8 - COMMON RISK VARIANTS AND POLYGENIC HETEROGENEITY IN AUTISM

Abstract

Background Autism Spectrum Disorder (ASD) is a psychiatric disorder with a World Wide prevalence of about 1%. ASD is characterized by impairments in social interaction, communication and repetitive stereotypic behavior. The etiology of ASD is largely unknown, but it is highly heritable and common variation is estimated to explain half of the genetic risk. Shared genetics between different psychiatric disorders have been widely reported, as have overlaps with phenotypes such as educational attainment and IQ. Over the past couple of years, iPSYCH and Broad/MGH have conducted the largest GWAS of ASD to date. Altogether more than 47k subjects from the Danish Neonatal Screening Biobank were included in the ASD GWAS and subsequently meta-analyzed together with additional 11k samples ASD GWAS from the Psychiatric Genomics Consortium (PGC). Methods The iPSYCH sample is a population sample with cases from the Danish Psychiatric Central Research Register and a random sample from the same birth cohorts as control group. All subjects were identified in the Danish Neonatal Screening Biobank, their DNA extracted, whole-genome amplified and genotyped on the PsychChip. We conducted the analyses in the Ricopili pipeline of PGC, and using LDSC, GCTA and R. Results We report here on the final freeze of the ASD GWAS. Almost 36k were analyzed as part of the CEU sample that was subsequently meta-analyzed together with the additional 11k samples ASD GWAS from the Psychiatric Genomics Consortium (PGC). While we will describe the 3 genome-wide significant the single locus findings as well as 2 more genome-wide significant loci in the meta-analysis with the replication sample, the main focus will be on polygenic features. We confirm previously reported genetic correlations, eg. for education (rg= 0:20, p=2.6E-9 for SSGAC and rg= 0.27, p=2.1E-11 for UKB) and follow up with results for newly analyzed phenotypes. Moreover, we will show an emerging polygenic structure that relates polygenic risk scores (PRS) to ASD subtypes (Asperger, childhood autism, atypical autism, other pervasive developmental disorder and pervasive developmental disorder, unspecified). E.g. the PRS for educational attainment loads differently on disjoint subtype groups, p=2.6E-11 (p=5.3E-8 when excluding intellectual disability) while for schizophrenia there is no such heterogeneity, p=0.98. Discussion Despite being the largest GWAS of autism yet conducted and despite showing a handful of genome-wide significant loci, it is clear that it will take a significant increase in sample size before ASD GWASes will be powered well enough for full-fledged gene-discovery. There is however already sufficient power that we can begin to dissect the polygenic structures and here new and interesting contours are developing with PRSs for other phenotypes loading differential on ASD subtypes.