Shared genetic basis between reproductive behaviors and anxiety-related disorders

Reproductive behaviors are associated with risks for psychiatric disorders. Reproductive phenotypes are moderately heritable and have genetic overlaps with risks for psychiatric disorders. However, the genetic and causal relationships between anxiety-related disorders or specific anxiety disorders and reproductive phenotypes remain unknown. We utilized large-scale genome-wide association study (GWAS) results (n = 9537-542,901) for five reproductive phenotypes [age at menarche, age at first sexual intercourse (AFS), age at first birth (AFB), number of children ever born (NEB), and age at menopause] and five anxiety-related disorders [panic disorder, anxiety disorders from the ANGST and the UK biobank (UKBB), posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD)]. To assess genetic correlations and causal associations, linkage disequilibrium score regression and Mendelian randomization analyses, respectively, were performed. We found that AFS and AFB were negatively correlated with anxiety disorders ANGST (AFS: r_g ± SE = -0.28 ± 0.08, p = 6.00 × 10^-4; AFB: -0.45 ± 0.11, p = 3.26 × 10^-5), anxiety disorders UKBB (AFS: -0.18 ± 0.03, p = 9.64 × 10^-9; AFB; -0.25 ± 0.03, p = 2.90 × 10^-13) and PTSD (AFS: -0.42 ± 0.12, p = 4.00 × 10^-4; AFB: -0.44 ± 0.12, p = 2.00 × 10^-4) and positively correlated with OCD (AFS: 0.25 ± 0.05, p = 2.46 × 10^-6; AFB: 0.25 ± 0.05, p = 3.92 × 10^-7). Conversely, NEB was negatively correlated with OCD (-0.28 ± 0.08, p = 6.00 × 10^-4). We revealed bidirectional effects between earlier AFS and AFB and anxiety disorders (odds ratios: OR_{earlier AFS→Anxiety} = 1.64, p = 2.27 × 10^-8; OR_{earlier AFB→Anxiety} = 1.15, p = 2.28 × 10^-3; OR_{Anxiety→earlier AFS} = 1.02, p = 6.62 × 10^-8; OR_{Anxiety→earlier AFB} = 1.08, p = 1.60 × 10^-4). In contrast, we observed unidirectional effects of later AFS and AFB on OCD (OR_{later AFS→OCD} = 2.18, p = 2.16 × 10^-6; OR_{later AFB→OCD} = 1.22, p = 0.016). We suggest that those who have earlier sexual debut and childbirth are prone to risk for anxiety disorders and vice versa, while those who have later sexual debut and childbirth are genetically prone to risk for OCD. Our findings further support revising the diagnostic criteria (DSM-5) such that OCD is independent from anxiety disorders.