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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 '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.

SUBMITTER: Jang SK

PROVIDER: S-EPMC9985486 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Rare genetic variants explain missing heritability in smoking.

Jang Seon-Kyeong SK Evans Luke L Fialkowski Allison A Arnett Donna K DK Ashley-Koch Allison E AE Barnes Kathleen C KC Becker Diane M DM Bis Joshua C JC Blangero John J Bleecker Eugene R ER Boorgula Meher Preethi MP Bowden Donald W DW Brody Jennifer A JA Cade Brian E BE Jenkins Brenda W Campbell BWC Carson April P AP Chavan Sameer S Cupples L Adrienne LA Custer Brian B Damrauer Scott M SM David Sean P SP de Andrade Mariza M Dinardo Carla L CL Fingerlin Tasha E TE Fornage Myriam M Freedman Barry I BI Garrett Melanie E ME Gharib Sina A SA Glahn David C DC Haessler Jeffrey J Heckbert Susan R SR Hokanson John E JE Hou Lifang L Hwang Shih-Jen SJ Hyman Matthew C MC Judy Renae R Justice Anne E AE Kaplan Robert C RC Kardia Sharon L R SLR Kelly Shannon S Kim Wonji W Kooperberg Charles C Levy Daniel D Lloyd-Jones Donald M DM Loos Ruth J F RJF Manichaikul Ani W AW Gladwin Mark T MT Martin Lisa Warsinger LW Nouraie Mehdi M Melander Olle O Meyers Deborah A DA Montgomery Courtney G CG North Kari E KE Oelsner Elizabeth C EC Palmer Nicholette D ND Payton Marinelle M Peljto Anna L AL Peyser Patricia A PA Preuss Michael M Psaty Bruce M BM Qiao Dandi D Rader Daniel J DJ Rafaels Nicholas N Redline Susan S Reed Robert M RM Reiner Alexander P AP Rich Stephen S SS Rotter Jerome I JI Schwartz David A DA Shadyab Aladdin H AH Silverman Edwin K EK Smith Nicholas L NL Smith J Gustav JG Smith Albert V AV Smith Jennifer A JA Tang Weihong W Taylor Kent D KD Telen Marilyn J MJ Vasan Ramachandran S RS Gordeuk Victor R VR Wang Zhe Z Wiggins Kerri L KL Yanek Lisa R LR Yang Ivana V IV Young Kendra A KA Young Kristin L KL Zhang Yingze Y Liu Dajiang J DJ Keller Matthew C MC Vrieze Scott S

Nature human behaviour 20220804 11

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 estimate ...[more]

PMID: 35927319

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Project description:The proportion of genetic variation in complex traits explained by rare variants is a key question for genomic prediction, and for identifying the basis of "missing heritability"--the proportion of additive genetic variation not captured by common variants on SNP arrays. Sequence variants in transcript and regulatory regions from 429 sequenced animals were used to impute high density SNP genotypes of 3311 Holstein sires to sequence. There were 675,062 common variants (MAF>0.05), 102,549 uncommon variants (0.01<MAF<0.05), and 83,856 rare variants (MAF<0.01). We describe a novel method for estimating the proportion of the rare variants that are sequencing errors using parent-progeny duos. We then used mixed model methodology to estimate the proportion of variance captured by these different classes of variants for fat, milk and protein yields, as well as for fertility. Common sequence variants captured 83%, 77%, 76% and 84% of the total genetic variance for fat, milk, and protein yields and fertility, respectively. This was between 2 and 5% more variance than that captured from 600k SNPs on a high density chip, although the difference was not significant. Rare variants captured 3%, 0%, 1% and 14% of the genetic variance for fat, milk and protein yields, and fertility respectively, whereas pedigree explained the remaining amount of genetic variance (none for fertility). The proportion of variation explained by rare variants is likely to be under-estimated due to reduced accuracies of imputation for this class of variants. Using common sequence variants slightly improved accuracy of genomic predictions for fat and milk yield, compared to high density SNP array genotypes. However, including rare variants from transcript regions did not increase the accuracy of genomic predictions. These results suggest that rare variants recover a small percentage of the missing heritability for complex traits, however very large reference sets will be required to exploit this to improve the accuracy of genomic predictions. Our results do suggest the contribution of rare variants to genetic variation may be greater for fitness traits.

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Rare genetic variants explain missing heritability in smoking.

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Rare genetic variants explain missing heritability in smoking.

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