Open AccessAssessing the contribution of rare variants to complex trait heritability from whole-genome sequence data
Author(s) -
Pierrick Wainschtein,
Deepti Jain,
Zhili Zheng,
Stella Aslibekyan,
Diane M. Becker,
Wenjian Bi,
Jennifer A. Brody,
Jenna C. Carlson,
Adolfo Correa,
Margaret Mengmeng Du,
Lindsay Fernández-Rhodes,
Kendra Ferrier,
Misa Graff,
Xiuqing Guo,
Jialin He,
Nancy L. HeardCosta,
Heather M. Highland,
Joel N. Hirschhorn,
Candace M Howard-Claudio,
Carmen R. Isasi,
Rebecca D. Jackson,
Jicai Jiang,
Roby Joehanes,
Anne E. Justice,
Rita R. Kalyani,
Sharon L. R. Kardia,
Ethan M. Lange,
Meryl S. LeBoff,
Seunggeun Lee,
Xihao Li,
Zilin Li,
Elise Lim,
Danyu Lin,
Xihong Lin,
Simin Liu,
Yingchang Lu,
JoAnn E. Manson,
Lisa W. Martin,
Caitlin McHugh,
Julie Mikulla,
Solomon K. Musani,
Maggie Ng,
Deborah A. Nickerson,
Nicholette D. Palmer,
James A. Perry,
Ulrike Peters,
Michael Preuss,
Qibin Qi,
Laura M. Raffield,
Laura J. RasmussenTorvik,
Alex P. Reiner,
Emily M. Russell,
Colleen M. Sitlani,
Jennifer A. Smith,
Cassandra N. Spracklen,
Tao Wang,
Zhe Wang,
Jennifer Wessel,
Hanfei Xu,
Mohammad Yaser,
Sachiko Yoneyama,
Kendra A. Young,
Jingwen Zhang,
Xinruo Zhang,
Hufeng Zhou,
Xiaofeng Zhu,
Sebastian Zoellner,
Namiko Abe,
Gonçalo R. Abecasis,
François Aguet,
Laura Almasy,
Álvaro Alonso,
Seth A. Ament,
Peter Anderson,
Pramod Anugu,
Deborah Applebaum-Bowden,
Kristin Ardlie,
Dan E. Arking,
Allison AshleyKoch,
Tim Assimes,
Paul L. Auer,
Dimitrios Avramopoulos,
Najib Ayas,
Adithya Balasubramanian,
John Barnard,
Kathleen C. Barnes,
R. Graham Barr,
Emily Barron-Casella,
Lucas Barwick,
Terri H. Beaty,
Gerald J. Beck,
Lewis C. Becker,
Rebecca Beer,
Amber L. Beitelshees,
Emelia J. Benjamin,
Takis Benos,
Marcos André Cavalcanti Bezerra,
Larry Bielak,
Joshua C. Bis,
Thomas W. Blackwell,
John Blangero,
Donald W. Bowden,
Russell P. Bowler,
Ulrich Broeckel,
Jai Broome,
Deborah Brown,
Karen Bunting,
Esteban G. Burchard,
Carlos D. Bustamante,
Erin Buth,
Brian E. Cade,
Jonathan Cardwell,
Vincent J. Carey,
Julie Carrier,
April P. Carson,
Cara L. Carty,
Richard Casaburi,
Juan Pablo Romero,
James F. Casella,
Peter J. Castaldi,
Mark Chaffin,
Christy Chang,
YiCheng Chang,
Sameer Chavan,
Bo-Juen Chen,
Weimin Chen,
Michael Cho,
Seung Hoan Choi,
LeeMing Chuang,
RenHua Chung,
Clary B. Clish,
Suzy Comhair,
Matthew P. Conomos,
Elaine Cornell,
Carolyn Crandall,
James D. Crapo,
Joanne E. Curran,
Jeffrey L. Curtis,
Brian Custer,
Coleen M. Damcott,
Dawood Darbar,
Sean P. David,
Colleen Davis,
Michelle Daya,
Lisa de las Fuentes,
Paul de Vries,
Michael R. DeBaun,
Ranjan Deka,
Dawn L. DeMeo,
Scott E. Devine,
Huyen Dinh,
Harshavardhan Doddapaneni,
Qing Duan,
Shan Dugan-Perez,
Ravi Duggirala,
