Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus.

Mathieson I, Day FR, Barban N, Tropf FC, Brazel DM, eQTLGen Consortium , BIOS Consortium , Vaez A, van Zuydam N, Bitarello BD, Gardner EJ, Akimova ET, Azad A, Bergmann S, Bielak LF, Boomsma DI, Bosak K, Brumat M, Buring JE, Cesarini D, Chasman DI, Chavarro JE, Cocca M, Concas MP, Davey Smith G, Davies G, Deary IJ, Esko T, Faul JD, FinnGen Study , Franco O, Ganna A, Gaskins AJ, Gelemanovic A, de Geus EJC, Gieger C, Girotto G, Gopinath B, Grabe HJ, Gunderson EP, Hayward C, He C, van Heemst D, Hill WD, Hoffmann ER, Homuth G, Hottenga JJ, Huang H, Hyppӧnen E, Ikram MA, Jansen R, Johannesson M, Kamali Z, Kardia SLR, Kavousi M, Kifley A, Kiiskinen T, Kraft P, Kühnel B, Langenberg C, Liew G, Lifelines Cohort Study , Lind PA, Luan J, Mägi R, Magnusson PKE, Mahajan A, Martin NG, Mbarek H, McCarthy MI, McMahon G, Medland SE, Meitinger T, Metspalu A, Mihailov E, Milani L, Missmer SA, Mitchell P, Møllegaard S, Mook-Kanamori DO, Morgan A, van der Most PJ, de Mutsert R, Nauck M, Nolte IM, Noordam R, Penninx BWJH, Peters A, Peyser PA, Polašek O, Power C, Pribisalic A, Redmond P, Rich-Edwards JW, Ridker PM, Rietveld CA, Ring SM, Rose LM, Rueedi R, Shukla V, Smith JA, Stankovic S, Stefánsson K, Stöckl D, Strauch K, Swertz MA, Teumer A, Thorleifsson G, Thorsteinsdottir U, Thurik AR, Timpson NJ, Turman C, Uitterlinden AG, Waldenberger M, Wareham NJ, Weir DR, Willemsen G, Zhao JH, Zhao W, Zhao Y, Snieder H, den Hoed M, Ong KK, Mills MC, Perry JRB

Nat Hum Behav - (-) - [2023-03-02; online 2023-03-02]

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.

NGI SNP genotyping [Service]

NGI Uppsala (SNP&SEQ Technology Platform) [Service]

National Genomics Infrastructure [Service]

PubMed 36864135

DOI 10.1038/s41562-023-01528-6

Crossref 10.1038/s41562-023-01528-6

pii: 10.1038/s41562-023-01528-6

Publications 9.2.2