Exploring shared genetic bases and causal relationships of schizophrenia and bipolar disorder with 28 cardiovascular and metabolic traits

So, Hon‐Cheong; Chau, K. L.; Ao, Fu‐Kiu; Mo, Cheuk‐Hei; Sham, Pak-Chung

doi:10.1017/s0033291718001812

Cited by 59 publications

(78 citation statements)

References 99 publications

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“…In light of the observed association between PRS and binge eating, often associated with greater BMI, our finding that schizophrenia PRS predict lower BMI is difficult to interpret. This association, however, has been previously observed, 35 and is in line with findings of genetic studies showing an inverse correlation between schizophrenia and BMI, 8 and with those of epidemiological investigations showing that low BMI is a risk factor for schizophrenia. 9 The pathophysiological mechanisms underpinning the association between genetic liability for schizophrenia and low BMI are unclear, particularly as clinically, overweight and obesity are more frequently observed in individuals with psychotic illnesses.…”

Section: Comparisons With Previous Literature and Interpretation Of Tsupporting

confidence: 91%

Polygenic risk for schizophrenia, disordered eating behaviours and body mass index in adolescents

et al. 2019

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BackgroundRecent studies suggest psychotic and eating disorders can be comorbid and could have shared genetic liability. However, this comorbidity has been overlooked in the epidemiological literature. AimsTo test whether polygenic risk scores (PRS) for schizophrenia are associated with disordered eating behaviours and body mass index (BMI) in the general population. MethodUsing data from the Avon Longitudinal Study of Parents and Children and random-effects logistic and linear regression models, we investigated the association between PRS for schizophrenia and self-reported disordered eating behaviours (binge eating, purging, fasting and excessive exercise) and BMI at 14, 16 and 18 years. ResultsOf the 6920 children with available genetic data, 4473 (64.6%) and 5069 (73.3%) had at least one disordered eating and one BMI outcome measurement, respectively. An s.d. increase in PRS was associated with greater odds of having binge eating behaviours (odds ratio, 1.36; 95% CI 1.16-1.60) and lower BMI (coefficient, −0.03; 95% CI, −0.06 to −0.01). ConclusionsOur findings suggest the presence of shared genetic risk between schizophrenia and binge eating behaviours. Intermediate phenotypes such as impaired social cognition and irritability, previously shown to be positively correlated in this sample with schizophrenia PRS, could represent risk factors for both phenotypes. Shared genetic liability between binge eating and schizophrenia could also explain higher rates of metabolic syndrome in individuals with schizophrenia, as binge eating could be a mediator of this association in drug-naïve individuals. The finding of an association between greater PRS and lower BMI, although consistent with existing epidemiological and genetic literature, requires further investigation. Declaration of interestNone.

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Section: Comparisons With Previous Literature and Interpretation Of Tsupporting

confidence: 91%

Polygenic risk for schizophrenia, disordered eating behaviours and body mass index in adolescents

et al. 2019

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“…However, only one pathway (MAPK-TRK pathway) shared between SCZ and BMI, and two pathways including growth hormone signaling and regulation of insulin secretion signaling shared between SCZ and T2D were confirmed by MAGMA ( Table 2, Supplementary Table S12). Among the three pathways, regulation of insulin secretion signaling was previously reported to be associated with the comorbidity of SCZ and CMD (8). The other pathways can be considered as novel.…”

Section: Common Pathway Identified For the Comorbidity Of Scz And Cmdmentioning

confidence: 99%

“…Historically, the high prevalence of CMD among schizophrenic patients has been primarily attributed to unhealthy lifestyle factors and the side effects of antipsychotic medications (5). However, recent evidences have suggested that genetic basis and common biological pathways shared between SCZ and CMD (6)(7)(8). For example, Andreassen et al using genetic-pleiotropy-informed methods detected 10 loci associated with both SCZ and CVD risk factors, which include waist-to-hip ratio, systolic blood pressure, BMI, LDL, HDL, and TG (6).…”

