Rare genetic variants explain missing heritability in smoking

Seon-Kyeong Jang, Luke Evans, Allison Fialkowski, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, Diane M. Becker, Joshua C. Bis, John Blangero, Eugene R. Bleecker, Meher Preethi Boorgula, Donald W. Bowden, Jennifer A. Brody, Brian E. Cade, Brenda W. Campbell Jenkins, April P. Carson, Sameer Chavan, L. Adrienne Cupples, Brian Custer, Scott M. Damrauer, Sean P. David, Mariza Andrade, Carla L. Dinardo, Tasha E. Fingerlin, Myriam Fornage, Barry I. Freedman, Melanie E. Garrett, Sina A. Gharib, David C. Glahn, Jeffrey Haessler, Susan R. Heckbert, John E. Hokanson, Lifang Hou, Shih-Jen Hwang, Matthew C. Hyman, Renae Judy, Anne E. Justice, Robert C. Kaplan, Sharon L. R. Kardia, Shannon Kelly, Wonji Kim, Charles Kooperberg, Daniel Levy, Donald M. Lloyd-Jones, Ruth J. F. Loos, Ani W. Manichaikul, Mark T. Gladwin, Lisa Warsinger Martin, Mehdi Nouraie, Olle Melander, Deborah A. Meyers, Courtney G. Montgomery, Kari E. North, Elizabeth C. Oelsner, Nicholette D. Palmer, Marinelle Payton, Anna L. Peljto, Patricia A. Peyser, Michael Preuss, Bruce M. Psaty, Dandi Qiao, Daniel J. Rader, Nicholas Rafaels, Susan Redline, Robert M. Reed, Alexander P. Reiner, Stephen S. Rich, Jerome I. Rotter, David A. Schwartz, Aladdin H. Shadyab, Edwin K. Silverman, Nicholas L. Smith, J. Gustav Smith, Albert V. Smith, Jennifer A. Smith, Weihong Tang, Kent D. Taylor, Marilyn J. Telen, Ramachandran S. Vasan, Victor R. Gordeuk, Zhe Wang, Kerri L. Wiggins, Lisa R. Yanek, Ivana V. Yang, Kendra A. Young, Kristin L. Young, Yingze Zhang, Dajiang J. Liu, Matthew C. Keller and Scott Vrieze ()
Additional contact information
Seon-Kyeong Jang: University of Minnesota
Luke Evans: University of Colorado Boulder
Allison Fialkowski: University of Minnesota
Donna K. Arnett: University of Kentucky College of Public Health
Allison E. Ashley-Koch: Duke University School of Medicine
Kathleen C. Barnes: University of Colorado Anschutz Medical Campus
Diane M. Becker: Johns Hopkins University School of Medicine
Joshua C. Bis: University of Washington
John Blangero: University of Texas Rio Grande Valley School of Medicine
Eugene R. Bleecker: University of Arizona
Meher Preethi Boorgula: University of Colorado Anschutz Medical Campus
Donald W. Bowden: Wake Forest School of Medicine
Jennifer A. Brody: University of Washington
Brian E. Cade: Harvard Medical School
Brenda W. Campbell Jenkins: Jackson State University School of Public Health
April P. Carson: University of Mississippi Medical Center
Sameer Chavan: University of Colorado Anschutz Medical Campus
L. Adrienne Cupples: Boston University School of Public Health
Brian Custer: Vitalant Research Institute
Scott M. Damrauer: University of Pennsylvania
Sean P. David: University of Chicago
Mariza Andrade: Mayo Clinic
Carla L. Dinardo: Fundação Pro Sangue
Tasha E. Fingerlin: University of Colorado Anschutz Medical Campus
Myriam Fornage: University of Texas Health Science Center at Houston
Barry I. Freedman: Wake Forest School of Medicine
Melanie E. Garrett: Duke University School of Medicine
Sina A. Gharib: University of Washington
David C. Glahn: Boston Children’s Hosptial and Harvard Medical School
Jeffrey Haessler: Fred Hutchinson Cancer Research Center
Susan R. Heckbert: University of Washington
John E. Hokanson: University of Colorado Anschutz Medical Campus
Lifang Hou: Northwestern University
Shih-Jen Hwang: National Institutes of Health
Matthew C. Hyman: University of Pennsylvania
Renae Judy: University of Pennsylvania
