Sex Differences in the role of Additive Genetic Variants in Autism: A Systematic Review

OBJECTIVE: Autism shows a male-biased diagnostic sex ratio. Given the heritability of autism, genetic factors likely contribute to this ratio. This study systematically reviews sex differences in additive common genetic effects related to autism and autistic traits.

METHODS: Original research was collected from PubMed, Web of Science, APA PsycInfo and Scopus (2008 - July 2025) following PRISMA guidelines. Genome wide association studies (GWASs) on autism, and related downstream analyses, including polygenic scores (PGS), Single-Nucleotide Polymorphism (SNP) heritability, and genetic correlations were included when sex-stratified results were reported. Risk of bias was assessed, followed by a best-evidence synthesis.

RESULTS: Of 6,053 records screened, 21 studies were eligible. In clinical populations, results on mean PGS differences were inconclusive. In subgroups without intellectual disability, strong evidence indicated higher mean PGS in females. In general population samples, weak evidence supported this pattern. PGS associations with autistic traits showed inconsistent results, although stronger associations were reported for sensory sensitivity in males with weak evidence. SNP heritability findings were inconclusive. Genetic correlations between the sexes were significantly different from 1 ( r g = 0.80 ( SE = 0.09), but evidence was considered weak.

DISCUSSION: Findings suggest an axis of heterogeneity around intellectual disability. Inconsistent findings largely resulted in inconclusive evidence. Results highlight a lack of sex-stratified reporting and were limited by sample makeup such as male- and European ancestry dominated cohorts. Future sex-balanced and stratified GWAS and downstream analyses with complete reporting of female and male data are needed to clarify potential genetic sex differences in autism.