Common mechanisms for type 2 diabetes and psychosis: Findings from a prospective birth cohort

Abstract

Background Psychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation. Methods Psychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses. Results Genetic predisposition for T2DM was associated with PEs (adjusted OR = 1.21; 95% CI, 1.01–1.45) and psychotic disorder (adjusted OR = 1.51; 95% CI, 1.04–2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR = 1.10; 95% C·I, 0.99–1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP ( p = .040). Conclusions Comorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood.

Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses

“…We identified a trend of positive genetic correlation between schizophrenia and a range of cardiometabolic and inflammation-related traits in the lowest MAF-quartile, though most results did not surpass the a priori determined Bonferroni significance threshold. This trend of results aligns with observational findings, 19 , 20 and also with studies using other methods to examine for genetic overlap between schizophrenia and cardiometabolic traits, eg analyses of GWAS pleiotropy, 40 polygenic risk score analysis, 38 transcriptomic and functional enrichment analysis, 41 and genetic colocalization analysis, 39 all of which reported evidence in support of genetic similarity between schizophrenia and cardiometabolic traits. We also identified a pattern of “cardioprotective” partial correlation in the highest MAF-quartile of schizophrenia with BMI and T2D, in line with whole-genome correlation estimates.…”

“…This finding is inconsistent with observational studies suggesting increased T2DM risk in schizophrenia, 4 , 37 and studies reporting evidence of positive genetic overlap between schizophrenia and T2DM when using other genomic methods. 38–41 The observed partial negative correlation between schizophrenia and BMI could be one explanation for this, since T2DM and BMI are themselves highly genetically correlated. 42 Future research may seek to explore this in more detail.…”

Prenatal and Childhood Immuno-Metabolic Risk Factors for Adult Depression and Psychosis

“…For instance, recent work from ALSPAC has found that genetic predisposition to type 2 diabetes was associated with an increased risk of psychosis at age 18 years, and vice versa; genetic predisposition to schizophrenia was associated with an increased risk of insulin resistance at age 18 years. 4 The study also found that the genotype-phenotype associations were mediated by inflammatory markers measured in childhood. These results indicate the potential for common underlying genetic mechanisms for comorbid psychosis and disrupted glucose-insulin homeostasis, which may involve genetic influences on inflammatory pathways.…”

More must be done to reduce cardiovascular risk for patients on antipsychotic medications

“…On the former, environmental adversity in early life through infection, stressful life events or malnutrition – each known risk factor for psychosis and cardiometabolic disorders – may permanently alter the immune system (Merlot et al ., 2008). On the latter, genetic predisposition to schizophrenia has been shown to associate with decreased cardiac volumes, increased ejection fractions and decreased absolute peak diastolic strain rates (Pillinger et al ., 2023) as well as other cardiometabolic traits including increased BMI (Bahrami et al ., 2020), insulin resistance (Perry et al ., 2022a) and type 2 diabetes (Perry et al ., 2020a).…”