Anne E. Justice: Geisinger Health System
Robert C. Kaplan: Fred Hutchinson Cancer Research Center
Sharon L. R. Kardia: University of Michigan
Shannon Kelly: UCSF Benioff Children’s Hospital Oakland
Wonji Kim: Brigham and Women’s Hospital and Harvard Medical School
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Daniel Levy: National Institutes of Health
Donald M. Lloyd-Jones: Northwestern University
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Ani W. Manichaikul: University of Virginia
Mark T. Gladwin: University of Pittsburgh School of Medicine
Lisa Warsinger Martin: School of Medicine and Health Sciences
Mehdi Nouraie: University of Pittsburgh School of Medicine
Olle Melander: Lund University
Deborah A. Meyers: University of Arizona
Courtney G. Montgomery: Oklahoma Medical Research Foundation
Kari E. North: University of North Carolina at Chapel Hill
Elizabeth C. Oelsner: Columbia University
Nicholette D. Palmer: Wake Forest School of Medicine
Marinelle Payton: Jackson State University School of Public Health
Anna L. Peljto: University of Colorado School of Medicine
Patricia A. Peyser: University of Michigan
Michael Preuss: Icahn School of Medicine at Mount Sinai
Bruce M. Psaty: University of Washington
Dandi Qiao: Brigham and Women’s Hospital and Harvard Medical School
Daniel J. Rader: University of Pennsylvania
Nicholas Rafaels: University of Colorado Anschutz Medical Campus
Susan Redline: Harvard Medical School
Robert M. Reed: University of Maryland School of Medicine
Alexander P. Reiner: Fred Hutchinson Cancer Research Center
Stephen S. Rich: University of Virginia
Jerome I. Rotter: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
David A. Schwartz: University of Colorado Denver
Aladdin H. Shadyab: University of California, San Diego
Edwin K. Silverman: Brigham and Women’s Hospital and Harvard Medical School
Nicholas L. Smith: University of Washington
J. Gustav Smith: Gothenburg University
Albert V. Smith: University of Michigan
Jennifer A. Smith: University of Michigan
Weihong Tang: University of Minnesota
Kent D. Taylor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Marilyn J. Telen: Duke University School of Medicine
Ramachandran S. Vasan: Boston University School of Medicine
Victor R. Gordeuk: University of Illinois at Chicago
Zhe Wang: Icahn School of Medicine at Mount Sinai
Kerri L. Wiggins: University of Washington
Lisa R. Yanek: Johns Hopkins University School of Medicine
Ivana V. Yang: University of Colorado School of Medicine
Kendra A. Young: University of Colorado Anschutz Medical Campus
Kristin L. Young: University of North Carolina at Chapel Hill
Yingze Zhang: University of Pittsburgh School of Medicine
Dajiang J. Liu: Penn State College of Medicine
Matthew C. Keller: University of Colorado Boulder
Scott Vrieze: University of Minnesota

Nature Human Behaviour, 2022, vol. 6, issue 11, 1577-1586

Abstract: Abstract Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ( $$h^2_{\mathrm{SNP}}$$ h SNP 2 ) was estimated from 0.13 to 0.28 (s.e., 0.10–0.13) in European ancestries, with 35–74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5–4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ( $$h^2_{\mathrm{ped}}$$ h ped 2 , 0.18–0.34). In the African ancestry samples, $$h^2_{\mathrm{SNP}}$$ h SNP 2 was estimated from 0.03 to 0.33 (s.e., 0.09–0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Date: 2022
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DOI: 10.1038/s41562-022-01408-5

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