Physical and neuro-behavioural determinants of reproductive onset and success

Abstract

The ages of puberty, first sexual intercourse and first birth signify the onset of reproductive ability, behaviour and success, respectively. These sequenced events have behavioural, physiological and health significance, and may also influence overall reproductive fitness. In a genome-wide association study of 125,667 white men and women aged 40-69 in the UK Biobank Study, we identify 38 sequence variants with association P-values <5×10-8 with age at first sexual intercourse. Findings were taken forward in up to 241,910 men and women from deCODE Iceland and 20,187 from Women’s Genome Health Study. Several of these loci also exhibit strong associations with behavioural traits (rs4856591 in CADM2 and risk taking propensity: P=4.3×10-10; rs73195303 in MSRA and irritable temperament: P=5.8×10-11) and other reproductive traits (rs67229052 in ESR1 and both age at first birth: P=1.2x10-13 and number of children: P=4.8×10-12; rs2188151 in SEMA3F and age at first birth: P=8.76×10-15). In Mendelian randomisation analyses, we demonstrate likely causal influences of earlier puberty timing on earlier first sexual intercourse, earlier first birth and fewer years of education. In turn, likely causal consequences of earlier first sexual intercourse include reproductive, educational, psychiatric and cardiometabolic outcomes. These findings point to the existence of developmental and neuro-behavioural regulators of reproductive activity and success.