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Schizophrenia risk and reproductive success: a Mendelian randomization study.

ABSTRACT: Schizophrenia is a debilitating and heritable mental disorder associated with lower reproductive success. However, the prevalence of schizophrenia is stable over populations and time, resulting in an evolutionary puzzle: how is schizophrenia maintained in the population, given its apparent fitness costs? One possibility is that increased genetic liability for schizophrenia, in the absence of the disorder itself, may confer some reproductive advantage. We assessed the correlation and causal effect of genetic liability for schizophrenia with number of children, age at first birth and number of sexual partners using data from the Psychiatric Genomics Consortium and UK Biobank. Linkage disequilibrium score regression showed little evidence of genetic correlation between genetic liability for schizophrenia and number of children (r g = 0.002, p = 0.84), age at first birth (r g = -0.007, p = 0.45) or number of sexual partners (r g = 0.007, p = 0.42). Mendelian randomization indicated no robust evidence of a causal effect of genetic liability for schizophrenia on number of children (mean difference: 0.003 increase in number of children per doubling in the natural log odds ratio of schizophrenia risk, 95% confidence interval (CI): -0.003 to 0.009, p = 0.39) or age at first birth (-0.004 years lower age at first birth, 95% CI: -0.043 to 0.034, p = 0.82). We find some evidence of a positive effect of genetic liability for schizophrenia on number of sexual partners (0.165 increase in the number of sexual partners, 95% CI: 0.117-0.212, p = 5.30×10-10). These results suggest that increased genetic liability for schizophrenia does not confer a fitness advantage but does increase mating success.

SUBMITTER: Lawn RB

PROVIDER: S-EPMC6458425 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Schizophrenia risk and reproductive success: a Mendelian randomization study.

Lawn Rebecca B RB Sallis Hannah M HM Taylor Amy E AE Wootton Robyn E RE Smith George Davey GD Davies Neil M NM Hemani Gibran G Fraser Abigail A Penton-Voak Ian S IS Munafò Marcus R MR

Royal Society open science 20190306 3

Schizophrenia is a debilitating and heritable mental disorder associated with lower reproductive success. However, the prevalence of schizophrenia is stable over populations and time, resulting in an evolutionary puzzle: how is schizophrenia maintained in the population, given its apparent fitness costs? One possibility is that increased genetic liability for schizophrenia, in the absence of the disorder itself, may confer some reproductive advantage. We assessed the correlation and causal effec ...[more]

PMID: 31031992

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Project description:ImportancePositive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias, such as reverse causation and residual confounding, thus limiting our understanding of the effect (if any) of inflammatory biomarkers on schizophrenia risk.ObjectiveTo evaluate whether inflammatory biomarkers have an effect on the risk of developing schizophrenia.Design, setting, and participantsTwo-sample mendelian randomization study using genetic variants associated with inflammatory biomarkers as instrumental variables to improve inference. Summary association results from large consortia of candidate gene or genome-wide association studies, including several epidemiologic studies with different designs, were used. Gene-inflammatory biomarker associations were estimated in pooled samples ranging from 1645 to more than 80 000 individuals, while gene-schizophrenia associations were estimated in more than 30 000 cases and more than 45 000 ancestry-matched controls. In most studies included in the consortia, participants were of European ancestry, and the prevalence of men was approximately 50%. All studies were conducted in adults, with a wide age range (18 to 80 years).ExposuresGenetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R).Main outcomes and measuresRisk of developing schizophrenia. Individuals with schizophrenia or schizoaffective disorders were included as cases. Given that many studies contributed to the analyses, different diagnostic procedures were used.ResultsThe pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (random effects 95% CI, 0.84-0.97; P = .005) per 2-fold increment in CRP levels; consistent results were obtained using different mendelian randomization methods and a more conservative set of instruments. The odds ratio for sIL-6R was 1.06 (95% CI, 1.01-1.12; P = .02) per 2-fold increment. Estimates for IL-1Ra were inconsistent among instruments, and pooled estimates were imprecise and centered on the null.Conclusions and relevanceUnder mendelian randomization assumptions, our findings suggest a protective effect of CRP and a risk-increasing effect of sIL-6R (potentially mediated at least in part by CRP) on schizophrenia risk. It is possible that such effects are a result of increased susceptibility to early life infection.

Project description:Background: Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect. Aims: To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and vice versa using bi-directional two-sample Mendelian randomization (MR) analysis. Methods: We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS (n = 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10-8). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods. Results: In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001-0.024 SD; p = 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002-0.025 SD; p = 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis. Discussion: Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis.

Project description:BackgroundComplex immune-brain interactions that affect neural development, survival and function might have causal and therapeutic implications for psychiatric illnesses. However, previous studies examining the association between immune inflammation and schizophrenia (SCZ) have yielded inconsistent findings.MethodsComprehensive two-sample Mendelian randomization (MR) analysis was performed to determine the causal association between immune cell signatures and SCZ in this study. Based on publicly available genetic data, we explored causal associations between 731 immune cell signatures and SCZ risk. A total of four types of immune signatures (median fluorescence intensities (MFI), relative cell (RC), absolute cell (AC), and morphological parameters (MP)) were included. Comprehensive sensitivity analyses were used to verify the robustness, heterogeneity, and horizontal pleiotropy of the results.ResultsAfter FDR correction, SCZ had no statistically significant effect on immunophenotypes. It was worth mentioning some phenotypes with unadjusted low P-values, including FSC-A on NKT (β = 0.119, 95% CI = 0.044 ~ 0.194, P = 0.002), DN (CD4-CD8-) NKT %T cell (β = 0.131, 95% CI = 0.054 ~ 0.208, P = 9.03 × 10- 4), and SSC-A on lymphocytes (β = 0.136, 95% CI = 0.059 ~ 0.213, P = 5.43 × 10- 4). The causal effect of SCZ IgD on transitional was estimated to 0.127 (95% CI = 0.051 ~ 0.203, P = 1.09 × 10- 3). SCZ also had a causal effect on IgD+ %B cell (β = 0.130, 95% CI = 0.054 ~ 0.207, P = 8.69 × 10- 4), and DP (CD4+CD8+) %T cell (β = 0.131, 95% CI = 0.054 ~ 0.207, P = 8.05 × 10- 4). Furthermore, four immunophenotypes were identified to be significantly associated with SCZ risk: naive CD4+ %T cell (OR = 0.986, 95% CI = 0.979 ~ 0.992, P = 1.37 × 10- 5), HLA DR on CD14- CD16- (OR = 0.738 (95% CI = 0.642 ~ 0.849, P = 2.00 × 10- 5), CD33dim HLA DR+ CD11b- AC (OR = 0.631, 95% CI = 0.529 ~ 0.753, P = 3.40 × 10- 7) and activated & resting Treg % CD4 Treg (OR = 0.937, 95% CI = 0.906 ~ 0.970, P = 1.96 × 10- 4).ConclusionsOur study has demonstrated the close connection between immune cells and SCZ by genetic means, thus providing guidance for future clinical research.

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Schizophrenia risk and reproductive success: a Mendelian randomization study.

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Schizophrenia risk and reproductive success: a Mendelian randomization study.

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