Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

George Hindy; Peter Dornbos; Mark D. Chaffin; Dajiang J. Liu; Minxian Wang; Margaret Sunitha Selvaraj; David Zhang; Joseph Park; Carlos A. Aguilar-Salinas; Lucinda Antonacci-Fulton; Diego Ardissino; Donna K. Arnett; Stella Aslibekyan; Gil Atzmon; Christie M. Ballantyne; Francisco Barajas-Olmos; Nir Barzilai; Lewis C. Becker; Lawrence F. Bielak; Joshua C. Bis; John Blangero; Eric Boerwinkle; Lori L. Bonnycastle; Erwin Bottinger; Donald W. Bowden; Matthew J. Bown; Jennifer A. Brody; Jai G. Broome; Noel P. Burtt; Brian E. Cade; Federico Centeno-Cruz; Edmund Chan; Yi-Cheng Chang; Yii-Der I. Chen; Ching-Yu Cheng; Won Jung Choi; Rajiv Chowdhury; Cecilia Contreras-Cubas; Emilio J. Cordova; Adolfo Correa; L. Adrienne Cupples; Joanne E. Curran; John Danesh; Paul S. de Vries; Ralph A. DeFronzo; Harsha Doddapaneni; Ravindranath Duggirala; Susan K. Dutcher; Patrick T. Ellinor; Leslie S. Emery; Jose C. Florez; Myriam Fornage; Barry I. Freedman; Valentin Fuster; Ma. Eugenia Garay-Sevilla; Humberto Garcia-Ortiz; Soren Germer; Richard A. Gibbs; Christian Gieger; Benjamin Glaser; Clicerio Gonzalez; Maria Elena Gonzalez-Villalpando; Mariaelisa Graff; Sarah E. Graham; Niels Grarup; Leif C. Groop; Xiuqing Guo; Namrata Gupta; Sohee Han; Craig L. Hanis; Torben Hansen; Jiang He; Nancy L. Heard-Costa; Yi-Jen Hung; Mi Yeong Hwang; Marguerite R. Irvin; Sergio Islas-Andrade; Gail P. Jarvik; Hyun Min Kang; Sharon L. R. Kardia; Tanika Kelly; Eimear E. Kenny; Alyna T. Khan; Bong-Jo Kim; Ryan W. Kim; Young Jin Kim; Heikki A. Koistinen; Charles Kooperberg; Johanna Kuusisto; Soo Heon Kwak; Markku Laakso; Leslie A. Lange; Jiwon Lee; Juyoung Lee; Seonwook Lee; Donna M. Lehman; Rozenn N. Lemaitre; Allan Linneberg; Jianjun Liu; Ruth J. F. Loos; Steven A. Lubitz; Valeriya Lyssenko; Ronald C. W. Ma; Lisa Warsinger Martin; Angelica Martinez-Hernandez; Rasika A. Mathias; Stephen T. McGarvey; Ruth McPherson; James B. Meigs; Thomas Meitinger; Olle Melander; Elvia Mendoza-Caamal; Ginger A. Metcalf; Xuenan Mi; Karen L. Mohlke; May E. Montasser; Jee-Young Moon; Hortensia Moreno-Macias; Alanna C. Morrison; Donna M. Muzny; Sarah C. Nelson; Peter M. Nilsson; Jeffrey R. O'Connell; Marju Orho-Melander; Lorena Orozco; Colin N. A. Palmer; Nicholette D. Palmer; Cheol Joo Park; Kyong Soo Park; Oluf Pedersen; Juan M. Peralta; Patricia A. Peyser; Wendy S. Post; Michael Preuss; Bruce M. Psatsy; Qibin Qi; D. C. Rao; Susan Redline; Alexander P. Reiner; Cristina Revilla-Monsalve; Stephen S. Rich; Nilesh Samani; Heribert Schunkert; Claudia Schurmann; Daekwan Seo; Jeong-Sun Seo; Xueling Sim; Rob Sladek; Kerrin S. Small; Wing Yee So; Adrienne M. Stilp; E. Shyong Tai; Claudia H. T. Tam; Kent D. Taylor; Yik Ying Teo; Farook Thameem; Brian Tomlinson; Michael Y. Tsai; Tiinamaij Tuomi; Jaakko Tuomilehto; Teresa Tusie-Luna; Miriam S. Udler; Rob M. van Dam; Ramachandran S. Vasan; Karine A. Viaud Martinez; Fei Fei Wang; Xuzhi Wang; Hugh Watkins; Daniel E. Weeks; James G. Wilson; Daniel R. Witte; Tien-Yin Wong; Lisa R. Yanek; Sekar Kathiresan; Daniel J. Rader; Jerome I. Rotter; Michael Boehnke; Mark I. McCarthy; Cristen J. Willer; Pradeep Natarajan; Jason A. Flannick; Amit V. Khera; Gina M. Peloso; AMP-T2D-GENES

