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There are substantial sex-differences in the prevalence of psychiatric disorders; autism, substance use and ADHD are more common in males, whereas eating disorders, depression and anxiety are more common in females [1,2,3,4,5,6]. Current diagnostics and prevention and treatment practices are generally uniform and do not take into account effects of biological sex or of gender norms on disease etiology, symptomatology, or disease course. In this project we will advance understanding of sex bias in psychiatric disorders and substance use. We will do so by re-analyzing existing large-scale epidemiological, genetic, epigenetic, and gene expression data which have not yet been systematically analyzed for sex-differences.

Our first aim is estimate sex- and gender-differences in the causes and presentation of psychiatric disease and substance use, as well as their comorbidity. Not all sex-differences in psychiatric traits will manifest as differences in prevalence; the presentation of symptoms may be sex-specific, and risk factors, disease progression and co-morbidities may be different between sexes. To determine influences of gender on disease etiology, we will examine how risk factors related to labor market participation and family situation influence psychopathology differently in males and females. To clarify the role of hormones in psychopathology, we will for females further differentiate between pre- and post-menopausal women, and users and non-users of hormonal contraception. We will consider heterogeneity within and co-morbidity between psychiatric disorders at the disorder and symptom level. We will use existing “population scale” epidemiological datasets (N>650,000) with extensive data on gender roles within and outside the home environment, psychiatric symptoms and diagnoses and co-morbid somatic outcomes. To generalize our findings to the Dutch population, we will collect data on psychiatric diagnosis and symptomatology, gender identity, and gender-norm variables in a Dutch population-based sample and select Dutch psychiatric and gender disorder patient populations. Findings from this project can be translated to clinical practice by enabling the development of sex- and gender-differentiated diagnostic criteria and guidance on sex- and gender-differentiated disease course and comorbid risks.

Our second aim is to identify genetic causes of sex-differences in psychiatric disease. From prior research we know that the heritability of psychiatric diseases is between 40% and 80%, implying genes play an important role in disease etiology. There is mixed evidence of genetic differences between male and female disease etiology (e.g. it is unclear whether the same sets of genes underlie disease vulnerability in both sexes). We will use large existing datasets with genome-wide genetic data and clinical data to determine whether gene effects on disease vulnerability differ between sexes by computing the between-sex genetic correlation. For psychiatric traits for which we find a genetic correlation between sexes below 1.0 (i.e. evidence for sex-differences in the genetic etiology of disease), we take forward the result of the sex stratified genome-wide association analyses to identify genes that underlie disease vulnerability in one sex but less so in the other. We systematically determine for all know genetic effects on psychiatric traits whether there is evidence for a sex difference.

Our third aim is to use large existing datasets and advanced methodology to identify sex- and gender-specific gene expression and epigenetic mechanisms in the brain, and relate these to sex-differences in psychiatric disease. Gene expression refers to the actual transcription of, and biological availability in a tissue of, a specific gene. Epigenetic regulation involves biomechanical modifications of the DNA strand (though not sequence) which can change after birth due to biological and environmental influences. Both gene expression and epigenetics can be influenced by biological sex-differences, but could also be caused by effects of gender norms (for example gender differences in alcohol or tobacco use). The results of this subproject will provide essential insight in the biological mechanisms of sex-differences in the brain. These differences in the male and female brain can be related to (psychiatric) disease etiology, and provide important genetic and biological targets for subsequent functional and translational research. Our findings will advance knowledge of causes and manifestation of sex-differences in gene expression and regulation in the brain, specifically for genes related to psychiatric disease.

Our fourth aim is to inform patients, clinicians, and policy makers who may benefit from our findings. Findings may improve mental health care, as knowledge on the differences in disease severity and presentation can be directly used to improve disease detection, intervention and prevention, for both males and females.

 

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