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 (\(h^2_{\mathrm{SNP}}\)) 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.
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Data availability
Phenotypes are available through an authorized access portal in dbgap (https://dbgap.ncbi.nlm.nih.gov/) or direct request to TOPMed principal investigators. Accession numbers and email addresses of the principal investigators are presented in the Supplementary Note. Genetic data are available through the dbgap TOPMed exchange area.
Code availability
All software used is publicly available and can be found at the references cited.
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Acknowledgements
The molecular data for the TOPMed programme was supported by the National Heart, Lung and Blood Institute. See the TOPMed Omics Support Table (Supplementary Note) 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 Supplementary Note. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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S.-K.J., S.V., M.C.K. and L.E. designed the study. A.F. contributed to the data analysis. All authors contributed to the data collection and curation and critically reviewed the manuscript.
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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.
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Jang, SK., Evans, L., Fialkowski, A. et al. Rare genetic variants explain missing heritability in smoking. Nat Hum Behav 6, 1577–1586 (2022). https://doi.org/10.1038/s41562-022-01408-5
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DOI: https://doi.org/10.1038/s41562-022-01408-5
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