Shared genetic etiology between obsessive-compulsive disorder, obsessive-compulsive symptoms in the population, and insulin signaling

Obsessive-compulsive symptoms (OCS) in the population have been linked to obsessive-compulsive disorder (OCD) in genetic and epidemiological studies. Insulin signaling has been implicated in OCD. We extend previous work by assessing genetic overlap between OCD, population-based OCS, and central nervous system (CNS) and peripheral insulin signaling. We conducted genome-wide association studies (GWASs) in the population-based Philadelphia Neurodevelopmental Cohort (PNC, 650 children and adolescents) of the total OCS score and six OCS factors from an exploratory factor analysis of 22 questions. Subsequently, we performed polygenic risk score (PRS)-based analysis to assess shared genetic etiologies between clinical OCD (using GWAS data from the Psychiatric Genomics Consortium), the total OCS score and OCS factors. We then performed gene-set analyses with a set of OCD-linked genes centered around CNS insulin-regulated synaptic function and PRS-based analyses for five peripheral insulin signaling-related traits. For validation purposes, we explored data from the independent Spit for Science population cohort (5,047 children and adolescents). In the PNC, we found a significant shared genetic etiology between OCD and ‘guilty taboo thoughts’. In the Spit for Science cohort, we additionally observed genetic sharing between ‘symmetry/counting/ordering’ and ‘contamination/cleaning’. The CNS insulin-linked gene-set also associated with ‘symmetry/counting/ordering’ in the PNC. Further, we identified genetic sharing between peripheral insulin signaling-related traits: type 2 diabetes with ‘aggressive taboo thoughts’, and levels of fasting insulin and 2 h glucose with OCD. In conclusion, OCD, OCS in the population and insulin-related traits share genetic risk factors, indicating a common etiological mechanism underlying somatic and psychiatric disorders.