Section: Introductionmentioning

confidence: 99%

“…For example, Andreassen et al using genetic-pleiotropy-informed methods detected 10 loci associated with both SCZ and CVD risk factors, which include waist-to-hip ratio, systolic blood pressure, BMI, LDL, HDL, and TG (6). So et al performed polygenic risk scores, linkage disequilibrium score regression, and Mendelian randomization analysis and showed that genetic basis shared between SCZ and BMI, the causal relationship between SCZ and TG, and common biological pathways (e.g., aldosterone synthesis and secretion, neuronal system, and insulin secretion) shared between SCZ and CMD (8). These evidences provide the foundation for the genetic factors contribute to the comorbidity of SCZ and CMD.…”

Section: Introductionmentioning

confidence: 99%

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Integrated Analysis of Summary Statistics to Identify Pleiotropic Genes and Pathways for the Comorbidity of Schizophrenia and Cardiometabolic Disease

et al. 2020

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Genome-wide association studies (GWAS) have identified abundant risk loci associated with schizophrenia (SCZ), cardiometabolic disease (CMD) including body mass index, coronary artery diseases, type 2 diabetes, low-and high-density lipoprotein, total cholesterol, and triglycerides. Although recent studies have suggested that genetic risk shared between these disorders, the pleiotropic genes and biological pathways shared between them are still vague. Here we integrated comprehensive multi-dimensional data from GWAS, expression quantitative trait loci (eQTL), and gene set database to systematically identify potential pleiotropic genes and biological pathways shared between SCZ and CMD. By integrating the results from different approaches including FUMA, Sherlock, SMR, UTMOST, FOCUS, and DEPICT, we revealed 21 pleiotropic genes that are likely to be shared between SCZ and CMD. These genes include VRK2,

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“…This is somewhat surprising given the known phenotypic correlation between schizophrenia and obesity 41 . Nonetheless, three prior reports found significant inverse genetic correlations between body mass index and schizophrenia [42][43][44] , while a fourth reported an inverse, but non-significant relationship 45 . This may suggest that increased rates of obesity among patients with schizophrenia may be a consequence of the disease, potentially due to antipsychotic use or poor support for proper nutrition.…”

Section: Discussionmentioning

confidence: 87%

Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four healthcare systems

Zheutlin

Dennis

Restrepo³

et al. 2018

Preprint

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OBJECTIVE: Individuals at high risk for schizophrenia may benefit from early intervention but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts, but its utility in clinical settings remains largely unexplored. Moreover, the broad health consequences of a high genetic risk of schizophrenia are poorly understood, despite being relevant to treatment decisions. METHOD:We used electronic health records for 106,160 patients from four healthcare systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites.RESULTS: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS=1.55 [95% confidence interval (CI), 1.4-1.7], p=4.48 x 10 -16 ) and patients in the highest risk decile of the PRS distribution had up to 4.6-fold increased odds of schizophrenia compared to those in the bottom decile (95% CI, 2.9-7.3, p=1.37 x 10 -10 ). PRSs were also positively associated with a range of other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. CONCLUSIONS:We demonstrate that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in healthcare settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. Our results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in healthcare systems.

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Exploring shared genetic bases and causal relationships of schizophrenia and bipolar disorder with 28 cardiovascular and metabolic traits

Abstract: Our findings suggest that SCZ patients may be genetically predisposed to several CM abnormalities independent of medication side effects. On the other hand, CM abnormalities in BD may be more likely to be secondary. However, the findings require further validation.

Cited by 59 publications

References 99 publications

Polygenic risk for schizophrenia, disordered eating behaviours and body mass index in adolescents

Polygenic risk for schizophrenia, disordered eating behaviours and body mass index in adolescents

Integrated Analysis of Summary Statistics to Identify Pleiotropic Genes and Pathways for the Comorbidity of Schizophrenia and Cardiometabolic Disease

Penetrance and pleiotropy of polygenic risk scores for schizophrenia in 106,160 patients across four healthcare systems

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