V.

AU - Schreiner, Pamela J.

AU - Feitosa, Mary F.

AU - Zhang, Qunyuan

AU - Huffman, Jennifer E.

AU - Crosby, Jacy

AU - Wassel, Christina L.

AU - Do, Ron

AU - Franceschini, Nora

AU - Martin, Lisa W.

AU - Liu, Jiankang

PY - 2014/2/6

Y1 - 2014/2/6

N2 - Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

AB - Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

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DO - 10.1016/j.ajhg.2014.01.010

M3 - 文章

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AN - SCOPUS:84893720400

SN - 0002-9297

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SP - 233

EP - 245

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

Abstract

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