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Shared genetic basis between reproductive behaviors and anxiety-related disorders

Abstract

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: rg ± 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: ORearlier AFS→Anxiety = 1.64, p = 2.27 × 10−8; ORearlier AFB→Anxiety = 1.15, p = 2.28 × 10−3; ORAnxiety→earlier AFS = 1.02, p = 6.62 × 10−8; ORAnxiety→earlier AFB = 1.08, p = 1.60 × 10−4). In contrast, we observed unidirectional effects of later AFS and AFB on OCD (ORlater AFS→OCD = 2.18, p = 2.16 × 10−6; ORlater 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.

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Fig. 1: Outline of analyses performed in the current study.
Fig. 2: Genetic correlations (rg) across reproductive phenotypes and across anxiety-related disorders.
Fig. 3: Genetic correlations (rg) of five reproductive phenotypes with anxiety-related disorders.
Fig. 4: Genetic correlations (rg) of female and male reproductive behaviors with anxiety-related disorders.
Fig. 5: Bidirectional causal relationships between reproductive behaviors and risks for anxiety disorders UKBB and OCD.

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Acknowledgements

We would like to thank all individuals who participated in this study.

Funding

This work was supported by Grants-in-Aid for Scientific Research (C) (19K08081, 21K07497, 22K07614) from the Japan Society for the Promotion of Science (JSPS) and a grant from the Smoking Research Foundation.

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KO supervised the entire project, collected the data, wrote the manuscript and was critically involved in the design, analysis and interpretation of the data. KO, AK, DF, KT, and SS were responsible for performing the literature review. KO, AK, DF, and TS were heavily involved in the collection of the majority of the data and intellectually contributed to data interpretation. All authors contributed to and approved the final manuscript.

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Correspondence to Kazutaka Ohi.

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Ohi, K., Kuramitsu, A., Fujikane, D. et al. Shared genetic basis between reproductive behaviors and anxiety-related disorders. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01667-8

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