Association of Parental Genetic Heterogeneity with Prevalence of Autistic Spectrum Disorder

Importance The increase in prevalence of autistic spectrum disorder (ASD) in children in most countries of the world has been attributed to assortative mating meaning that spouses have found each other guided by features of ASD leading to increased genetic predisposition in the offspring. This does not explain the differences in prevalence of ASD in subgroups of the population with similar mating patterns. Objective: To test the hypothesis that parental genetic heterogeneity is associated with ASD in the offspring.Design: In this comparative observational study data were included from population based studies reporting number of patients with ASD in populations with known high, moderate or low genetic heterogeneity. The prevalence (per 10000 of population) was compared between groups. Compared were the percentages of children with learning difficulties in the three groups.Setting: All countries with data from investigations reporting prevalence of ASD in ethnic subgroups of the population.Participants: Children with and without ASD of parents with a known degree of genetic heterogeneity from population based studies allowing analysis of individual participant data.Exposures: Based on pre-existing data of genetic and anthropological studies subgroups of childhood populations with low, moderate and high parental genetic heterogeneity were investigated.Main outcome and measures: Prevalence of ASD and percentage of children with ASD and learning difficulties in offspring of parents with different degrees of genetic heterogeneity were compared. The hypothesis that parental genetic heterogeneity is associated with ASD in offspring was formulated prior to the study as a result of data of a previous study and stated there.Results: The prevalence of ASD across spouse pairs of high, moderate or low genetic heterogeneity for 182016 children with ASD in childhood populations totalling 62290632 children in the USA, the United Kingdom, Sweden, Israel and Australia were compared. In all studies reporting data prevalence of ASD was significantly higher in offspring of parents with high genetic heterogeneity ranging from 12.9 to 280.5 compared to offspring of parents with moderate genetic heterogeneity with a range of 9.0 to 243.1 and low genetic heterogeneity with a range of 4.6 to 71.7. The percentage of children with learning difficulties showed no consistent difference between groups.Conclusion and relevance: Autism spectrum disorder in offspring is associated with parental genetic heterogeneity. This will direct future research towards gene constellations protective against expression of ASD predisposing genes.