The genetic relationship between female reproductive traits and six psychiatric disorders

Ni, Guiyan; Amare, Azmeraw T; Zhou, Xuan; Mills, Natalie; Gratten, Jacob; Lee, Sang

doi:10.1101/433946

Cited by 4 publications

(7 citation statements)

References 52 publications

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“…We substantiate the genetic correlation between reproductive factors shown in previous studies, while showing additional correlations that have not been previously investigated. (57,58) Our study supports evidence for a positive causal link between AAM and age at menopause, (11)(12)(13)(14)(15)(16)59,60) and opposes previous studies that have shown the inverse association, (17,18) or no association. (19)(20)(21)(22)(23)(24) Furthermore our findings support one study that found little evidence for an association between AAM and parity.…”

Section: Discussionsupporting

confidence: 75%

The relationships between women’s reproductive factors: a Mendelian randomization analysis

Prince

Sharp²,

Howe³

et al. 2021

Preprint

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Background: Women's reproductive factors include their age at menarche and menopause, the age at which they start and stop having children, and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors. Methods: We used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age at first sex and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomization (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap. Results: LDSC indicated that most reproductive factors are genetically correlated (rg range: |0.06 - 0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (rg < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (Beta (B)=0.09 SD, 95% confidence intervals (CI)=0.06,0.11), age at first birth (B=0.07 SD, CI=0.04,0.10), age at last birth (B=0.06 SD, CI=0.04,0.09) and age at menopause (B=0.06 SD, CI=0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B=0.21 SD, CI=0.13,0.29), age at last birth (B=0.72 SD, CI=0.67,0.77) and a lower number of births (B=-0.38 SD, CI=-0.44,-0.32). Conclusion: This study presents evidence that women's reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman's entire reproductive history, including the causal interplay between reproductive factors.

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Section: Discussionsupporting

confidence: 75%

The relationships between women’s reproductive factors: a Mendelian randomization analysis

Prince

Sharp²,

Howe³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Childhood adiposity may confound the relationships between reproductive factors that we identify since adiposity is genetically correlated with age at menarche [63], and age at menarche is genetically correlated with other reproductive factors [64,65]. To investigate this, we performed multivariable MR (MVMR) using the "MVMR" R package, adjusting for childhood body size from UK Biobank [66].…”

Section: Evaluating the Role Of Adipositymentioning

confidence: 99%

The relationships between women’s reproductive factors: a Mendelian randomisation analysis

Prince

Sharp

Howe

et al. 2022

BMC Med

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Background Women’s reproductive factors include their age at menarche and menopause, the age at which they start and stop having children and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors. Methods We used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomisation (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap. Results LDSC indicated that most reproductive factors are genetically correlated (rg range: |0.06–0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (rg < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (beta (B) = 0.09 SD, 95% confidence intervals (CI) = 0.06,0.11), age at first birth (B = 0.07 SD, CI = 0.04,0.10), age at last birth (B = 0.06 SD, CI = 0.04,0.09) and age at menopause (B = 0.06 SD, CI = 0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B = 0.21 SD, CI = 0.13,0.29), age at last birth (B = 0.72 SD, CI = 0.67, 0.77) and a lower number of births (B = −0.38 SD, CI = −0.44, −0.32). Conclusion This study presents evidence that women’s reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman’s entire reproductive history, including the causal interplay between reproductive factors.

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“…et al, 2018aDuncan L.E. et al, , 2018bFrei et al, 2019;Gibson et al, 2017;Grotzinger et al, 2019;Hammerschlag et al, 2017;Hill et al, 2016;Hofer et al, 2020;Hubbard et al, 2016;Hübel et al, 2019;Ikeda et al, 2019;Masashi Ikeda et al, 2018;Jang et al, 2020;Jansen et al, 2019;Kafle et al, 2020;Khramtsova et al, 2019;Lam et al, 2019;Lane et al, 2017;Lee et al, 2019;Levey et al, 2020;Li et al, 2021;Lind et al, 2020;Lo et al, 2017; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (Corporate Collaborator) et al, 2015;Marees et al, 2021Marees et al, , 2020Meier et al, 2019;Meng et al, 2020;Milaneschi et al, 2017;Mullins et al, 2021;Ni et al, 2019;Nudel et al, 2019;Ohi et al, 2020aOhi et al, , 2020bPasman et al, 2018;Peterson et al, 2018;Polimanti et al, 2018;Purves et al, 2020;Roelfs et al, 2021;Ruderfer et al, 2020;Savage et al, 2018;…”

Section: Resultsunclassified

A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders

Wang

Alda

Trappenberg

et al. 2021

Psychiatric Genetics

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An improved understanding of genetic etiological heterogeneity in a psychiatric condition may help us (a) isolate a neurophysiological 'final common pathway' by identifying its upstream genetic origins and (b) facilitate characterization of the condition's phenotypic variation. This review aims to identify existing genetic heterogeneity measurements in the psychiatric literature and provides a conceptual review of their mechanisms, limitations, and assumptions. The Scopus database was searched for studies that quantified genetic heterogeneity or correlation of psychiatric phenotypes with human genetic data. Ninety studies were included. Eighty-seven reports quantified genetic correlation, five applied genomic structural equation modelling, three evaluated departure from the Hardy-Weinberg equilibrium at one or more loci, and two applied a novel approach known as MiXeR. We found no study that rigorously measured genetic etiological heterogeneity across a large number of markers. Developing such approaches may help better characterize the biological diversity of psychopathology.

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The genetic relationship between female reproductive traits and six psychiatric disorders

Cited by 4 publications

References 52 publications

The relationships between women’s reproductive factors: a Mendelian randomization analysis

The relationships between women’s reproductive factors: a Mendelian randomization analysis

The relationships between women’s reproductive factors: a Mendelian randomisation analysis

A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders

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