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 | |
| State | Published - Dec 2022 |
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Whole genome sequence analysis of blood lipid levels in >66,000 individuals. / NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium.
In: Nature communications, Vol. 13, No. 1, 5995, 12.2022.Research output: Contribution to journal › Article › peer-review
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
N1 - Funding Information: Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). P.N. is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152), Fondation Leducq (TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine). G.M.P. is supported by NIH grants R01HL142711 and R01HL127564. X.Lin is supported by grants R35-CA197449, U19-CA203654, R01-HL113338, and U01-HG009088. Prior to his employment at Novartis and during this work S.A.L. was supported by NIH grants R01HL139731, R01HL157635, and American Heart Association 18SFRN34250007. We like to acknowledge all the grants that supported this study, R01 HL121007, U01 HL072515, R01 AG18728, X01HL134588, HL 046389, HL113338, and 1R35HL135818, K01 HL135405, R03 HL154284, U01HL072507, R01HL087263, R01HL090682, P01HL045522, R01MH078143, R01MH078111, R01MH083824, U01DK085524, R01HL113323, R01HL093093, R01HL140570, R01HL142711, R01HL127564, R01HL148050, R01HL148565, HL105756, and Leducq TNE-18CVD04. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S.Department of Health and Human Services. Detailed acknowledgements provided in Supplementary Note 2. Funding Information: Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). P.N. is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, R01HL148565, R01HL135242, R01HL151152), Fondation Leducq (TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine). G.M.P. is supported by NIH grants R01HL142711 and R01HL127564. X.Lin is supported by grants R35-CA197449, U19-CA203654, R01-HL113338, and U01-HG009088. Prior to his employment at Novartis and during this work S.A.L. was supported by NIH grants R01HL139731, R01HL157635, and American Heart Association 18SFRN34250007. We like to acknowledge all the grants that supported this study, R01 HL121007, U01 HL072515, R01 AG18728, X01HL134588, HL 046389, HL113338, and 1R35HL135818, K01 HL135405, R03 HL154284, U01HL072507, R01HL087263, R01HL090682, P01HL045522, R01MH078143, R01MH078111, R01MH083824, U01DK085524, R01HL113323, R01HL093093, R01HL140570, R01HL142711, R01HL127564, R01HL148050, R01HL148565, HL105756, and Leducq TNE-18CVD04. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S.Department of Health and Human Services. Detailed acknowledgements provided in Supplementary Note . Funding Information: P.N. reports investigator-initiated grant support from Amgen, Apple, AstraZeneca, and Boston Scientific, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech, TenSixteen Bio, and Novartis, scientific advisory board membership of geneXwell and TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. B.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. M.E.M. receives funding from Regeneron Pharmaceutical Inc. unrelated to this work. S.A. has employment and equity in 23andMe, Inc. The spouse of C.J.W. works at Regeneron. S.A.L. is a full-time employee of Novartis as of July 18, 2022. S.A.L. has received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. X. Lin is a consultant of AbbVie Pharmaceuticals and Verily Life Sciences. The remaining authors declare no competing interests. Publisher Copyright: © 2022, The Author(s).
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
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5995
ER -