Common genetic variants are associated with increased likelihood of some co-occurring mental health conditions among autistic individuals

IMPORTANCEAutism frequently co-occurs with other mental health conditions. In the general population, these co-occurring mental health conditions are highly heritable and genetically correlated; however, the genetic architecture of co-occurring mental health conditions among autistic individuals is unclear. OBJECTIVETo investigate the relationship between common and rare genetic variation and co-occurring mental health conditions and latent factors among autistic individuals. DESIGNCross-sectional SETTINGThe study was conducted with the Simons Foundation Powering Autism Research (SPARK) dataset, V9 release (12 December 2022). PARTICIPANTSPhenotypic data exploration and factor analyses was conducted in 74,204 autistic individuals, and genetic analyses were conducted in a maximum of 17,582 individuals with genetic data. MAIN OUTCOMES AND MEASURESGenetic analysis was limited to those probands included in the SPARK iWES1 dataset [n=17,582]. SNP heritability estimates and genetic correlations were computed for three factor scores and six diagnostic categories (attention deficit hyperactivity disorder or ADHD, bipolar disorder, depression, schizophrenia, anxiety disorder and disruptive behaviour disorders or DBD) using bivariate GCTA-GREML and LDSC. Polygenic scores were generated using summary statistics from the most recent genome wide association studies (GWAS) for five traits and six conditions. Associations with factor scores and categorical diagnoses were tested separately for polygenic scores (PGS), de novo variants (DNVs) and copy number variants (CNVs). RESULTS56% of autistic individuals presented a co-occurring psychiatric condition. Confirmatory factor analysis identified three minimally correlated factors: a behavioural factor, cothymic factor, and a Kraepelin or thought disorder factor, with SNP heritabilities ranging from 0.21 (s.e. 0.02) for behavioural to 0.09 (s.e. 0.03) for cothymic factor. Among conditions, moderate and significant SNP heritabilites were observed for ADHD (0.18, s.e. = 0.04) and DBD (0.52, s.e. = 0.08). Moderate positive genetic correlations were found between co-occurring ADHD, DBD, anxiety and the three factors in autistic individuals and corresponding conditions in external population cohorts. PGS for ADHD, depression, and educational attainment were significantly associated with all mental health factors and some of the conditions tested. We found no evidence for an association between common variants for autism, rare CNVs, and DNVs in highly constrained genes with increased likelihood of mental health phenotypes among autistic individuals. CONCLUSION AND RELEVANCEAmong autistic individuals, some mental health conditions and all mental health factors are heritable, but have a distinct genetic architecture from autism itself. Key PointsO_ST_ABSQuestionC_ST_ABSDo genetic variants contribute to co-occurring mental health conditions and latent factors in autistic individuals? FindingsIn this cross-sectional study of 17,582 autistic individuals with and without co-occurring conditions, we found significant single nucleotide polymorphism (SNP) heritability for co-occurring ADHD, Disruptive Behaviour Disorders (DBD), and mental-health latent factors. Co-occurring ADHD, DBD, anxiety, and all mental health factors among autistic individuals had moderate genetic correlations with corresponding case-control GWAS. We found no evidence linking common genetic variants linked to autism and rare genetic variants with increased likelihood for mental health conditions among autistic individuals. MeaningAmong autistic individuals, the genetic correlates of co-occurring mental health conditions are distinct from that of autism, suggesting that additional genetic factors contribute to the development of these conditions among autistic individuals.