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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1038/s41467-022-33510-7

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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

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36 Scopus citations

Abstract

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.

Original language	English
Article number	5995
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33510-7
State	Published - Dec 2022

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10.1038/s41467-022-33510-7

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@article{b9ec22214dee4c1085029054ad506973,

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

abstract = "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.",

author = "{NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Selvaraj, {Margaret Sunitha} and Xihao Li and Zilin Li and Akhil Pampana and Zhang, {David Y.} and Joseph Park and Stella Aslibekyan and Bis, {Joshua C.} and Brody, {Jennifer A.} and Cade, {Brian E.} and Chuang, {Lee Ming} and Chung, {Ren Hua} and Curran, {Joanne E.} and {de las Fuentes}, Lisa and {de Vries}, {Paul S.} and Ravindranath Duggirala and Freedman, {Barry I.} and Mariaelisa Graff and Xiuqing Guo and Nancy Heard-Costa and Bertha Hidalgo and Hwu, {Chii Min} and Irvin, {Marguerite R.} and Kelly, {Tanika N.} and Kral, {Brian G.} and Leslie Lange and Xiaohui Li and Martin Lisa and Lubitz, {Steven A.} and Manichaikul, {Ani W.} and Preuss Michael and Montasser, {May E.} and Morrison, {Alanna C.} and Take Naseri and O{\textquoteright}Connell, {Jeffrey R.} and Palmer, {Nicholette D.} and Peyser, {Patricia A.} and Reupena, {Muagututia S.} and Smith, {Jennifer A.} and Xiao Sun and Taylor, {Kent D.} and Tracy, {Russell P.} and Tsai, {Michael Y.} and Zhe Wang and Yuxuan Wang and Wei Bao and Wilkins, {John T.} and Yanek, {Lisa R.} and Wei Zhao and Arnett, {Donna K.} and John Blangero and Eric Boerwinkle and Bowden, {Donald W.} and Chen, {Yii Der Ida} and Adolfo Correa and Cupples, {L. Adrienne} and Dutcher, {Susan K.} and Ellinor, {Patrick T.} and Myriam Fornage and Stacey Gabriel and Soren Germer and Richard Gibbs and Jiang He and Kaplan, {Robert C.} and Kardia, {Sharon L.R.} and Ryan Kim and Charles Kooperberg and Loos, {Ruth J.F.} and Viaud-Martinez, {Karine A.} and Mathias, {Rasika A.} and McGarvey, {Stephen T.} and Mitchell, {Braxton D.} and Deborah Nickerson and North, {Kari E.} and Psaty, {Bruce M.} and Susan Redline and Reiner, {Alexander P.} and Vasan, {Ramachandran S.} and Rich, {Stephen S.} and Cristen Willer and Rotter, {Jerome I.} and Rader, {Daniel J.} and Xihong Lin and Namiko Abe and Gon{\c c}alo Abecasis and Francois Aguet and Christine Albert and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Deborah Applebaum-Bowden and Kristin Ardlie and Dan Arking and Allison Ashley-Koch and Tim Assimes and Paul Auer and Dimitrios Avramopoulos and Najib Ayas and Adithya Balasubramanian and John Barnard and Kathleen Barnes and Barr, {R. Graham} and Emily Barron-Casella and Lucas Barwick and Terri Beaty and Gerald Beck and Diane Becker and Lewis Becker and Rebecca Beer and Amber Beitelshees and Emelia Benjamin and Takis Benos and Marcos Bezerra and Larry Bielak and Thomas Blackwell and Russell Bowler and Ulrich Broeckel and Jai Broome and Deborah Brown and Karen Bunting and Esteban Burchard and Carlos Bustamante and Erin Buth and Jonathan Cardwell and Vincent Carey and Julie Carrier and Cara Carty and Richard Casaburi and Romero, {Juan P.Casas} and James Casella and Peter Castaldi and Mark Chaffin and Christy Chang and Chang, {Yi Cheng} and Daniel Chasman and Sameer Chavan and Chen, {Bo Juen} and Chen, {Wei Min} and Chen, {Yii Der Ida} and Michael Cho and Choi, {Seung Hoan} and Mina Chung and Clary Clish and Suzy Comhair and Matthew Conomos and Elaine Cornell and Carolyn Crandall and James Crapo and Cupples, {L. Adrienne} and Jeffrey Curtis and Brian Custer and Coleen Damcott and Dawood Darbar and Sean David and Colleen Davis and Michelle Daya and {de Andrade}, Mariza and Michael DeBaun and Ranjan Deka and Dawn DeMeo and Scott Devine and Huyen Dinh and Harsha Doddapaneni and Qing Duan and Shannon Dugan-Perez and Ravi Duggirala and Durda, {Jon Peter} and Charles Eaton and Lynette Ekunwe and Boueiz, {Adel El} and Leslie Emery and Serpil Erzurum and Charles Farber and Jesse Farek and Tasha Fingerlin and Matthew Flickinger and Nora Franceschini and Chris Frazar and Mao Fu and Fullerton, {Stephanie M.} and Lucinda Fulton and Weiniu Gan and Shanshan Gao and Yan Gao and Margery Gass and Heather Geiger and Bruce Gelb and Mark Geraci and Robert Gerszten and Auyon Ghosh and Chris Gignoux and Mark Gladwin and David Glahn and Stephanie Gogarten and Gong, {Da Wei} and Gu, {C. Charles} and Rao, {D. C.} and Sung, {Yun Ju}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-33510-7",

language = "English",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

number = "1",

}

TY - JOUR

T1 - Whole genome sequence analysis of blood lipid levels in >66,000 individuals

AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

AU - Selvaraj, Margaret Sunitha

AU - Li, Xihao

AU - Li, Zilin

AU - Pampana, Akhil

AU - Zhang, David Y.

AU - Park, Joseph

AU - Aslibekyan, Stella

AU - Bis, Joshua C.

AU - Brody, Jennifer A.

AU - Cade, Brian E.

AU - Chuang, Lee Ming

AU - Chung, Ren Hua

AU - Curran, Joanne E.

AU - de las Fuentes, Lisa

AU - de Vries, Paul S.

AU - Duggirala, Ravindranath

AU - Freedman, Barry I.

AU - Graff, Mariaelisa

AU - Guo, Xiuqing

AU - Heard-Costa, Nancy

AU - Hidalgo, Bertha

AU - Hwu, Chii Min

AU - Irvin, Marguerite R.

AU - Kelly, Tanika N.

AU - Kral, Brian G.

AU - Lange, Leslie

AU - Li, Xiaohui

AU - Lisa, Martin

AU - Lubitz, Steven A.

AU - Manichaikul, Ani W.

AU - Michael, Preuss

AU - Montasser, May E.

AU - Morrison, Alanna C.

AU - Naseri, Take

AU - O’Connell, Jeffrey R.

AU - Palmer, Nicholette D.

AU - Peyser, Patricia A.

AU - Reupena, Muagututia S.

AU - Smith, Jennifer A.

AU - Sun, Xiao

AU - Taylor, Kent D.

AU - Tracy, Russell P.

AU - Tsai, Michael Y.

AU - Wang, Zhe

AU - Wang, Yuxuan

AU - Bao, Wei

AU - Wilkins, John T.

AU - Yanek, Lisa R.

AU - Zhao, Wei

AU - Arnett, Donna K.

AU - Blangero, John

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

AU - Chen, Yii Der Ida

AU - Correa, Adolfo

AU - Cupples, L. Adrienne

AU - Dutcher, Susan K.

AU - Ellinor, Patrick T.

AU - Fornage, Myriam

AU - Gabriel, Stacey

AU - Germer, Soren

AU - Gibbs, Richard

AU - He, Jiang

AU - Kaplan, Robert C.

AU - Kardia, Sharon L.R.

AU - Kim, Ryan

AU - Kooperberg, Charles

AU - Loos, Ruth J.F.

AU - Viaud-Martinez, Karine A.

AU - Mathias, Rasika A.

AU - McGarvey, Stephen T.

AU - Mitchell, Braxton D.

AU - Nickerson, Deborah

AU - North, Kari E.

AU - Psaty, Bruce M.

AU - Redline, Susan

AU - Reiner, Alexander P.

AU - Vasan, Ramachandran S.

AU - Rich, Stephen S.

AU - Willer, Cristen

AU - Rotter, Jerome I.

AU - Rader, Daniel J.

AU - Lin, Xihong

AU - Abe, Namiko

AU - Abecasis, Gonçalo

AU - Aguet, Francois

AU - Albert, Christine

AU - Almasy, Laura

AU - Alonso, Alvaro

AU - Ament, Seth

AU - Anderson, Peter

AU - Anugu, Pramod

AU - Applebaum-Bowden, Deborah

AU - Ardlie, Kristin

AU - Arking, Dan

AU - Ashley-Koch, Allison

AU - Assimes, Tim

AU - Auer, Paul

AU - Avramopoulos, Dimitrios

AU - Ayas, Najib

AU - Balasubramanian, Adithya

AU - Barnard, John

AU - Barnes, Kathleen

AU - Barr, R. Graham

AU - Barron-Casella, Emily

AU - Barwick, Lucas

AU - Beaty, Terri

AU - Beck, Gerald

AU - Becker, Diane

AU - Becker, Lewis

AU - Beer, Rebecca

AU - Beitelshees, Amber

AU - Benjamin, Emelia

AU - Benos, Takis

AU - Bezerra, Marcos

AU - Bielak, Larry

AU - Blackwell, Thomas

AU - Bowler, Russell

AU - Broeckel, Ulrich

AU - Broome, Jai

AU - Brown, Deborah

AU - Bunting, Karen

AU - Burchard, Esteban

AU - Bustamante, Carlos

AU - Buth, Erin

AU - Cardwell, Jonathan

AU - Carey, Vincent

AU - Carrier, Julie

AU - Carty, Cara

AU - Casaburi, Richard

AU - Romero, Juan P.Casas

AU - Casella, James

AU - Castaldi, Peter

AU - Chaffin, Mark

AU - Chang, Christy

AU - Chang, Yi Cheng

AU - Chasman, Daniel

AU - Chavan, Sameer

AU - Chen, Bo Juen

AU - Chen, Wei Min

AU - Chen, Yii Der Ida

AU - Cho, Michael

AU - Choi, Seung Hoan

AU - Chung, Mina

AU - Clish, Clary

AU - Comhair, Suzy

AU - Conomos, Matthew

AU - Cornell, Elaine

AU - Crandall, Carolyn

AU - Crapo, James

AU - Cupples, L. Adrienne

AU - Curtis, Jeffrey

AU - Custer, Brian

AU - Damcott, Coleen

AU - Darbar, Dawood

AU - David, Sean

AU - Davis, Colleen

AU - Daya, Michelle

AU - de Andrade, Mariza

AU - DeBaun, Michael

AU - Deka, Ranjan

AU - DeMeo, Dawn

AU - Devine, Scott

AU - Dinh, Huyen

AU - Doddapaneni, Harsha

AU - Duan, Qing

AU - Dugan-Perez, Shannon

AU - Duggirala, Ravi

AU - Durda, Jon Peter

AU - Eaton, Charles

AU - Ekunwe, Lynette

AU - Boueiz, Adel El

AU - Emery, Leslie

AU - Erzurum, Serpil

AU - Farber, Charles

AU - Farek, Jesse

AU - Fingerlin, Tasha

AU - Flickinger, Matthew

AU - Franceschini, Nora

AU - Frazar, Chris

AU - Fu, Mao

AU - Fullerton, Stephanie M.

AU - Fulton, Lucinda

AU - Gan, Weiniu

AU - Gao, Shanshan

AU - Gao, Yan

AU - Gass, Margery

AU - Geiger, Heather

AU - Gelb, Bruce

AU - Geraci, Mark

AU - Gerszten, Robert

AU - Ghosh, Auyon

AU - Gignoux, Chris

AU - Gladwin, Mark

AU - Glahn, David

AU - Gogarten, Stephanie

AU - Gong, Da Wei

AU - Gu, C. Charles

AU - Rao, D. C.

AU - Sung, Yun Ju

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85139608936&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-33510-7

DO - 10.1038/s41467-022-33510-7

M3 - Article

C2 - 36220816

AN - SCOPUS:85139608936

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5995

ER -

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

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