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

The NHLBI Grand Opportunity Exome Sequencing Project

Research output: Contribution to journalArticle

137 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)233-245
Number of pages13
JournalAmerican Journal of Human Genetics
Volume94
Issue number2
DOIs
StatePublished - Feb 6 2014

Fingerprint

Exome
LDL Cholesterol
Genome-Wide Association Study
Genes
Lipids
Phospholipases
Single Nucleotide Polymorphism
Cardiovascular Diseases
Genotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. / The NHLBI Grand Opportunity Exome Sequencing Project.

In: American Journal of Human Genetics, Vol. 94, No. 2, 06.02.2014, p. 233-245.

Research output: Contribution to journalArticle

The NHLBI Grand Opportunity Exome Sequencing Project. / Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 2. pp. 233-245.
@article{1819cb2f6b1b4342961cf586d855b347,
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 Robinson, {Jennifer G.}",
year = "2014",
month = "2",
day = "6",
doi = "10.1016/j.ajhg.2014.01.010",
language = "English (US)",
volume = "94",
pages = "233--245",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol

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 - Robinson, Jennifer G.

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.

UR - http://www.scopus.com/inward/record.url?scp=84893720400&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893720400&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.01.010

DO - 10.1016/j.ajhg.2014.01.010

M3 - Article

C2 - 24507775

AN - SCOPUS:84893720400

VL - 94

SP - 233

EP - 245

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -