ABSTRACT Background Several lines of evidence point toward the presence of shared genetic factors underlying Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). However, Genome-Wide Association Studies (GWAS) have yet to identify risk variants (i.e. Single-Nucleotide Polymorphisms, SNPs) shared by ADHD and ASD. Methods Two complementary multivariate analyses – genomic structural equation modelling (SEM) and colocalization analysis – were exploited to identify the shared SNPs for ASD and ADHD, using summary data from two independent GWAS of ASD (N=46,350) and ADHD individuals (N=55,374). Results Genomic SEM identified 7 novel SNPs shared between ASD and ADHD ( p genome-wide &lt;5e-8), including three SNPs that were not identified in any of the original univariate GWAS of ASD and ADHD (rs227378, rs2391769 and rs325506). We also mapped 4 novel genes (MANBA, DPYD, INSM1, and PAX1) to SNPs shared by ASD and ADHD, as well as 4 genes that had already been mapped to SNPs identified in either ASD or ADHD GWAS (SORCS3, XRN2, PTBP2 and NKX2-4). All the shared genes between ADHD and ASD were more prominently expressed in the brain than the genes mapped to SNPs specific to ASD or ADHD. Colocalization analyses revealed that 44% percent of the SNPs associated with ASD ( p &lt;1e-6) colocalized with ADHD SNPs and 26% of the SNPs associated with ADHD ( p &lt;1e-6) colocalized with ASD SNPs. Conclusions Using multivariate genomic analyses, the present study reveals the shared genetic pathways that underlie ASD and ADHD. Further investigation of these pathways may help identify new targets for treatment of these disorders.

Combining multivariate genomic approaches to elucidate the comorbidity between ASD and ADHD