Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.
Iain MathiesonFelix R DayNicola BarbanFelix C TropfDavid M Brazelnull nullnull nullAhmad VaezNatalie van ZuydamBárbara D BitarelloEugene J GardnerEvelina T AkimovaAjuna AzadSven BergmannLawrence F BielakDorret I BoomsmaKristina BosakMarco BrumatJulie E BuringDavid CesariniDaniel I ChasmanJorge E ChavarroMassimiliano CoccaMaria Pina ConcasGeorge Davey SmithGail DaviesIan J DearyTõnu EskoJessica D Faulnull nullOscar H FrancoAndrea GannaAudrey J GaskinsAndrea GelemanovicEco J C de GeusChristian GiegerGiorgia GirottoBamini GopinathHans Jörgen GrabeErica P GundersonCaroline HaywardChunyan HeDiana van HeemstW David HillEva R HoffmanGeorg HomuthJouke- Jan HottengaHongyang HuangElina HyppӧnenMohammad Arfan IkramRick JansenMagnus JohannessonZoha KamaliSharon L R KardiaMaryam KavousiAnnette KifleyTuomo Tapio Johannes KiiskinenPeter KraftBrigitte KühnelClaudia LangenbergGerald Liewnull nullPenelope A LindJian'an LuanReedik MägiPatrik K E MagnussonAnubha MahajanNicholas G MartinHamdi MbarekMark I McCarthyGeorge McMahonSarah E MedlandThomas MeitingerAndres MetspaluEvelin MihailovLili A MilaniStacey A MissmerPaul MitchellStine MøllegaardDennis O Mook-KanamoriAnna MorganPeter J van der MostRenée de MutsertMatthias NauckIlja Maria NolteRaymond NoordamBrenda W J H PenninxAnnette PetersPatricia A PeyserOzren PolašekChris PowerAjka PribisalicPaul RedmondJanet W Rich-EdwardsPaul M RidkerCornelius A RietveldSusan M RingLynda M RoseRico RueediVallari ShuklaJennifer A SmithStasa StankovicKári StefánssonDoris StöcklKonstantin StrauchMorris A SwertzAlexander TeumerGudmar ThorleifssonUnnur ThorsteinsdottirA Roy ThurikNicholas John TimpsonConstance TurmanAndre G UitterlindenMelanie WaldenbergerNicholas J WarehamDavid R WeirGonneke WillemsenJing Hau ZhaoWei ZhaoYajie ZhaoHarold SniederMarcel den HoedKen K OngMelinda C MillsJohn R B PerryPublished in: Nature human behaviour (2023)
Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.
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