TY - JOUR
T1 - A Common Genetic Factor Underlies Genetic Risk for Gynaecological and Reproductive Disorders and Is Correlated with Risk to Depression
AU - Kiewa, Jacqueline
AU - Mortlock, Sally
AU - Meltzer-Brody, Samantha
AU - Middeldorp, Christel
AU - Wray, Naomi R.
AU - Byrne, Enda M.
N1 - Funding Information: This work was funded by NHMRC grant 1145645 and generously supported by a donation from the Axelsen family. J.K. has been supported by a UQ Research Training Program scholarship, and E.M.B. received funding from the NHMRC Centre for Research Excellence (APP1198304). S.M.B. receives sponsored research grants from Sage Therapeutics. Publisher Copyright: © 2023 S. Karger AG. All rights reserved.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Introduction: Sex steroid hormone fluctuations may underlie both reproductive disorders and sex differences in lifetime depression prevalence. Previous studies report high comorbidity among reproductive disorders and between reproductive disorders and depression. This study sought to assess the multivariate genetic architecture of reproductive disorders and their loading onto a common genetic factor and investigated whether this latent factor shares a common genetic architecture with female depression, including perinatal depression (PND). Method: Using UK Biobank and FinnGen data, genome-wide association meta-analyses were conducted for nine reproductive disorders, and genetic correlation between disorders was estimated. Genomic Structural Equation Modelling identified a latent genetic factor underlying disorders, accounting for their significant genetic correlations. SNPs significantly associated with both latent factor and depression were identified. Results: Excellent model fit existed between a latent factor underlying five reproductive disorders (χ2 (5) = 6.4; AIC = 26.4; CFI = 1.00; SRMR = 0.03) with high standardised loadings for menorrhagia (0.96, SE = 0.05); ovarian cysts (0.94, SE = 0.05); endometriosis (0.83, SE = 0.05); menopausal symptoms (0.77, SE = 0.10); and uterine fibroids (0.65, SE = 0.05). This latent factor was genetically correlated with PND (rG = 0.37, SE = 0.15, p = 1.4e-03), depression in females only (rG = 0.48, SE = 0.06, p = 7.2e-11), and depression in both males and females (MD) (rG = 0.35, SE = 0.03, p = 1.8e-30), with its top locus associated with FSHB/ARL14EP (rs11031006; p = 9.1e-33). SNPs intronic to ESR1, significantly associated with the latent factor, were also associated with PND, female depression, and MD. Conclusion: A common genetic factor, correlated with depression, underlies risk of reproductive disorders, with implications for aetiology and treatment. Genetic variation in ESR1 is associated with reproductive disorders and depression, highlighting the importance of oestrogen signalling for both reproductive and mental health.
AB - Introduction: Sex steroid hormone fluctuations may underlie both reproductive disorders and sex differences in lifetime depression prevalence. Previous studies report high comorbidity among reproductive disorders and between reproductive disorders and depression. This study sought to assess the multivariate genetic architecture of reproductive disorders and their loading onto a common genetic factor and investigated whether this latent factor shares a common genetic architecture with female depression, including perinatal depression (PND). Method: Using UK Biobank and FinnGen data, genome-wide association meta-analyses were conducted for nine reproductive disorders, and genetic correlation between disorders was estimated. Genomic Structural Equation Modelling identified a latent genetic factor underlying disorders, accounting for their significant genetic correlations. SNPs significantly associated with both latent factor and depression were identified. Results: Excellent model fit existed between a latent factor underlying five reproductive disorders (χ2 (5) = 6.4; AIC = 26.4; CFI = 1.00; SRMR = 0.03) with high standardised loadings for menorrhagia (0.96, SE = 0.05); ovarian cysts (0.94, SE = 0.05); endometriosis (0.83, SE = 0.05); menopausal symptoms (0.77, SE = 0.10); and uterine fibroids (0.65, SE = 0.05). This latent factor was genetically correlated with PND (rG = 0.37, SE = 0.15, p = 1.4e-03), depression in females only (rG = 0.48, SE = 0.06, p = 7.2e-11), and depression in both males and females (MD) (rG = 0.35, SE = 0.03, p = 1.8e-30), with its top locus associated with FSHB/ARL14EP (rs11031006; p = 9.1e-33). SNPs intronic to ESR1, significantly associated with the latent factor, were also associated with PND, female depression, and MD. Conclusion: A common genetic factor, correlated with depression, underlies risk of reproductive disorders, with implications for aetiology and treatment. Genetic variation in ESR1 is associated with reproductive disorders and depression, highlighting the importance of oestrogen signalling for both reproductive and mental health.
KW - Depression
KW - FSHB
KW - Genetics
KW - Oestrogen
KW - Reproductive disorders
KW - Sex difference
UR - http://www.scopus.com/inward/record.url?scp=85175001134&partnerID=8YFLogxK
U2 - https://doi.org/10.1159/000533413
DO - https://doi.org/10.1159/000533413
M3 - Article
C2 - 37544299
SN - 0028-3835
VL - 113
SP - 1059
EP - 1075
JO - Neuroendocrinology
JF - Neuroendocrinology
IS - 10
ER -