Genetic Basis of Autism Spectrum Disorder: A Review

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental condition, yet it is also markedly heterogeneous at the molecular level, with contributions ranging from rare, highly penetrant single-gene mutations and copy-number variants to common polymorphisms in genes encoding neurotransmitter and neuropeptide systems. Objectives to review the genetic basis of ASD across four complementary lines of evidence – family and twin studies, single-gene and copy-number variation, epigenetic mechanisms, and functional candidate genes in the serotonin, oxytocin and melatonin pathways – and to integrate these findings with a case-control genotyping study of oxytocin-pathway polymorphisms performed by the authors in Iraqi children. A narrative review of the English-language literature indexed in PubMed, Scopus and Google Scholar was conducted using the terms “autism”, “genetics”, “twin study”, “copy number variation”, “epigenetics”, “serotonin transporter”, “oxytocin receptor” and “melatonin”, used alone and in combination, together with the authors’ own case-control study of OXT/rs2770378 and OXTR/rs53576 polymorphisms in 60 Iraqi male children with autism and 26 controls. Twin studies show markedly higher concordance in monozygotic than dizygotic twins, confirming strong heritability, although a substantial shared-environment component has also been demonstrated. Genetic heterogeneity is extensive, with more than 100 genes and dozens of recurrent copy-number variants implicated, alongside epigenetic mechanisms exemplified by MECP2 in Rett syndrome and FMR1 in fragile X syndrome. Among functional candidate genes, the serotonin transporter (SLC6A4), the oxytocin/oxytocin-receptor system (OXT/OXTR) and the melatonin-synthesis gene ASMT show biologically plausible but inconsistently replicated associations with ASD. In the authors’ Iraqi cohort, the OXT rs2770378 G/G genotype was associated with significantly higher autism risk and lower serum oxytocin, particularly in severe autism, while OXTR rs53576 showed no significant overall association. The genetic architecture of ASD spans rare, highly penetrant syndromic causes and common, functionally modest variation in neurotransmitter and neuropeptide pathways. Continued integration of family-based, genomic and candidate-gene approaches, including ethnically diverse case-control data such as the authors’ own, is required to refine the genetic map of autism and to move toward clinically useful genetic biomarkers.