Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.
Laurence J HoweMichel G NivardTim T MorrisAilin F HansenHumaira RasheedYoonsu ChoGeetha ChittoorRafael AhlskogPenelope A LindTeemu PalviainenMatthijs D van der ZeeRosa CheesmanMassimo ManginoYunzhang WangShuai LiLucija KlarićScott M RatliffLawrence F BielakMarianne NygaardAlexandros GiannelisEmily A WilloughbyChandra A ReynoldsJared V BalbonaOle Andreas AndreassenHelga AskAris BarasChristopher R BauerDorret I BoomsmaArchie I CampbellHarry CampbellZhengming ChenParaskevi ChristofidouElizabeth C CorfieldChristina C DahmDeepika R DokuruLuke M EvansEco J C de GeusSudheer GiddaluruScott D GordonKathryn Paige HardenW David HillAmanda M HughesShona M KerrYongkang KimHyeokmoon KweonAntti LatvalaDeborah A LawlorLiming LiKuang LinPer MagnusPatrik K E MagnussonTravis T MallardPekka T MartikainenMelinda C MillsPal Rasmus NjolstadJohn D OvertonNancy L PedersenDavid J PorteousJeffrey G ReidKarri SilventoinenMelissa C SoutheyCamilla StoltenbergElliot M Tucker-DrobMargaret J Wrightnull nullnull nullJohn K HewittMatthew C KellerMichael C StallingsJames J LeeKaare ChristensenSharon L R KardiaPatricia A PeyserJennifer A SmithJames F WilsonJohn L HopperSara HäggTimothy D SpectorJean-Baptiste PingaultRobert PlominKaroline Alexandra HavdahlMeike BartelsNicholas G MartinSven OskarssonAnne E JusticeIona Y MillwoodKristian HveemØyvind NaessCristen J WillerBjørn Olav ÅsvoldPhilipp D KoellingerJaakko A KaprioSarah E MedlandRobin G WaltersDaniel J BenjaminPatrick TurleyDavid M EvansGeorge Davey SmithCaroline HaywardBen Michael BrumptonGibran HemaniNeil Martin DaviesPublished in: Nature genetics (2022)
Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.