Genome-wide association studies of social participation and occupational engagement in the UK Biobank

Psychosis is a clinically heterogenous disorder associated with significant difficulties with social and occupational function (psychosocial disability; PD). While environmental and cognitive factors are identified predictors of PD, the genetic contribution remains unclear. Here, we investigated the hypothesis that objective social participation (SP) and occupational engagement are genetically influenced. We performed mixed-linear-model genome-wide association studies of these phenotypes in the UK Biobank (N[~]404,500) and a series of post-hoc analyses including Mendelian randomization (MR) to interpret findings. SP was defined as the frequency of social visits and leisure activities based on response to questionnaires. Occupational engagement was represented by two variables; occupational function (OF) and the established Not in Education, Employment, and Training (NEET) measure, both derived from employment status responses. We identified 17 independent loci for SP, with a SNP-based heritability of 4.1%. A list of contributory genes included CSE1L, TNRC6B, STAU1, CDH7, GBE1, ZNF536, DDX27, and the known schizophrenia risk gene, TCF4. The regulation of synaptic signalling was implicated in the biology of SP by gene-set analysis. SNP-based heritabilities for OF and NEET were 1.8% and 1.2% respectively and DRD2 was associated with both phenotypes. Reduced SP and occupational engagement demonstrated genetic correlations with an increased risk for neuropsychiatric disorders, socioeconomic deprivation, lower cognitive ability, loneliness, neuroticism and chronic pain. MR indicated that attention-deficit hyperactivity disorder and schizophrenia were causal for reduced occupational engagement. PD has a genetic component with shared genetic links and relationships with neuropsychiatric disorders and related traits.