doi:10.1016/j.ajhg.2021.11.021

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Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

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Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes

George Hindy, Peter Dornbos, Mark D. Chaffin, Dajiang J. Liu, Minxian Wang, Margaret Sunitha Selvaraj, David Zhang, Joseph Park, Carlos A. Aguilar-Salinas, Lucinda Antonacci-Fulton, …

American journal of human genetics, Vol.109(1), pp.81-96

06/01/2022

DOI: https://doi.org/10.1016/j.ajhg.2021.11.021

PMID: 34932938

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency 1%) predicted damaging coding variation by using sequence data from 170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

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Title: Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes
Creators - without role: George Hindy - Qatar University
Peter Dornbos - Broad Institute
Mark D. Chaffin - Broad Institute
Dajiang J. Liu - Pennsylvania State University
Minxian Wang - Broad Institute
Margaret Sunitha Selvaraj - Broad Institute
David Zhang - University of Pennsylvania
Joseph Park - University of Pennsylvania
Carlos A. Aguilar-Salinas - Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Lucinda Antonacci-Fulton - Washington University in St. Louis
Diego Ardissino - University of Parma
Donna K. Arnett - University of Kentucky
Stella Aslibekyan - University of Alabama at Birmingham
Gil Atzmon - Albert Einstein College of Medicine
Christie M. Ballantyne - Houston Methodist
Francisco Barajas-Olmos - National Institute of Genomic Medicine
Nir Barzilai - Albert Einstein College of Medicine
Lewis C. Becker - Johns Hopkins University
Lawrence F. Bielak - University of Michigan–Ann Arbor
Joshua C. Bis - University of Washington
John Blangero - The University of Texas Rio Grande Valley
Eric Boerwinkle - The University of Texas Health Science Center at Houston
Lori L. Bonnycastle - National Institutes of Health
Erwin Bottinger - Icahn School of Medicine at Mount Sinai
Donald W. Bowden - Wake Forest University
Matthew J. Bown - University of Leicester
Jennifer A. Brody - University of Washington
Jai G. Broome - University of Washington
Noel P. Burtt - Broad Institute
Brian E. Cade - Brigham and Women's Hospital
Federico Centeno-Cruz - National Institute of Genomic Medicine
Edmund Chan - National University Health System
Yi-Cheng Chang - Institute of Biomedical Sciences, Academia Sinica
Yii-Der I. Chen - Harbor–UCLA Medical Center
Ching-Yu Cheng - National University Health System
Won Jung Choi - Psomagen Inc, 1330 Piccard Dr Ste 103, Rockville, MD 20850 USA
Rajiv Chowdhury - University of Cambridge
Cecilia Contreras-Cubas - National Institute of Genomic Medicine
Emilio J. Cordova - National Institute of Genomic Medicine
Adolfo Correa - University of Mississippi Medical Center
L. Adrienne Cupples - Boston University
Joanne E. Curran - The University of Texas Rio Grande Valley
John Danesh - University of Cambridge
Paul S. de Vries - The University of Texas Health Science Center at Houston
Ralph A. DeFronzo - The University of Texas Health Science Center at San Antonio
Harsha Doddapaneni - College Station Medical Center
Ravindranath Duggirala - The University of Texas Rio Grande Valley
Susan K. Dutcher - Washington University in St. Louis
Patrick T. Ellinor - Broad Institute
Leslie S. Emery - University of Washington
Jose C. Florez - Massachusetts General Hospital
