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Complement genes contribute sex-biased vulnerability in diverse disorders.

ABSTRACT: Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

SUBMITTER: Kamitaki N

PROVIDER: S-EPMC7319891 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Complement genes contribute sex-biased vulnerability in diverse disorders.

Kamitaki Nolan N Sekar Aswin A Handsaker Robert E RE de Rivera Heather H Tooley Katherine K Morris David L DL Taylor Kimberly E KE Whelan Christopher W CW Tombleson Philip P Loohuis Loes M Olde LMO Boehnke Michael M Kimberly Robert P RP Kaufman Kenneth M KM Harley John B JB Langefeld Carl D CD Seidman Christine E CE Pato Michele T MT Pato Carlos N CN Ophoff Roel A RA Graham Robert R RR Criswell Lindsey A LA Vyse Timothy J TJ McCarroll Steven A SA

Nature 20200511 7813

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men<sup>1</sup>, whereas schizophrenia affects men with greater frequency and severity relative to women<sup>2</sup>. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE ...[more]

PMID: 32499649

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Project description:Humans exhibit sex differences in the prevalence and presentation of many psychiatric and neurodevelopmental conditions, including Alzheimer’s disease, autism spectrum disorder (ASD), and schizophrenia; however, the ‘omic’, developmental, and environmental underpinnings of these conditions remain elusive. To illuminate these mechanisms and their interactions, and to identify potential therapies, we need large, sex-specific neurobiological data sets from model organisms whose brains exhibit similar characteristics to those of humans, including comparable sex differences. Among existing models, the rhesus macaque is likely to have the greatest translatability; however, comprehensive analyses of brain sex differences in this species are necessary to demonstrate their relevance to sex-biased human conditions. We present an in-depth investigation of sex differences in the rhesus macaque brain transcriptome (RNA-seq) across 527 samples of 15 regions from 36 free-ranging adult individuals (20F/16M), representing the largest collection of bulk brain gene expression data for this species. We identified hundreds of sex-biased genes throughout the rhesus macaque brain, most of which were shared across regions, suggesting convergent regulatory mechanisms. Similar to studies of human brains, these sex-biased genes are regulated by sex hormones and transcription factors that interact with these hormones, male-biased genes are associated with multiple sex-biased human neurological conditions (e.g., ASD, schizophrenia) and energy metabolism, and female-biased genes are associated with the immune response. We also accurately predicted sex from a relatively small number of genes per region and found that, among genes reported to escape X chromosome inactivation in humans, similar genes are the most predictive of sex both across human tissues and in this dataset. Finally, we demonstrated that sex-biased genes exhibit characteristics that facilitate rapid evolution, including a tendency to be located on the sex chromosomes, more tissue-specific expression, and higher genetic variance for expression. Overall, these findings suggest that the rhesus macaque may be an appropriate model for sex-biased human neurological conditions.

Project description:BackgroundStudies on major depressive and anxiety disorders suggest dysfunctions in brain corticolimbic circuits, including altered gamma-aminobutyric acid (GABA) and modulatory (serotonin and dopamine) neurotransmission. Interestingly, sexual dimorphisms in GABA, serotonin, and dopamine systems are also reported. Understanding the mechanisms behind these sexual dimorphisms may help unravel the biological bases of the heightened female vulnerability to mood disorders. Here, we investigate the contribution of sex-related factors (sex chromosome complement, developmental gonadal sex, or adult circulating hormones) to frontal cortex expression of selected GABA-, serotonin-, and dopamine-related genes.MethodsAs gonadal sex is determined by sex chromosome complement, the role of sex chromosomes cannot be investigated individually in humans. Therefore, we used the Four Core Genotypes (FCG) mouse model, in which sex chromosome complement and gonadal sex are artificially decoupled, to examine the expression of 13 GABA-related genes, 6 serotonin- and dopamine-related genes, and 8 associated signal transduction genes under chronic stress conditions. Results were analyzed by three-way ANOVA (sex chromosome complement?×?gonadal sex?×?circulating testosterone). A global perspective of gene expression changes was provided by heatmap representation and gene co-expression networks to identify patterns of transcriptional activities related to each main factor.ResultsWe show that under chronic stress conditions, sex chromosome complement influenced GABA/serotonin/dopamine-related gene expression in the frontal cortex, with XY mice consistently having lower gene expression compared to XX mice. Gonadal sex and circulating testosterone exhibited less pronounced, more complex, and variable control over gene expression. Across factors, male conditions were associated with a tightly co-expressed set of signal transduction genes.ConclusionsUnder chronic stress conditions, sex-related factors differentially influence expression of genes linked to mood regulation in the frontal cortex. The main factor influencing expression of GABA-, serotonin-, and dopamine-related genes was sex chromosome complement, with an unexpected pro-disease effect in XY mice relative to XX mice. This effect was partially opposed by gonadal sex and circulating testosterone, although all three factors influenced signal transduction pathways in males. Since GABA, serotonin, and dopamine changes are also observed in other psychiatric and neurodegenerative disorders, these findings have broader implications for the understanding of sexual dimorphism in adult psychopathology.

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Complement genes contribute sex-biased vulnerability in diverse disorders.

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Complement genes contribute sex-biased vulnerability in diverse disorders.

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