IMPORTANCE: Autism 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. OBJECTIVE: To investigate the relationship between common and rare genetic variation and co-occurring mental health conditions and latent factors among autistic individuals. DESIGN: Cross-sectional SETTING: The study was conducted with the Simons Foundation Powering Autism Research (SPARK) dataset, V9 release (12 December 2022). PARTICIPANTS: Phenotypic 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 MEASURES: Genetic 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). RESULTS: 56% 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 RELEVANCE: Among autistic individuals, some mental health conditions and all mental health factors are heritable, but have a distinct genetic architecture from autism itself.

SBC received funding from the Wellcome Trust 214322\Z\18\Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. SBC also received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. SBC also received funding from the Autism Centre of Excellence (ACE) at Cambridge, SFARI, the Templeton World Charitable Fund, the MRC, and the NIHR Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East of England. Any views expressed are those of the author(s) and not necessarily those of the funder. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders (including IHI-JU2, the NIHR and the Department of Health and Social Care).

SBC received funding from the Wellcome Trust 214322\Z\18\Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. SBC also received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. SBC also received funding from the Autism Centre of Excellence (ACE) at Cambridge, SFARI, the Templeton World Charitable Fund, the MRC, and the NIHR Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East of England. Any views expressed are those of the author(s) and not necessarily those of the funder. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders (including IHI-JU2, the NIHR and the Department of Health and Social Care).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

We obtained ethics approval from the Cambridge Human Biology Research Ethics Committee to analyse pseudonymised human genetic data.

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All data produced in the present study are available upon reasonable request to the authors