Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

Adams, Danielle M.; Geaghan, Michael P; Cairns, Murray J.

doi:10.1101/2020.03.09.984690

Cited by 3 publications

(2 citation statements)

References 86 publications

(75 reference statements)

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“…Exploring further the genetic links between these neuropsychiatric disorders and glycaemic traits linked to insulin resistance, we revealed a novel positive correlation between ADHD and FPG, as well as negative bivariate correlations between AN and both FPI and HOMA-IR that replicate and update previous findings [29,46]. A Mendelian randomisation study had also previously shown that higher levels of FPI have a causal effect in reducing the risk of AN [51].…”

Section: Table 2 Genetic Correlation Table Reporting the Detailed Res...supporting

confidence: 84%

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

et al. 2022

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The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer’s disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain “insulinopathies” were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (rg = −0.315, p = 3.9 × 10−8), OCD and obesity (rg = −0.379, p = 3.4 × 10−5), and OCD and T2DM (rg = −0.172, p = 3 × 10−4). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 × 10−4). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 × 10−4). Overall, our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on “insulinopathies” of the brain.

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Section: Table 2 Genetic Correlation Table Reporting the Detailed Res...supporting

confidence: 84%

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Exploring further the genetic links between these neuropsychiatric disorders and glycaemic traits linked to insulin resistance, we revealed a novel positive correlation between ADHD and FGlu, as well as negative bivariate correlations between AN and both FIns and HOMA-IR that replicate and update previous findings (32, 42). A Mendelian randomisation study had also previously shown that higher levels of FIns have a causal effect in reducing the risk of AN (47).…”

Section: Discussionmentioning

confidence: 91%

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

Fanelli

Franke

Witte

et al. 2021

Preprint

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The prevalence of Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) is higher among patients with somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie these observed comorbidities. We investigated genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise genetic correlations using the summary statistics of the largest available genome-wide association studies for these diseases. Stratified covariance analyses were performed to investigate the contribution of insulin-related gene-sets. Having tested these hypotheses, novel brain "insulinopathies" were explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Significant genetic correlations were found between OCD and MetS (rg=-0.315, p=3.9e-8), OCD and obesity (rg=-0.379, p=3.4e-5), and OCD and T2DM (rg=-0.172, p=3e-4). Stratified analyses showed negative genetic covariances between ASD and MetS/T2DM through gene-sets comprising insulin signalling and/or insulin processing genes, and between AD/OCD and MetS/T2DM through an insulin receptor recycling gene-set (p<6.17e-4). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa, attention-deficit/hyperactivity disorder, major depression, and schizophrenia (p<6.17e-4). Our findings suggest the existence of two clusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases and traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain, which may support the development of more effective/tolerated treatment strategies for neuropsychiatric disorders.

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Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders

Penner-Goeke

Bothe

Kappelmann

et al. 2022

Preprint

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Exposure to stressful events increases risk for psychiatric disorders. Mechanistic insight into genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3662 SNPs from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these variants were enriched for those differentially expressed in psychiatric disorders in postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neuro-behavioral traits, including psychiatric disorders. Finally, functional gene scores derived from these variants were significantly associated with differences in physiological stress measures, suggesting that these may alter disease risk by moderating the individual set point of the stress response.

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Investigating the effect of glycaemic traits on the risk of psychiatric illness using Mendelian randomisation

Cited by 3 publications

References 86 publications

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

Insulinopathies of the brain? Genetic overlap between somatic insulin-related and neuropsychiatric disorders

Assessment of glucocorticoid-induced enhancer activity of eSNP regions using STARR-seq reveals novel molecular mechanisms in psychiatric disorders

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