Rare genetic variants explain missing heritability in smoking,Nature Human Behaviour

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Rare genetic variants explain missing heritability in smoking
Nature Human Behaviour ( IF 21.4 ) Pub Date : 2022-08-04 , DOI: 10.1038/s41562-022-01408-5
Seon-Kyeong Jang ₁ , Luke Evans _{2,

3} , Allison Fialkowski ₁ , Donna K Arnett ₄ , Allison E Ashley-Koch ₅ , Kathleen C Barnes ₆ , Diane M Becker ₇ , Joshua C Bis ₈ , John Blangero ₉ , Eugene R Bleecker ₁₀ , Meher Preethi Boorgula ₆ , Donald W Bowden ₁₁ , Jennifer A Brody ₈ , Brian E Cade ₁₂ , Brenda W Campbell Jenkins ₁₃ , April P Carson ₁₄ , Sameer Chavan ₆ , L Adrienne Cupples ₁₅ , Brian Custer ₁₆ , Scott M Damrauer _{17,

18} , Sean P David _{19,

20} , Mariza de Andrade ₂₁ , Carla L Dinardo ₂₂ , Tasha E Fingerlin _{23,

24} , Myriam Fornage ₂₅ , Barry I Freedman ₂₆ , Melanie E Garrett ₅ , Sina A Gharib _{8,

27} , David C Glahn ₂₈ , Jeffrey Haessler ₂₉ , Susan R Heckbert _{30,

31} , John E Hokanson ₃₂ , Lifang Hou ₃₃ , Shih-Jen Hwang ₃₄ , Matthew C Hyman ₃₅ , Renae Judy ₁₇ , Anne E Justice ₃₆ , Robert C Kaplan _{29,

37} , Sharon L R Kardia ₃₈ , Shannon Kelly ₃₉ , Wonji Kim ₄₀ , Charles Kooperberg ₂₉ , Daniel Levy _{34,

41} , Donald M Lloyd-Jones ₃₃ , Ruth J F Loos _{42,

43} , Ani W Manichaikul ₄₄ , Mark T Gladwin ₄₅ , Lisa Warsinger Martin ₄₆ , Mehdi Nouraie ₄₅ , Olle Melander _{47,

48} , Deborah A Meyers ₁₀ , Courtney G Montgomery ₄₉ , Kari E North ₅₀ , Elizabeth C Oelsner ₅₁ , Nicholette D Palmer ₁₁ , Marinelle Payton ₅₂ , Anna L Peljto ₅₃ , Patricia A Peyser ₃₈ , Michael Preuss _{42,

43} , Bruce M Psaty ₅₄ , Dandi Qiao ₄₀ , Daniel J Rader _{35,

55} , Nicholas Rafaels ₆ , Susan Redline ₁₂ , Robert M Reed ₅₆ , Alexander P Reiner ₂₉ , Stephen S Rich ₄₄ , Jerome I Rotter ₅₇ , David A Schwartz _{58,

59} , Aladdin H Shadyab ₆₀ , Edwin K Silverman ₄₀ , Nicholas L Smith _{30,

31} , J Gustav Smith _{61,

62} , Albert V Smith ₆₃ , Jennifer A Smith ₃₈ , Weihong Tang ₆₄ , Kent D Taylor ₅₇ , Marilyn J Telen ₅ , Ramachandran S Vasan _{65,

66} , Victor R Gordeuk ₆₇ , Zhe Wang _{42,

43} , Kerri L Wiggins ₈ , Lisa R Yanek ₇ , Ivana V Yang ₅₃ , Kendra A Young ₃₂ , Kristin L Young ₅₀ , Yingze Zhang ₄₅ , Dajiang J Liu ₆₈ , Matthew C Keller ₂ , Scott Vrieze ₁

Affiliation

Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
Department of Ecology & Evolution, University of Colorado Boulder, Boulder, CO, USA.
Dean's Office, University of Kentucky College of Public Health, Lexington, KY, USA.
Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Division of Biomedical Informatics & Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Department of Medicine, University of Arizona, Tucson, AZ, USA.
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jackson Heart Study Graduate Training and Education Center, Jackson State University School of Public Health, Jackson, MS, USA.
Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Vitalant Research Institute, San Francisco, CA, USA.
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Family Medicine, Prtizker School of Medicine, University of Chicago, Chicago, IL, USA.
NorthShore University HealthSystem, Evanston, IL, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Fundação Pro Sangue, São Paulo, Brazil.
Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Center for Genes Environment and Health, National Jewish Health, Denver, CO, USA.
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA.
Department of Psychiatry, Boston Children's Hosptial and Harvard Medical School, Boston, MA, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Epidemiology, University of Washington, Seattle, WA, USA.
Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA.
Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Population Health Sciences, Geisinger Health System, Danville, PA, USA.
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Framingham Heart Study, Framingham, MA, USA.
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, VA, USA.
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Division of Cardiology, School of Medicine and Health Sciences, Washington, DC, USA.
Department of Clinical Sciences, Lund University, Malmö, Sweden.
Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of General Medicine, Columbia University Irving Medical Center, Columbia University, New York, NY, USA.
Department of Epidemiology and Biostatistics, Jackson Heart Study Graduate Training and Education Center, Jackson State University School of Public Health, Jackson, MS, USA.
Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
University of Maryland School of Medicine, Baltimore, MD, USA.
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Department of Medicine, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA.
Wallenberg Laboratory/Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University, Gothenburg, Sweden.
Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Sections of Preventive Medicine and Epidemiology and Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA.

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 (\(h^2_{\mathrm{SNP}}\)) 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 (\(h^2_{\mathrm{ped}}\), 0.18–0.34). In the African ancestry samples, \(h^2_{\mathrm{SNP}}\) 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.

中文翻译：

罕见的基因变异解释了吸烟遗传性缺失的原因

与基于家庭的研究推断的相比，常见的遗传变异对复杂表型的变异解释较少，并且对于这种“缺失的遗传性”的来源存在争议。我们利用多达 26,257 名无关欧洲血统个体和 11,743 名非洲血统个体的全基因组序列调查了罕见遗传变异对烟草使用的影响。在四种吸烟特征中，欧洲血统中基于单核苷酸多态性的遗传力 ( \(h^2_{\mathrm{SNP}}\) ) 估计为 0.13 至 0.28 (se, 0.10–0.13)，其中 35–74其中 % 归因于较小等位基因频率在 0.01% 至 1% 之间的罕见变异。这些遗传力估计值比过去仅基于常见变异的估计值高出 1.5–4 倍，占我们基于谱系的狭义遗传力估计值的 60% 到 100% ( \(h^2_{\mathrm{ped}}\ ），0.18–0.34）。在非洲血统样本中，四种吸烟特征的\(h^2_{\mathrm{SNP}}\)估计为 0.03 到 0.33 (se, 0.09–0.14)。这些结果表明，罕见变异是吸烟遗传性的重要贡献者。

更新日期：2022-08-05

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