Jon Peter Durda,
Susan K. Dutcher,
Charles B. Eaton,
Lynette Ekunwe,
Adel El Boueiz,
Leslie S. Emery,
Serpil C. Erzurum,
Charles R. Farber,
Jesse Farek,
Tasha E. Fingerlin,
Matthew Flickinger,
Nora Franceschini,
Chris Frazar,
Mao Fu,
Stephanie M. Fullerton,
Lucinda L. Fulton,
Stacey Gabriel,
Weiniu Gan,
Shanshan Gao,
Yan Gao,
Margery Gass,
Heather Geiger,
Bruce D. Gelb,
Mark W. Geraci,
Søren Germer,
Robert E. Gerszten,
Auyon Ghosh,
Richard A. Gibbs,
Chris Gignoux,
Mark T. Gladwin,
David C. Glahn,
Stephanie M. Gogarten,
Da-Wei Gong,
Harald H.H. Göring,
Sharon Graw,
Kathryn J. Gray,
Daniel Grine,
Colin Gross,
C. Charles Gu,
Yue Guan,
Namrata Gupta,
David M. Haas,
Jeff Haessler,
Michael E. Hall,
Yi Han,
Patrick J. Hanly,
Daniel Harris,
Nicola L. Hawley,
Ben Heavner,
David M. Herrington,
Craig P. Hersh,
Bertha Hidalgo,
James E. Hixson,
Brian D. Hobbs,
John E. Hokanson,
Elliott Hong,
Karin F. Hoth,
Chao A. Hsiung,
Jianhong Hu,
YiJen Hung,
Haley Huston,
Chii Min Hwu,
Marguerite R. Irvin,
Cashell E. Jaquish,
Jill M. Johnsen,
Andrew M. Johnson,
Craig W. Johnson,
Rich Johnston,
Kimberly Jones,
Hyun Min Kang,
Robert C. Kaplan,
Shan Kelly,
Eimear E. Kenny,
Michael Kessler,
Alyna Khan,
Ziad Khan,
Wonji Kim,
John Kimoff,
Gregory L. Kinney,
Barbara A. Konkle,
Holly Kramer,
Christoph Lange,
Jiwon Lee,
Sandra Lee,
WenJane Lee,
Jonathon LeFaive,
David Levine,
Dan Levy,
Joshua P. Lewis,
Xiaohui Li,
Yun Li,
Henry J. Lin,
Honghuang Lin,
Yongmei Liu,
Yu Liu,
Kathryn L. Lunetta,
James Luo,
Ulysses J. Magalang,
Michael C. Mahaney,
Barry J. Make,
Ani Manichaikul,
Alisa K. Manning,
Melissa Marton,
Susan K. Mathai,
Susanne May,
Patrick F. McArdle,
Sean McFarland,
Daniel McGoldrick,
Becky McNeil,
Hao Mei,
James B. Meigs,
Vipin Me,
Luisa Mestroni,
Ginger Metcalf,
Deborah A. Meyers,
Emmanuel Mignot,
Julie Mikulla,
Nancy Min,
Mollie A. Minear,
Ryan L. Minster,
Matt Moll,
Zeineen Momin,
May E. Montasser,
Courtney Montgomery,
Donna M. Muzny,
Josyf C. Mychaleckyj,
Girish N. Nadkarni,
Rakhi P. Naik,
Take Naseri,
Pradeep Natarajan,
Sergeï Nekhai,
Sarah C. Nelson,
Bonnie Neltner,
Caitlin Nessner,
Osuji Nkechinyere,
Tim O’Connor,
Heather M. OchsBalcom,
Geoffrey Okwuonu,
Allan I Pack,
David T. Paik,
Nicholette D. Palmer,
James S. Pankow,
George Papanicolaou,
Cora Parker,
Gina M. Peloso,
Juan M. Peralta,
Marco Perez,
Patricia A. Peyser,
Lawrence Phillips,
Jacob Pleiness,
Toni I. Pollin,
Wendy S. Post,
Julia Powers Becker,
Meher Preethi Boorgula,
Pankaj Qasba,
Dandi Qiao,
Zhaohui Qin,
Nicholas Rafaels,
Mahitha Rajendran,
D. C. Rao,
Aakrosh Ratan,
Robert M. Reed,
Catherine Reeves,
Muagututi‘a Sefuiva Reupena,
Ken Rice,
Rébecca Robillard,
Nicolas Robine,
Carolina Roselli,
