Clinical autism subscales have common genetic liabilities that are heritable, pleiotropic, and generalizable to the general population

Abstract

The complexity of autism's phenotypic spectra is well-known, yet most genetic research uses case-control status as the target trait. It is unclear whether clinical autism instruments such as the Social Communication Questionnaire (SCQ), Repetitive Behaviors Scale-Revised (RBS-R), and Developmental Coordination Disorder Questionnaire (DCDQ) are more genetically informative than case-control. We employed the SPARK autism cohort (N = 6,449) to illuminate the genetic etiology of these twelve subscales. In comparison to the heritability of autism case-control at 0.12, the RBS-R subscales were increased, ranging from 0.18 to 0.30 (all p < 0.05). Heritability of the DCDQ subscales ranged from 0.07 to 0.09 and the SCQ subscales from 0 to 0.09 (all p > 0.05). We also found evidence for genetic correlations among the RBS-R, SCQ, and DCDQ. GWAS followed by projection of polygenic scores (PGS) into ABCD revealed significant associations with CBCL social and thought problems, while the autism case-control PGS did not significantly associate. In phenotypic correlation analyses, the autism case-control PGS did not predict the subscales in SPARK, and sex-stratified correlations showed no effect in males and a surprising negative effect in females. Notably, other PGS did predict the subscales, with the strongest being educational attainment negatively correlated, while ADHD and major depression were positively correlated. Overall, our analyses suggest that clinical subscales are more genetically powerful than case-control, and that of the three instruments investigated, the RBS-R shows the greatest evidence of common genetic signal in both autistic and general population samples.

Structural models of genome-wide covariance identify multiple common dimensions in autism

“…Thus, profound structural differences exist in common genetic influences distinguishing population-representative and simplex ASD manifesting in ascertainment-specific patterns. Our findings strengthen the evidence for common genetic contributions to phenotypic variation in ASD (8,9,12) and offer insight into the underlying multi-dimensional common genetic architecture.…”

“…For example, autistic individuals with intellectual disability (ID), compared to those without, carry a higher rate of contributing de novo variants (6) and show qualitative differences in their common genetic architecture (5). In addition, polygenic scores (PGS) for different disorders, aggregating common risk alleles, show distinct association profiles with phenotypic factor structures in groups comprising only autistic individuals (8,12). Thus, also common variation may present genetic factor structures linking phenotypic domains, although the number of factors and their nature is unknown.…”

LINE-1 and Alu methylation signatures in autism spectrum disorder and their associations with the expression of autism-related genes

“…We identified unique DMPs which target genes differentially expressed in the several ASD cohort studies including AluY within XKR6 (cg21300361), AluSq within ZNF107 (cg01772945), and L1MB3 within MYEOV2 (cg13749477). These genes were genetic risk variants for ASD identified in genome-wide association study (GWAS), single nucleotide polymorphisms (SNPs), and copy number variation (CNV) studies 36,56,57 . In the case of ASD with the CHD8 variants, we observed a widespread reduction of LINE-1 and Alu methylation levels in total methylation and the active LINE-1 and Alu families (L1P, L1H, and AluS).…”

Autism in gifted youth is associated with low processing speed and high verbal ability

“…Polygenic score analysis: Polygenic scores (PGS) for autism diagnostic status were computed in the ABCD sample (N=6,002) with LDPred2 [41] as described in [42]. Within ABCD, PGS were binned into three groups based on percentiles: depleted risk (20 th percentile and below), neutral risk (21 st -79 th percentile), and high risk (80 th percentile and above).…”