Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol

被引：176

作者：

Lange, Leslie A. ^{[1
]}

Hu, Youna ^{[2
]}

Zhang, He ^{[3
]}

Xue, Chenyi ^{[4
]}

Schmidt, Ellen M. ^{[4
]}

Tang, Zheng-Zheng ^{[5
]}

Bizon, Chris ^{[6
]}

Lange, Ethan M. ^{[1
,5
]}

Smith, Joshua D. ^{[7
]}

Turner, Emily H. ^{[7
]}

Jun, Goo ^{[2
]}

Kang, Hyun Min ^{[2
]}

Peloso, Gina ^{[8
,9
]}

Auer, Paul ^{[10
,11
]}

Li, Kuo-Ping ^{[2
]}

Flannick, Jason ^{[12
,13
]}

Zhang, Ji ^{[3
]}

Fuchsberger, Christian ^{[2
]}

Gaulton, Kyle ^{[14
]}

Lindgren, Cecilia ^{[14
]}

Locke, Adam ^{[2
]}

Manning, Alisa ^{[9
,11
,12
,15
]}

Sim, Xueling ^{[2
]}

Rivas, Manuel A. ^{[14
]}

Holmen, Oddgeir L. ^{[16
]}

Gottesman, Omri ^{[17
]}

Lu, Yingchang ^{[18
]}

Ruderfer, Douglas ^{[19
]}

Stah, Eli A. ^{[19
]}

Duan, Qing ^{[1
]}

Li, Yun ^{[1
,5
,20
]}

Durda, Peter ^{[21
]}

Jiao, Shuo ^{[10
]}

Isaacs, Aaron ^{[22
]}

Hofman, Albert ^{[23
]}

Bis, Joshua C. ^{[24
]}

Correa, Adolfo ^{[25
]}

Griswold, Michael E. ^{[25
]}

Jakobsdottir, Johanna ^{[26
]}

Smith, Albert V. ^{[26
,27
]}

Schreiner, Pamela J. ^{[28
]}

Feitosa, Mary E. ^{[29
]}

Zhang, Qunyuan ^{[29
]}

Huffman, Jennifer E. ^{[30
]}

Crosby, Jacy ^{[31
]}

Wasse, Christina L. ^{[32
]}

Do, Ron ^{[8
,9
]}

Franceschini, Nora ^{[33
]}

Martin, Lisa W. ^{[34
]}

Robinson, Jennifer G. ^{[35
,36
]}

机构：

[1] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[2] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[5] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA

[6] Renaissance Comp Inst, Chapel Hill, NC 27517 USA

[7] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[8] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[9] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02141 USA

[10] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA

[11] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA

[12] Broad Inst Harvard & MIT, Cambridge, MA 02141 USA

[13] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[14] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX1 2JD, England

[15] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02138 USA

[16] Norwegian Univ Sci & Technol, Dept Publ Hlth, HUNT Res Ctr, N-7600 Levanger, Norway

[17] Charles Bronfman Inst Personalized Med, Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[18] Charles Bronfman Inst Personalized Med, Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

[19] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA

[20] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA

[21] Univ Vermont, Dept Pathol, Colchester, VT 05446 USA

[22] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 DR Rotterdam, Netherlands

[23] Erasmus MC, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands

[24] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[25] Univ Mississippi Med Ctr, Dept Med, Jackson, MS 39216 USA

[26] Iceland Heart Assoc, IS-201 Kopavogur, Iceland

[27] Univ Iceland, IS-101 Reykjavik, Iceland

[28] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA

[29] Washington Univ, Div Stat Genom, Dept Genet, Sch Med, St Louis, MO 63110 USA

[30] Univ Edinburgh, Med Res Ctr Human Genet, Med Res Ctr Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland

[31] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[32] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA

[33] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA

[34] George Washington Sch Med & Hlth Sci, Div Cardiol, Washington, DC 20037 USA

[35] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA

[36] Univ Iowa, Dept Med, Iowa City, IA 52242 USA

[37] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[38] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA

[39] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[40] Univ Auckland, Dept Stat, Auckland 1142, New Zealand

[41] Ohio State Univ, Div Endocrinol, Columbus, OH 43210 USA

[42] Erasmus MC, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands

[43] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA

[44] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA

[45] Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA 90502 USA

[46] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA

[47] Tougaloo Coll, Jackson, MS 39174 USA

[48] Jackson State Univ, Jackson, MS 39217 USA

[49] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[50] Univ Washington, Dept Med, Med Ctr, Seattle, WA 98195 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2014年 / 94卷 / 02期

基金：

美国国家卫生研究院;

关键词：

DENSITY-LIPOPROTEIN-CHOLESTEROL; HEART-DISEASE; PLASMA; SUSCEPTIBILITY; OBJECTIVES; GENE;

D O I：

10.1016/j.ajhg.2014.01.010

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：233 / 245

页数：13

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