Ingo Ruczinski,
Alexi Runnels,
Pamela Russell,
Sarah Ruuska,
Kathleen A. Ryan,
Éster Cerdeira Sabino,
Danish Saleheen,
Saeedeh Salimi,
Sejal Salvi,
Steven L. Salzberg,
Kevin Sandow,
Vijay G. Sankaran,
Jireh Santibanez,
Karen Schwander,
David A. Schwartz,
Frank C. Sciurba,
Christine Seidman,
Jonathan G. Seidman,
Vivien A. Sheehan,
Stephanie L. Sherman,
Amol Shetty,
Aniket Shetty,
Wayne Hui-Heng Sheu,
Brian Silver,
Edwin K. Silverman,
Robert Skomro,
Albert V. Smith,
Josh Smith,
Tanja Smith,
Sylvia Smoller,
Beverly M. Snively,
M Snyder,
Tamar Sofer,
a Sotoodehnia,
Adrienne M. Stilp,
Garrett Storm,
Elizabeth A. Streeten,
Jessica Su,
Yun Ju Sung,
Jody S. Sylvia,
Adam A. Szpiro,
Daniel Taliun,
Hua Tang,
Margaret A. Taub,
Kent D. Taylor,
Matthew R.G. Taylor,
Simeon I. Taylor,
Marilyn J. Telen,
Timothy A. Thornton,
Machiko Threlkeld,
Lesley Tinker,
David Tirschwell,
Sarah A. Tishkoff,
Hemant K. Tiwari,
Catherine Tong,
Russell P. Tracy,
Michael Y. Tsai,
Dhananjay Vaidya,
David Van Den Berg,
Peter VandeHaar,
Scott Vrieze,
Tarik Walker,
Robert B. Wallace,
Avram Walts,
Feifei Wang,
Heming Wang,
Jiongming Wang,
Karol E. Watson,
Jennifer Watt,
Daniel E. Weeks,
Joshua Weinstock,
Scott T. Weiss,
LuChen Weng,
Cristen J. Willer,
Kayleen Williams,
L. Keoki Williams,
Carla Wilson,
James G. Wilson,
Lara Winterkorn,
Quenna Wong,
Joseph M. Wu,
Huichun Xu,
Ivana V. Yang,
Ketian Yu,
Seyedeh M. Zekavat,
Yingze Zhang,
Snow Xueyan Zhao,
Wei Zhao,
Michael C. Zody,
L. Adrienne Cupples,
Aladdin H. Shadyab,
Barbara McKnight,
Benjamin M. Shoemaker,
Braxton D. Mitchell,
Bruce M. Psaty,
Charles Kooperberg,
ChingTi Liu,
Christine M. Albert,
Dan M. Roden,
Daniel I. Chasman,
Donald M Lloyd-Jones,
Donna K. Arnett,
Elizabeth A. Regan,
Eric Boerwinkle,
Jerome I. Rotter,
Jeffrey R. O’Connell,
Lisa R. Yanek,
Mariza de Andrade,
Matthew Allison,
Merry-Lynn McDonald,
Mina K. Chung,
Myriam Fornage,
Nathalie Chami,
Patrick T. Ellinor,
Ramachandran S. Vasan,
Rasika A. Mathias,
Ruth J.F. Loos,
Stephen S. Rich,
Steven A. Lubitz,
Susan R. Heckbert,
Susan Redline,
Y. -D Ida Chen,
Cecelia Laurie,
Ryan D. Hernández,
Stephen T. McGarvey,
Michael E. Goddard,
Cathy C. Laurie,
Kari E. North,
Leslie A. Lange,
Bruce S. Weir,
Loïc Yengo,
Jian Yang,
Peter M. Visscher
Publication year - 2022
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-021-00997-7
Subject(s) - heritability , biology , linkage disequilibrium , genetics , minor allele frequency , single nucleotide polymorphism , missing heritability problem , genetic association , genome wide association study , trait , quantitative trait locus , genotype , gene , programming language , computer science
Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.