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Rare genetic variants explain missing heritability in smoking.
- Jang, Seon-Kyeong;
- Evans, Luke;
- Fialkowski, Allison;
- Arnett, Donna K;
- Ashley-Koch, Allison E;
- Barnes, Kathleen C;
- Becker, Diane M;
- Bis, Joshua C;
- Blangero, John;
- Bleecker, Eugene R;
- Boorgula, Meher Preethi;
- Bowden, Donald W;
- Brody, Jennifer A;
- Cade, Brian E;
- Jenkins, Brenda W Campbell;
- Carson, April P;
- Chavan, Sameer;
- Cupples, L Adrienne;
- Custer, Brian;
- Damrauer, Scott M;
- David, Sean P;
- de Andrade, Mariza;
- Dinardo, Carla L;
- Fingerlin, Tasha E;
- Fornage, Myriam;
- Freedman, Barry I;
- Garrett, Melanie E;
- Gharib, Sina A;
- Glahn, David C;
- Haessler, Jeffrey;
- Heckbert, Susan R;
- Hokanson, John E;
- Hou, Lifang;
- Hwang, Shih-Jen;
- Hyman, Matthew C;
- Judy, Renae;
- Justice, Anne E;
- Kaplan, Robert C;
- Kardia, Sharon LR;
- Kelly, Shannon;
- Kim, Wonji;
- Kooperberg, Charles;
- Levy, Daniel;
- Lloyd-Jones, Donald M;
- Loos, Ruth JF;
- Manichaikul, Ani W;
- Gladwin, Mark T;
- Martin, Lisa Warsinger;
- Nouraie, Mehdi;
- Melander, Olle;
- Meyers, Deborah A;
- Montgomery, Courtney G;
- North, Kari E;
- Oelsner, Elizabeth C;
- Palmer, Nicholette D;
- Payton, Marinelle;
- Peljto, Anna L;
- Peyser, Patricia A;
- Preuss, Michael;
- Psaty, Bruce M;
- Qiao, Dandi;
- Rader, Daniel J;
- Rafaels, Nicholas;
- Redline, Susan;
- Reed, Robert M;
- Reiner, Alexander P;
- Rich, Stephen S;
- Rotter, Jerome I;
- Schwartz, David A;
- Shadyab, Aladdin H;
- Silverman, Edwin K;
- Smith, Nicholas L;
- Smith, J Gustav;
- Smith, Albert V;
- Smith, Jennifer A;
- Tang, Weihong;
- Taylor, Kent D;
- Telen, Marilyn J;
- Vasan, Ramachandran S;
- Gordeuk, Victor R;
- Wang, Zhe;
- Wiggins, Kerri L;
- Yanek, Lisa R;
- Yang, Ivana V;
- Young, Kendra A;
- Young, Kristin L;
- Zhang, Yingze;
- Liu, Dajiang J;
- Keller, Matthew C;
- Vrieze, Scott
Published Web Location
https://doi.org/10.1038/s41562-022-01408-5Abstract
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 ([Formula: see text]) 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 ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] 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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