Polygenic Risk for Autism Spectrum Disorder in the Study to Explore Early Development

Background:

Autism spectrum disorder (ASD) is a polygenic disease that is moderately to highly heritable. Genome-wide association studies (GWAS) have been successful in identifying common genetic variants that predispose to complex traits.

The largest ASD GWAS meta-analysis to date includes >9 million single-nucleotide-polymorphisms (SNPs) in 18,381 ASD cases and 27,969 controls from the Psychiatric Genomic Consortium (PGC) and iPSYCH projects. These results provide, precise SNP-based association effect sizes that allow derivation of a polygenic risk score (PRS) to represent genetic susceptibility to ASD (ASD-PRS).

Objectives:

We applied GWAS effect sizes from the recent PGC/iPSYCH results to SNP data from the independent US population-based Study to Explore Early Development (SEED) to derive ASD-PRS and examine associations between ASD-PRS and ASD classification.

Methods:

SEED is a multi-site case-control study of children aged 3-5 years with ASD and a control group drawn from the general population, born between September 2003 and August 2006. Genotyping was performed on either Illumina or Affymetrix arrays and imputed using SHAPEIT and IMPUTE2. ASD- PRS was generated via pruning, thresholding and scoring in PLINK. The same process was used to derive a psychiatric cross-disorder PRS using PGC results (http://www.med.unc.edu/pgc/results-and-downloads). All ASD-PRS associations with ASD were assessed by logistic regression, accounting for sex and five principal components of genetic ancestry.

Results:

The PRS analysis included 1302 SEED children: 861 boys (467 with ASD) and 441 girls (115 with ASD). After evaluating Nagelkerke’s R-squared statistic across a range of discovery p-value thresholds, we observed that pdiscovery=0.30 maximized the variance explained. All PRS associations reflect this cutoff for SNPs to be selected into the summed score. The odds ratio of ASD for a single standard deviation increase in the ASD-PRS score, adjusted for sex and genetic ancestry, was 1.42 (95%CI: 1.13, 1.78; p-value=0.0028), which explained 0.87% of the variance in ASD status. A similar finding was observed for a subset of 799 children with European ancestry (OR=1.49; 95%CI: 1.12, 2.00; p-value=0.0066), which explained 1.1% of the variance in ASD status. We also observed an association with the CrossDisorder-PRS in the full sample (OR=1.28, 95%CI: 1.09,1.49, pl=0.0021) and in children of European descent (OR=1.46, 95%CI: 1.17, 1.82, p=0.0008). In a model that includes both ASD-PRS and CrossDisorder-PRS, the odds ratio for ASD-PRS, adjusted for the CrossDisorder-PRS, was 1.43 (95%CI: 1.07, 1.92, p=0.015), and the odds ratio for CrossDisorder-PRS, adjusted for ASD-PRS, was 1.43 (95%CI: 1.14, 1.79, p=0.0017).

Conclusions:

To our knowledge, this is the first effort to leverage the PGC/iPSYCH GWAS discovery results to investigate the utility of an ASD-PRS in a population-based ASD case-control sample. We show a strong main effect indicating genetic susceptibility for ASD, in a multi-ethnic sample and stratified by European ancestry. The variance explained, though small (~1%), is similar to PGC-based PRS for other psychiatric conditions (i.e., schizophrenia). We additionally show that the ASD-PRS association persists after adjustment for a general genetic susceptibility to psychiatric disorders. Further work will compare these results to similar analyses using a non-psychiatric phenotype to confirm the specificity of this finding.