Contribution of autosomal rare and de novo variants to sex differences in autism

Abstract

Autism is four times more prevalent in males than females. To study whether this reflects a difference in genetic predisposition attributed to autosomal rare variants, we evaluated the sex differences in effect size of damaging protein-truncating and missense variants on autism predisposition in 47,061 autistic individuals, then compared effect sizes between individuals with and without cognitive impairment or motor delay. Although these variants mediated differential likelihood of autism with versus without motor or cognitive impairment, their effect sizes on the liability scale did not differ significantly by sex exome-wide or in genes sex-differentially expressed in the cortex. Although de novo mutations were enriched in genes with male-biased expression in the fetal cortex, the liability they conferred did not differ significantly from other genes with similar loss-of-function intolerance and sex-averaged cortical expression. In summary, autosomal rare coding variants confer similar liability for autism in females and males.

Keywords: ASC; Autism Sequencing Consortium; SPARK; Simons Foundation Powering Autism Research for Knowledge; exome sequencing; rare variant association.

Figure 1:

Exome-wide rare variant burden and liability in SPARK and ASC trio-sequenced cohorts. a, The sample size of the trio-sequenced individuals in the Simons Foundation Powering Autism Research for Knowledge study (SPARK) and the Autism Sequencing Consortium (ASC) cohorts. b, Sex-stratified de novo mutation rate ratios (left) and liability (right) (see Methods). For sex differences, a rate ratio > 1 indicates that females show a higher enrichment; a Z score > 0 indicates that females show a higher effect size on the liability scale. c, Over-transmission and liability of inherited variants were assessed using similar comparisons between parental alleles transmitted to autistic individuals and untransmitted alleles (see Methods). Error bars show 95% confidence intervals. See Supplementary Table S5 for the results shown here (Extended Tables) and sections 2.1.3 and 2.2.3 of the Supplementary Results (Supplementary Note) for further details on synonymous variant imbalances.

Figure 2:

Rare variant burden in autistic individuals with and without cognitive impairment or motor delay in SPARK trio-sequenced cohort. a, The sample size in two sub-cohorts of trio-sequenced individuals from the Simons Foundation Powering Autism Research for Knowledge study (SPARK) divided based on the presence of co-occurring motor developmental delays or cognitive impairment. b, Sex-stratified observed de novo mutation rates (left) and average liability (right) (see Methods). In addition to the comparisons versus siblings, autistic probands with motor or cognitive difficulties were compared directly to sex-matched autistic individuals without these co-occurring conditions (‘with versus without’). c, Over-transmission of rare inherited variants (left) and their average liability (right) (see Methods). The results depicted in this figure are available in Supplementary Table S6 (see the Extended Tables). See section 4.1.3 of the Supplementary Results (see the Supplementary Note) for details on the imbalance of synonymous variants. Limiting the analysis in b to ultra-rare DNMs in ancestry-matched autistic females and siblings showed well-balanced synonymous DNM burden (p = 0.42; Figure S13).

Figure 3:

Burden and liability of damaging protein truncating de novo mutations in 856 genes with male-biased expression in the human fetal cortex. a, The relative risk (rate ratio) attributed to de novo mutations (DNM), examined along with rare inherited variants (not shown), in trio-sequenced individuals from the Autism Sequencing Consortium (ASC) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) cohorts, in two SPARK sub-cohorts of autistic individuals ascertained to have autism with or without co-occurring developmental delay or cognitive impairment (versus siblings), and compared directly between these two groups. b, The corresponding average liability attributed to DNMs (effect size on the liability scale). See Methods for details, Figures 1 and 2 for the sample sizes, and Figure S17 in section 6.2 of the Supplementary Methods (Supplementary Note) for a comparison against matched genes. The complete results of DNM and rare inherited variants (180 tests) are presented in Supplementary Table S7 (Extended Tables).