Exploring the common genetic architecture of autism spectrum disorder using a novel multi-polygenic risk score approach

Compared to disorders of similar heritability and contribution of common variants, few genome-wide significant loci have been implicated in autism spectrum disorder (ASD). This undermines the use of polygenic risk scores (PRSs) to investigate the common genetic architecture of ASD. Deconstructing PRS-ASD into its related traits via "developmental deconstruction" could reveal the underlying genetic liabilities of ASD. Using the data of >24k individuals with ASD and >28k of their unaffected family members from the SSC, SPARK, and MSSNG cohorts, we computed the PRSs for ASD and 11 genetically-related traits. We applied an unsupervised learning approach to the ASD-related PRSs to derive "multi-PRSs" that captured their variability in orthogonal dimensions. We found that multi-PRSs captured a similar proportion of genetic risk for ASD in cases versus intrafamilial controls (ORmulti-PRS=1.10, R2=0.501%), compared to PRS-ASD itself (ORPRS-ASD=1.16, R2=0.619%). While multi-PRS dimensions conferred risk for ASD, they had "mirroring" effects on developmental phenotypes among cases with ASD. We posit that this phenomenon may partially account for the paucity of genome-wide significant loci and the clinical heterogeneity of ASD. This approach can serve as a proxy for PRS-ASD in cases where non-overlapping and well-powered GWAS summary statistics are difficult to obtain, or accounting for heterogeneity in a single dimension is preferable. This approach may also capture the overall liability for a condition (i.e.: genetic "P-factor"). Altogether, we present a novel approach to studying the role of inherited, additive, and non-specific genetic risk factors in ASD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement ZS has received funding from Canadian Institutes of Health Research Frederick Banting & Charles Best Canada Graduate Scholarship (FRN 181433) and is supported by the Transforming Autism Care Consortium, a thematic network supported by the Fonds de Recherche Quebec-Sante. JPR has received funding from Canadian Institutes of Health Research Frederick Banting & Charles Best Canada Graduate Scholarship (FRN 159279). VRB is supported by a Quebec Research Funds - Health (FRQS) residency training scholarship. BC received a grant from the Fondation Bettencourt Schueller (CCA-INSERM Bettencourt). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Montreal Neurological Institute and Hospital Ethics committee of McGill University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.