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.