Myriam Fornage - The University of Texas Health Science Center at Houston
Barry I. Freedman - Wake Forest University
Valentin Fuster - Icahn School of Medicine at Mount Sinai
Ma. Eugenia Garay-Sevilla - Universidad de Guanajuato
Humberto Garcia-Ortiz - National Institute of Genomic Medicine
Soren Germer - New York Genome Center
Richard A. Gibbs - Baylor College of Medicine
Christian Gieger - Helmholtz Zentrum München
Benjamin Glaser - Hadassah Medical Center
Clicerio Gonzalez - Instituto Nacional de Salud Pública
Maria Elena Gonzalez-Villalpando - Ctr Estudios Diabet, Mexico City, DF, Mexico
Mariaelisa Graff - University of North Carolina at Chapel Hill
Sarah E. Graham - University of Michigan–Ann Arbor
Niels Grarup - Novo Nordisk Foundation
Leif C. Groop - University of Helsinki
Xiuqing Guo - Ronald Reagan UCLA Medical Center
Namrata Gupta - Broad Institute
Sohee Han - College Station Medical Center
Craig L. Hanis - The University of Texas Health Science Center at Houston
Torben Hansen - Novo Nordisk Foundation
Jiang He - Tulane University
Nancy L. Heard-Costa - Framingham Heart Study
Yi-Jen Hung - Tri-Service General Hospital Songshan Branch
Mi Yeong Hwang - College Station Medical Center
Marguerite R. Irvin - Alabama Department of Public Health
Sergio Islas-Andrade - Hospital General de México
Gail P. Jarvik - University of Washington Medical Center
Hyun Min Kang - University of Michigan–Ann Arbor
Sharon L. R. Kardia - University of Michigan–Ann Arbor
Tanika Kelly - Tulane University
Eimear E. Kenny - Icahn School of Medicine at Mount Sinai
Alyna T. Khan - University of Washington
Bong-Jo Kim - College Station Medical Center
Ryan W. Kim - Psomagen Inc, 1330 Piccard Dr Ste 103, Rockville, MD 20850 USA
Young Jin Kim - College Station Medical Center
Heikki A. Koistinen - Finnish Institute for Health and Welfare
Charles Kooperberg - Fred Hutch Cancer Center
Johanna Kuusisto - Kuopio University Hospital
Soo Heon Kwak - Seoul National University Hospital
Markku Laakso - Kuopio University Hospital
Leslie A. Lange - University of Colorado Denver
Jiwon Lee - Brigham and Women's Hospital
Juyoung Lee - College Station Medical Center
Seonwook Lee - Psomagen Inc, 1330 Piccard Dr Ste 103, Rockville, MD 20850 USA
Donna M. Lehman - The University of Texas Health Science Center at San Antonio
Rozenn N. Lemaitre - University of Washington
Allan Linneberg - Frederiksberg Hospital
Jianjun Liu - Supreme Council Of Health
Ruth J. F. Loos - Icahn School of Medicine at Mount Sinai
Steven A. Lubitz - Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA
Valeriya Lyssenko - Lund University
Ronald C. W. Ma - Chinese University of Hong Kong
Lisa Warsinger Martin - George Washington University
Angelica Martinez-Hernandez - College Station Medical Center
Rasika A. Mathias - Johns Hopkins University
Stephen T. McGarvey - Brown University
Ruth McPherson - University of Ottawa
James B. Meigs - Supreme Council Of Health
Thomas Meitinger - Deutsch Forschungszentrum Herz Kreislauferkrankun, Partner Site Munich Heart Alliance, Munich, Germany
Olle Melander - Lund University
Elvia Mendoza-Caamal - College Station Medical Center
Ginger A. Metcalf - College Station Medical Center
Xuenan Mi - Tulane University
Karen L. Mohlke - Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA
May E. Montasser - Supreme Council Of Health
Jee-Young Moon - Albert Einstein College of Medicine
Hortensia Moreno-Macias - Univ Autonoma Metropolitana, Mexico City, DF, Mexico
Alanna C. Morrison - Supreme Council Of Health
