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 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

doi:10.1038/s41562-022-01408-5

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

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	1577-1586
Number of pages	10
Journal	Nature Human Behaviour
Volume	6
Issue number	11
DOIs	https://doi.org/10.1038/s41562-022-01408-5
State	Published - Nov 2022

ASJC Scopus subject areas

Social Psychology
Experimental and Cognitive Psychology
Behavioral Neuroscience

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Jang, S. K., Evans, L., Fialkowski, A., Arnett, D. K., Ashley-Koch, A. E., Barnes, K. C., Becker, D. M., Bis, J. C., Blangero, J., Bleecker, E. R., Boorgula, M. P., Bowden, D. W., Brody, J. A., Cade, B. E., Jenkins, B. W. C., Carson, A. P., Chavan, S., Cupples, L. A., Custer, B., ... Vrieze, S. (2022). Rare genetic variants explain missing heritability in smoking. Nature Human Behaviour, 6(11), 1577-1586. https://doi.org/10.1038/s41562-022-01408-5

Jang, SK, Evans, L, Fialkowski, A, Arnett, DK, Ashley-Koch, AE, Barnes, KC, Becker, DM, Bis, JC, Blangero, J, Bleecker, ER, Boorgula, MP, Bowden, DW, Brody, JA, Cade, BE, Jenkins, BWC, Carson, AP, Chavan, S, Cupples, LA, Custer, B, Damrauer, SM, David, SP, de Andrade, M, Dinardo, CL, Fingerlin, TE, Fornage, M, Freedman, BI, Garrett, ME, Gharib, SA, Glahn, DC, Haessler, J, Heckbert, SR, Hokanson, JE, Hou, L, Hwang, SJ, Hyman, MC, Judy, R, Justice, AE, Kaplan, RC, Kardia, SLR, Kelly, S, Kim, W, Kooperberg, C, Levy, D, Lloyd-Jones, DM, Loos, RJF, Manichaikul, AW, Gladwin, MT, Martin, LW, Nouraie, M, Melander, O, Meyers, DA, Montgomery, CG, North, KE, Oelsner, EC, Palmer, ND, Payton, M, Peljto, AL, Peyser, PA, Preuss, M, Psaty, BM, Qiao, D, Rader, DJ, Rafaels, N, Redline, S, Reed, RM, Reiner, AP, Rich, SS, Rotter, JI, Schwartz, DA, Shadyab, AH, Silverman, EK, Smith, NL, Smith, JG, Smith, AV, Smith, JA, Tang, W, Taylor, KD, Telen, MJ, Vasan, RS, Gordeuk, VR, Wang, Z, Wiggins, KL, Yanek, LR, Yang, IV, Young, KA, Young, KL, Zhang, Y, Liu, DJ, Keller, MC & Vrieze, S 2022, 'Rare genetic variants explain missing heritability in smoking', Nature Human Behaviour, vol. 6, no. 11, pp. 1577-1586. https://doi.org/10.1038/s41562-022-01408-5

@article{c2009225621b470baf7138fe3f33872a,

title = "Rare genetic variants explain missing heritability in smoking",

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 {\textquoteleft}missing heritability{\textquoteright}. 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.",

author = "Jang, {Seon Kyeong} and Luke Evans and Allison Fialkowski and Arnett, {Donna K.} and Ashley-Koch, {Allison E.} and Barnes, {Kathleen C.} and Becker, {Diane M.} and Bis, {Joshua C.} and John Blangero and Bleecker, {Eugene R.} and Boorgula, {Meher Preethi} and Bowden, {Donald W.} and Brody, {Jennifer A.} and Cade, {Brian E.} and Jenkins, {Brenda W.Campbell} and Carson, {April P.} and Sameer Chavan and Cupples, {L. Adrienne} and Brian Custer and Damrauer, {Scott M.} and David, {Sean P.} and {de Andrade}, Mariza and Dinardo, {Carla L.} and Fingerlin, {Tasha E.} and Myriam Fornage and Freedman, {Barry I.} and Garrett, {Melanie E.} and Gharib, {Sina A.} and Glahn, {David C.} and Jeffrey Haessler and Heckbert, {Susan R.} and Hokanson, {John E.} and Lifang Hou and Hwang, {Shih Jen} and Hyman, {Matthew C.} and Renae Judy and Justice, {Anne E.} and Kaplan, {Robert C.} and Kardia, {Sharon L.R.} and Shannon Kelly and Wonji Kim and Charles Kooperberg and Daniel Levy and Lloyd-Jones, {Donald M.} and Loos, {Ruth J.F.} and Manichaikul, {Ani W.} and Gladwin, {Mark T.} and Martin, {Lisa Warsinger} and Mehdi Nouraie and Olle Melander and Meyers, {Deborah A.} and Montgomery, {Courtney G.} and North, {Kari E.} and Oelsner, {Elizabeth C.} and Palmer, {Nicholette D.} and Marinelle Payton and Peljto, {Anna L.} and Peyser, {Patricia A.} and Michael Preuss and Psaty, {Bruce M.} and Dandi Qiao and Rader, {Daniel J.} and Nicholas Rafaels and Susan Redline and Reed, {Robert M.} and Reiner, {Alexander P.} and Rich, {Stephen S.} and Rotter, {Jerome I.} and Schwartz, {David A.} and Shadyab, {Aladdin H.} and Silverman, {Edwin K.} and Smith, {Nicholas L.} and Smith, {J. Gustav} and Smith, {Albert V.} and Smith, {Jennifer A.} and Weihong Tang and Taylor, {Kent D.} and Telen, {Marilyn J.} and Vasan, {Ramachandran S.} and Gordeuk, {Victor R.} and Zhe Wang and Wiggins, {Kerri L.} and Yanek, {Lisa R.} and Yang, {Ivana V.} and Young, {Kendra A.} and Young, {Kristin L.} and Yingze Zhang and Liu, {Dajiang J.} and Keller, {Matthew C.} and Scott Vrieze",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = nov,

