Rare genetic variants explain missing heritability in smoking.
Seon-Kyeong JangLuke M EvansAllison FialkowskiDonna K ArnettAllison Elizabeth Ashley-KochKathleen C BarnesDiane M BeckerJoshua C BisJohn BlangeroEugene R BleeckerMeher Preethi BoorgulaDonald W BowdenJennifer A BrodyBrian E CadeBrenda W Campbell JenkinsApril P CarsonSameer ChavanL Adrienne CupplesBrian S CusterScott M DamrauerSean P DavidMariza de AndradeCarla L DinardoTasha E FingerlinMyriam FornageBarry I FreedmanMelanie E GarrettSina A GharibDavid C GlahnJeffrey HaesslerSusan R HeckbertJohn E HokansonLifang HouShih-Jen HwangMatthew C HymanRenae JudyAnne E JusticeRobert C KaplanSharon L R KardiaShannon KellyWonji KimCharles KooperbergDaniel LevyDonald M Lloyd-JonesRuth J F LoosAni W ManichaikulMark T GladwinLisa Warsinger MartinSeyed Mehdi NouraieOlle MelanderDeborah A MeyersCourtney G MontgomeryKari E NorthElizabeth C OelsnerNicholette D D AllredMarinelle PaytonAnna L PeljtoPatricia A PeyserMichael H PreussBruce M PsatyDandi QiaoDaniel James RaderNicholas RafaelsSusan RedlineRobert M ReedAlexander P ReinerStephen S RichJerome I RotterDavid A SchwartzAladdin H ShadyabEdwin K SilvermanNicholas L SmithJ Gustav SmithAlbert V SmithJennifer A SmithWeihong TangKent D TaylorMarilyn J TelenRamachandran S VasanVictor R GordeukZhe WangKerri L WigginsLisa R YanekIvana V YangKendra A YoungKristin L YoungYingze ZhangDajiang J LiuMatthew C KellerScott I VriezePublished in: Nature human behaviour (2022)
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.