Donna M. Muzny - College Station Medical Center
Sarah C. Nelson - University of Washington
Peter M. Nilsson - Lund University
Jeffrey R. O'Connell - Supreme Council Of Health
Marju Orho-Melander - Lund University
Lorena Orozco - College Station Medical Center
Colin N. A. Palmer - University of Dundee
Nicholette D. Palmer - Supreme Council Of Health
Cheol Joo Park - Psomagen Inc, 1330 Piccard Dr Ste 103, Rockville, MD 20850 USA
Kyong Soo Park - College Station Medical Center
Oluf Pedersen - University of Copenhagen
Juan M. Peralta - The University of Texas Rio Grande Valley
Patricia A. Peyser - Supreme Council Of Health
Wendy S. Post - Johns Hopkins University
Michael Preuss - Supreme Council Of Health
Bruce M. Psatsy - University of Washington
Qibin Qi - Albert Einstein College of Medicine
D. C. Rao - Washington Univ, Sch Med, Div Biostat, St Louis, MO 63108 USA
Susan Redline - Brigham and Women's Hospital
Alexander P. Reiner - University of Washington
Cristina Revilla-Monsalve - Inst Mexicano Seguro Social SXXI, Mexico City, DF, Mexico
Stephen S. Rich - University of Virginia
Nilesh Samani - University of Leicester
Heribert Schunkert - Tech Univ Munich, Deutsch Herzzentrum Munchen, Deutsch Zentrum Herz Kreislauf Forsch, Munich, Germany
Claudia Schurmann - Hasso Plattner Institute
Daekwan Seo - Psomagen Inc, 1330 Piccard Dr Ste 103, Rockville, MD 20850 USA
Jeong-Sun Seo - Psomagen Inc, 1330 Piccard Dr Ste 103, Rockville, MD 20850 USA
Xueling Sim - Supreme Council Of Health
Rob Sladek - McGill University
Kerrin S. Small - Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England
Wing Yee So - Chinese University of Hong Kong
Adrienne M. Stilp - University of Washington
E. Shyong Tai - Supreme Council Of Health
Claudia H. T. Tam - Broad Institute
Kent D. Taylor - College Station Medical Center
Yik Ying Teo - Supreme Council Of Health
Farook Thameem - Kuwait University
Brian Tomlinson - College Station Medical Center
Michael Y. Tsai - University of Minnesota
Tiinamaij Tuomi - Helsinki Univ Hosp, Dept Endocrinol, Abdominal Ctr, Helsinki, Finland
Jaakko Tuomilehto - Finnish Inst Hlth & Welf, Publ Hlth Promot Unit, Helsinki, Finland
Teresa Tusie-Luna - College Station Medical Center
Miriam S. Udler - Broad Institute
Rob M. van Dam - Supreme Council Of Health
Ramachandran S. Vasan - Framingham Heart Study
Karine A. Viaud Martinez - Illumina Inc, Illumina Lab Serv, San Diego, CA 92122 USA
Fei Fei Wang - University of Washington
Xuzhi Wang - Boston University
Hugh Watkins - University of Oxford
Daniel E. Weeks - University of Pittsburgh
James G. Wilson - College Station Medical Center
Daniel R. Witte - Aarhus University
Tien-Yin Wong - Supreme Council Of Health
Lisa R. Yanek - Johns Hopkins University
Sekar Kathiresan - Broad Institute
Daniel J. Rader - Supreme Council Of Health
Jerome I. Rotter - College Station Medical Center
Michael Boehnke - Biostat
Mark I. McCarthy - University of Oxford
Cristen J. Willer - College Station Medical Center
Pradeep Natarajan - Broad Institute
Jason A. Flannick - Broad Institute
Amit V. Khera - Broad Institute
Gina M. Peloso - Boston University
AMP-T2D-GENES
Publication Details: American journal of human genetics, Vol.109(1), pp.81-96
Publisher: Elsevier
Number of pages: 16
Grant note: R01HL142711; R01HL127564 / National Heart, Lung, and Blood Institute (NHLBI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 2016-06830 / Swedish Research Council
Identifiers: 9940224708331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article