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

Abstract

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.

Temporally ordered associations between type 2 diabetes and brain disorders – a Danish register-based cohort study

“…This may suggest that shared risk factors are at play. Indeed, recent data-driven genome-wide approaches indicate that T2DM and most of the psychiatric disorders share genetic risk factors [42]. Still, for several of the disorders, estimated effects were of different size in the two temporally ordered analyses, which could be explained by specific disease-related risk factors influencing the association in the one direction.…”

“…Studies have also found associations between T2DM and disorders of the brain, including vascular dementia and Alzheimer's disease [10], substance use disorder, schizophrenia, bipolar disorder, depression, personality disorder, and attention-deficit/ hyperactivity disorder (ADHD) [11][12][13][14][15][16][17], obsessive-compulsive disorder (OCD) [18], cognitive impairment [19], and also of filling a prescription for psychotropic drugs, including antidepressants, antipsychotics, and anxiolytics [20]. Recently, the term "insulinopathies of the brain" has been suggested to characterize these associations between T2DM and brain disorders [21,22]. It should be noted that from here and onwards we use the term brain disorder when referring to a broad range of specific psychiatric and neurological disorders, although late-onset neurodegenerative disorders were not assessed in the present study.…”

Abnormal functional connectivity of the frontostriatal circuits in type 2 diabetes mellitus

“…Type 2 diabetes mellitus (T2DM) is a metabolic disease with an increasing incidence worldwide (Lees et al, 2009;Bobbert et al, 2013). This disease constitutes a risk factor associated with an increased incidence of cognitive dysfunctions and emotional disorders [e.g., Parkinson's disease (PD), Alzheimer's disease (AD), obsessive-compulsive disorder (OCD), and major depressive disorder (MDD)] (den Braber et al, 2010;Pan et al, 2010;Zhang et al, 2013;Ashraghi et al, 2016;Athauda and Foltynie, 2016;De Pablo-Fernandez et al, 2018;Cheong et al, 2020;Wei et al, 2020;Sánchez-Gómez et al, 2021;Fanelli et al, 2022). However, the specific neural substrate of T2DM-related cognitive impairment and emotional disorders remains unclear.…”

Treatment Resistance in Schizophrenia Is Associated with Attention Deficit/Hyperactivity Disorder and Gut Microbiota: A Genetic Correlation and Mendelian Randomization Study

“…The genetic correlation was relatively moderate between schizophrenia and attention deficit/ hyperactivity disorder (ADHD) [13]. Stratified analyses showed negative genetic covariances between schizophrenia and somatic insulinopathies through gene sets related to insulin signaling and insulin receptor recycling [14]. Strongest associations were confirmed between type 2 diabetes mellitus and schizophrenia spectrum disorder [15].…”