Rare genetic variants explain missing heritability in smoking

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. The team of authors led by Seon-Kyeong Jang use whole-genome sequencing data and show that rare genetic variants explain much of the ‘missing heritability’ in smoking behaviours. These results help address a long-standing mystery in behavioural genetics.