The complexity of autism’s phenotypic spectra is well-known, yet most genetic research uses case-control status as the target trait. It is undetermined if autistic symptom domain severity underlying this heterogeneity is heritable and pleiotropic with other psychiatric and behavior traits in the same manner as autism case-control status. In N = 6064 autistic children in the SPARK cohort, we investigated the common genetic properties of twelve subscales from three clinical autism instruments measuring autistic traits: the Social Communication Questionnaire (SCQ), the Repetitive Behavior Scale-Revised (RBS-R), and the Developmental Coordination Disorder Questionnaire (DCDQ). Educational attainment polygenic scores (PGS) were significantly negatively correlated with eleven subscales, while ADHD and major depression PGS were positively correlated with ten and eight of the autism subscales, respectively. Loneliness and neuroticism PGS were also positively correlated with many subscales. Significant PGS by sex interactions were found—surprisingly, the autism case-control PGS was negatively correlated in females and had no strong correlation in males. SNP-heritability of the DCDQ subscales ranged from 0.04 to 0.08, RBS-R subscales ranged from 0.09 to 0.24, and SCQ subscales ranged from 0 to 0.12. GWAS in SPARK followed by estimation of polygenic scores (PGS) in the typically-developing ABCD cohort (N = 5285), revealed significant associations of RBS-R subscale PGS with autism-related behavioral traits, with several subscale PGS more strongly correlated than the autism case-control PGS. Overall, our analyses suggest that the clinical autism subscale traits show variability in SNP-heritability, PGS associations, and significant PGS by sex interactions, underscoring the heterogeneity in autistic traits at a genetic level. Furthermore, of the three instruments investigated, the RBS-R shows the greatest evidence of genetic signal in both (1) autistic samples (greater heritability) and (2) general population samples (strongest PGS associations).

Background Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. Methods Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. Results We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all $$p<0.05$$ p < 0.05 ), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ($$\rho =0.19$$ ρ = 0.19 , $$p=0.004$$ p = 0.004 ; $$\rho =0.2$$ ρ = 0.2 , $$p=0.004$$ p = 0.004 , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ($$t=4.0$$ t = 4.0 , $$p=8.8\times 10^{-5}$$ p = 8.8 × 10 - 5 ), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ($$t=-3.3$$ t = - 3.3 , $$p=0.001$$ p = 0.001 ). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ($$t=-2.3$$ t = - 2.3 , $$p=0.02$$ p = 0.02 , and $$t=4.2$$ t = 4.2 , $$p={3.2\times 10^{-5}}$$ p = 3.2 × 10 - 5 for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: $$-0.22\pm 0.05$$ - 0.22 ± 0.05 ; testosterone: $$-0.35\pm 0.15$$ - 0.35 ± 0.15 from 0.1%-ile to 99.9%-ile; SHBG: $$0.64\pm 0.15$$ 0.64 ± 0.15 from 0.1%-ile to 99.9%-ile). Limitations In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. Conclusions These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.

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.

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Autism with co-occurring exceptional cognitive ability is often accompanied by severe internalizing symptoms and feelings of inadequacy. Whether cognitive ability also translates into greater risk for suicidal ideation is unclear. To investigate this urgent question, we examined two samples of high-ability individuals with autism for factors that were predictive of suicidal ideation. In the first sample (N=1,074 individuals seen at a clinic specializing in gifted/talented youth), we observed a striking excess of parent-reported suicidal ideation in autistic individuals with IQ >= 120 (OR=5.9, p = 0.0007). In separate sample of N=1,983 SPARK participants, we confirmed higher rates of suicidal thoughts compared to non-autistic children from the ABCD cohort (OR=6.8, p < 2.2 x 10^-16), and further that autistic children with suicidal thoughts had significantly higher cognitive ability (p < 2.2 x 10^-16 ) than those without. Elevated polygenic scores (PGS) for cognitive performance were associated with increased suicidal thoughts (Z = 2.16, p = 0.03), with PGS for educational attainment trending in the same direction (Z = 1.4, p = 0.17). Notably, similar results were found in parents of these autistic youth, where higher PGS for educational attainment was associated with increasing thoughts of suicide (Z=2.28, p=0.02). Taken together, these results suggest that on a phenotypic and genetic level, increasing cognitive ability is an unexpected risk factor for suicidal ideation in individuals diagnosed with, or at risk for autism.