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. DamrauerSean P. David, Mariza de 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, Scott Vrieze

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 (hSNP2) 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 (hped2, 0.18–0.34). In the African ancestry samples, hSNP2 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.

Original languageEnglish (US)
Pages (from-to)1577-1586
Number of pages10
JournalNature Human Behaviour
Volume6
Issue number11
DOIs
StatePublished - Nov 2022

Bibliographical note

Funding Information:
The molecular data for the TOPMed programme was supported by the National Heart, Lung and Blood Institute. See the TOPMed Omics Support Table () for study-specific omics support information. Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract no. HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control and general programme coordination was provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract no. HHSN268201800001I). We acknowledge the studies and participants who provided biological samples and data for TOPMed. Funding for this project included grant nos R01DA044283, R01DA037904 and R01HG008983 to S.V. and grant no. R01MH100141 to M.C.K. Cohort-wise acknowledgement is provided in the . The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Funding Information:
B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. E.K.S. has received grant support from GSK and Bayer Research support to the University of Pennsylvania from RenalytixAI and personal fees from Calico Labs, both outside the current work. All other authors declare no competing interests.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Keywords

  • Genome-Wide Association Study
  • Gene Frequency
  • Polymorphism, Single Nucleotide/genetics
  • Phenotype
  • Smoking/genetics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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