doi = "10.1038/s41562-022-01408-5",

language = "English (US)",

volume = "6",

pages = "1577--1586",

journal = "Nature Human Behaviour",

issn = "2397-3374",

publisher = "Nature Publishing Group",

number = "11",

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TY - JOUR

T1 - Rare genetic variants explain missing heritability in smoking

AU - Jang, Seon Kyeong

AU - Evans, Luke

AU - Fialkowski, Allison

AU - Arnett, Donna K.

AU - Ashley-Koch, Allison E.

AU - Barnes, Kathleen C.

AU - Becker, Diane M.

AU - Bis, Joshua C.

AU - Blangero, John

AU - Bleecker, Eugene R.

AU - Boorgula, Meher Preethi

AU - Bowden, Donald W.

AU - Brody, Jennifer A.

AU - Cade, Brian E.

AU - Jenkins, Brenda W.Campbell

AU - Carson, April P.

AU - Chavan, Sameer

AU - Cupples, L. Adrienne

AU - Custer, Brian

AU - Damrauer, Scott M.

AU - David, Sean P.

AU - de Andrade, Mariza

AU - Dinardo, Carla L.

AU - Fingerlin, Tasha E.

AU - Fornage, Myriam

AU - Freedman, Barry I.

AU - Garrett, Melanie E.

AU - Gharib, Sina A.

AU - Glahn, David C.

AU - Haessler, Jeffrey

AU - Heckbert, Susan R.

AU - Hokanson, John E.

AU - Hou, Lifang

AU - Hwang, Shih Jen

AU - Hyman, Matthew C.

AU - Judy, Renae

AU - Justice, Anne E.

AU - Kaplan, Robert C.

AU - Kardia, Sharon L.R.

AU - Kelly, Shannon

AU - Kim, Wonji

AU - Kooperberg, Charles

AU - Levy, Daniel

AU - Lloyd-Jones, Donald M.

AU - Loos, Ruth J.F.

AU - Manichaikul, Ani W.

AU - Gladwin, Mark T.

AU - Martin, Lisa Warsinger

AU - Nouraie, Mehdi

AU - Melander, Olle

AU - Meyers, Deborah A.

AU - Montgomery, Courtney G.

AU - North, Kari E.

AU - Oelsner, Elizabeth C.

AU - Palmer, Nicholette D.

AU - Payton, Marinelle

AU - Peljto, Anna L.

AU - Peyser, Patricia A.

AU - Preuss, Michael

AU - Psaty, Bruce M.

AU - Qiao, Dandi

AU - Rader, Daniel J.

AU - Rafaels, Nicholas

AU - Redline, Susan

AU - Reed, Robert M.

AU - Reiner, Alexander P.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Schwartz, David A.

AU - Shadyab, Aladdin H.

AU - Silverman, Edwin K.

AU - Smith, Nicholas L.

AU - Smith, J. Gustav

AU - Smith, Albert V.

AU - Smith, Jennifer A.

AU - Tang, Weihong

AU - Taylor, Kent D.

AU - Telen, Marilyn J.

AU - Vasan, Ramachandran S.

AU - Gordeuk, Victor R.

AU - Wang, Zhe

AU - Wiggins, Kerri L.

AU - Yanek, Lisa R.

AU - Yang, Ivana V.

AU - Young, Kendra A.

AU - Young, Kristin L.

AU - Zhang, Yingze

AU - Liu, Dajiang J.

AU - Keller, Matthew C.

AU - Vrieze, Scott

PY - 2022/11

Y1 - 2022/11

N2 - 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.

AB - 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.

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SP - 1577

EP - 1586

JO - Nature Human Behaviour

JF - Nature Human Behaviour

IS - 11

ER -

Rare genetic variants explain missing heritability in smoking

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