RT Journal Article
SR Electronic
T1 Genetic overlap between obsessive-compulsive disorder, related symptoms in the population and insulin signaling: etiological implications
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 608034
DO 10.1101/608034
A1 Janita Bralten
A1 Joanna Widomska
A1 Ward De Witte
A1 Dongmei Yu
A1 Carol A. Mathews
A1 Jeremiah M. Scharf
A1 Jan Buitelaar
A1 Jennifer Crosbie
A1 Russell Schachar
A1 Paul Arnold
A1 Mathieu Lemire
A1 Christie L. Burton
A1 Barbara Franke
A1 Geert Poelmans
YR 2019
UL http://biorxiv.org/content/early/2019/04/13/608034.abstract
AB Objective Obsessive-compulsive symptoms in the population have been linked to obsessive-compulsive disorder (OCD) in previous genetic and epidemiological studies. Genetic studies also show a link to insulin signalling. Here we aim to assess the presence and extent of genetic and biological overlap between OCD, OCD symptoms in the population, and insulin signalling, making use of the largest data sets currently available.Methods We used phenotypic and genetic data from a population based cohort (n=650) of children and adolescents to conduct genome-wide association studies (GWAS) to six factors derived from exploratory factor analyses on OCD symptom scores. We performed polygenic risk score analyses to check whether these OCD symptom traits had a shared genetic etiology with clinically diagnosed OCD (using GWAS data of the PGC, n=2688 OCD cases and 7037 controls). Subsequently we investigated potential shared biology performing gene-set analyses with an earlier defined set of 51 OCD-associated genes centered around insulin-regulated synaptic function and polygenic risk score analyses of five peripheral insulin signaling-related traits (type 2 diabetes (T2D) and the blood levels of four T2D biomarkers (n between 42,854-159,208)).Results We found genetic sharing between diagnosed OCD and four out of six factors based on OCD symptoms in the population: ‘impairment’, ‘contamination/cleaning’, ‘guilty taboo thoughts’, and ‘symmetry/counting/ordering’. Gene-set analysis with insulin-related genes revealed an association with ‘symmetry/counting/ordering’. We also identified genetic sharing between OCD, the total score of OCD symptoms and six of the derived symptom factors with the peripheral insulin signaling-related traits. We were able to validate part of our results on symmetry/counting/ordering and contamination/cleaning in an independent population-based cohort (n=5047).Conclusions Our findings suggest that GWASs of OCD symptoms in population-based cohorts could be used to discover OCD-relevant genes. Our results also imply that altered insulin signaling, as relevant to T2D, is also involved in different aspects of compulsive and obsessive behaviours and clinical OCD. This may open up a new field of brain-based insulin-related disorders.