Whole genome sequence analysis of blood lipid levels in >66,000 individuals

被引：29

作者：

Selvaraj, Margaret Sunitha ^{[1
,2
,3
]}

Li, Xihao ^{[4
]}

Li, Zilin ^{[4
]}

Pampana, Akhil ^{[2
]}

Zhang, David Y. ^{[5
,6
]}

Park, Joseph ^{[5
,6
]}

Aslibekyan, Stella ^{[7
]}

Bis, Joshua C. ^{[8
]}

Brody, Jennifer A. ^{[8
]}

Cade, Brian E. ^{[9
]}

Chuang, Lee-Ming ^{[10
]}

Chung, Ren-Hua ^{[11
]}

Curran, Joanne E. ^{[12
,13
]}

de Las Fuentes, Lisa ^{[14
,15
]}

de Vries, Paul S. ^{[16
]}

Duggirala, Ravindranath ^{[12
,13
]}

Freedman, Barry, I ^{[17
]}

Graff, Mariaelisa ^{[18
]}

Guo, Xiuqing ^{[19
]}

Heard-Costa, Nancy ^{[20
]}

Hidalgo, Bertha ^{[7
]}

Hwu, Chii-Min ^{[21
]}

Irvin, Marguerite R. ^{[7
]}

Kelly, Tanika N. ^{[22
,23
]}

Kral, Brian G. ^{[24
]}

Lange, Leslie ^{[25
]}

Li, Xiaohui ^{[19
]}

Lisa, Martin ^{[26
]}

Lubitz, Steven A. ^{[1
,27
]}

Manichaikul, Ani W. ^{[28
]}

Michael, Preuss ^{[29
]}

Montasser, May E. ^{[30
]}

Morrison, Alanna C. ^{[16
]}

Naseri, Take ^{[31
]}

O'Connell, Jeffrey R. ^{[30
]}

Palmer, Nicholette D. ^{[32
]}

Peyser, Patricia A. ^{[33
]}

Reupena, Muagututia S. ^{[34
]}

Smith, Jennifer A. ^{[33
]}

Sun, Xiao ^{[22
]}

Taylor, Kent D. ^{[19
]}

Tracy, Russell P. ^{[35
,36
]}

Tsai, Michael Y. ^{[37
]}

Wang, Zhe ^{[29
]}

Wang, Yuxuan ^{[38
]}

Bao, Wei ^{[39
]}

Wilkins, John T. ^{[40
,41
]}

Yanek, Lisa R. ^{[24
]}

Zhao, Wei ^{[33
]}

Arnett, Donna K. ^{[42
]}

机构：

[1] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[2] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[3] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[4] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[5] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA

[7] Univ Alabama Birmingham, Dept Epidemiol, Sch Publ Hlth, Birmingham, AL USA

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

[9] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[10] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan

[11] Natl Hlth Res Inst, Inst Populat Hlth Sci, Zhunan 350, Taiwan

[12] Univ Texas Rio Grande Valley, Sch Med, Dept Human Genet, Brownsville, TX 78520 USA

[13] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Sch Med, Brownsville, TX 78520 USA

[14] Washington Univ, Sch Med, Dept Med, Cardiovasc Div, St Louis, MO 63110 USA

[15] Washington Univ, Div Biostat, Sch Med, St Louis, MO USA

[16] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA

[17] Wake Forest Sch Med, Dept Internal Med, Sect Nephrol, Winston Salem, NC 27157 USA

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

[19] Harbor UCLA Med Ctr, Lundquist Inst Biomed Innovat, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA

[20] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[21] Taipei Vet Gen Hosp, Dept Med, Sect Endocrinol & Metab, Taipei, Taiwan

[22] Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA

[23] Tulane Univ, Translat Sci Inst, New Orleans, LA 70112 USA

[24] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21205 USA

[25] Univ Colorado, Dept Med, Div Biomed Informat & Personalized Med, Anschutz Med Campus, Aurora, CO USA

[26] George Washington Univ, Dept Med, Washingron, DC USA

[27] Broad Inst MIT & Harvard, Cardiovasc Dis Initiat, Cambridge, MA 02142 USA

[28] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA USA

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

[30] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[31] Govt Samoa, Minist Hlth, Pago Pago, AS USA

[32] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC 27157 USA

[33] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[34] Lutia Puava Mapu Fagalele, Apia, Samoa

[35] Univ Vermont, Larner Coll Med, Dept Pathol, Colchester, VT USA

[36] Univ Vermont, Larner Coll Med, Dept Biochem, Colchester, VT USA

[37] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[38] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[39] Univ Sci & Technol China, Inst Publ Hlth, Div Life Sci & Med, Hefei 230026, Anhui, Peoples R China

[40] Northwestern Univ, Feinberg Sch Med, Dept Med Cardiol, Chicago, IL USA

[41] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA

[42] Univ Kentucky, Coll Publ Hlth, Deans Off, Lexington, KY USA

[43] Harbor UCLA Med Ctr, Lundquist Inst Biomed Innovat, Torrance, CA 90509 USA

[44] Univ Mississippi, Med Ctr, Dept Populat Hlth Sci, Jackson, MS USA

[45] Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63108 USA

[46] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, McGovern Med Sch, Houston, TX 77030 USA

[47] Broad Inst, Cambridge, MA 02142 USA

[48] New York Genome Ctr, New York, NY 10013 USA

[49] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[50] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

关键词：

FAMILIAL HYPERCHOLESTEROLEMIA; MISSING HERITABILITY; LOW-FREQUENCY; HIGH-RISK; LOW LDL; ASSOCIATION; MUTATIONS; VARIANT; METAANALYSIS; POPULATION;

D O I：

10.1038/s41467-022-33510-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; -400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

引用

页数：18

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Whole genome sequence analysis of blood lipid levels in &gt;66,000 individuals

Whole genome sequence analysis of blood lipid levels in >66,000 individuals