The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder

Social skills group training (SSGT) is one of the most frequently used behavior interventions in children and adolescents with autism spectrum disorder (ASD). Current evidence suggests that the effects are moderate and heterogeneous. Genetic predisposition could be one of the factors contributing to this heterogeneity. Therefore, we used polygenic risk score (PRS) and gene-set analysis to investigate the association between SSGT response and common variants in autistic individuals. Participants from the largest randomized clinical trial of SSGT in ASD to date were selected for genotyping. Polygenic risk scores (PRSs) for ASD, attention deficit hyperactivity disorder (ADHD), and educational attainment (EA) were calculated, and their associations with the intervention outcome at post-intervention and follow-up were tested using mixed linear model. In addition, thirty-two gene sets within five categories (synaptic, glial, FMRP, glutamate, and mitochondrial) were selected to evaluate their role in the intervention outcome. Individuals with higher PRSs for ASD and ADHD had inferior response after SSGT. After multiple test correction, significant results were kept for higher ADHD PRS at follow-up (β = 6.67, p = 0.016). Five gene sets within synaptic category showed modest association with reduced response to SSGT in ASD. Taken together, we provided preliminary evidence that genetic liability calculated using PRS and common variants in synapse gene sets could influence the outcome of SSGT. Our results hold promise for future research into the genetic contribution to individual response to ASD interventions, and should be validated in larger cohorts. ### Competing Interest Statement Sven Bölte is an author of the German and Swedish KONTAKT manuals and receives royalties from Huber/Hogrefe publishers. Dr. Bölte discloses that he has in the last 5 years acted as an author, consultant or lecturer for Shire/Takeda, Medice, Roche, Eli Lilly, Prima Psychiatry, and SB Education and Psychological Consulting AB. He receives royalties for text books and diagnostic tools from Huber/Hogrefe, Kohlhammer and UTB. Nora Choque-Olsson and Ulf Jonsson are authors of the Swedish KONTAKT manuals. The other authors do not report financial interests or potential conflicts of interest. ### Clinical Trial NCT01854346 ### Clinical Protocols ### Funding Statement This work was supported by grants from the Swedish Research Council clinical therapy framework grant (921-2014-6999, Drs. Bölte, Tammimies), the Swedish Research Council, in partnership with the Swedish Research Council for Health, Working Life and Welfare, Formas and VINNOVA (cross-disciplinary research program concerning children’s and young people’s mental health, 259-2012-24, Dr. Bölte) Stockholm County Council (20130314 Dr. Bölte, 20170415 Dr. Tammimies), Swedish Foundation for Strategic Research (ICA14-0028, Dr. Tammimies), The Swedish Brain Foundation (Dr. Tammimies), the Harald and Greta Jeanssons Foundations (Dr. Tammimies), Åke Wiberg Foundation (Dr. Tammimies), StratNeuro (Dr. Tammimies), the L’Oréal-UNESCO for Women in Science prize in Sweden with support from the Young Academy of Sweden (Dr. Tammimies), Sällskapet Barnavård (Dr. Tammimies, Ms Li), China Scholarship Council (Ms Li), Drottning Silvias Jubileumsfond (Ms Li) and Board of Research at Karolinska Institutet (Dr Tammimies). ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Due to the legal restriction in the Swedish law we are not allow to share the raw genetic data used in the study