Abstract
BACKGROUND: Autism spectrum disorder (ASD) is highly familial, with a positively skewed male-to-female ratio that is purported to arise from the so-called female protective effect. A serious implication of a female protective effect is that familial ASD liability would be expected to aggregate asymptomatically in sisters of affected probands, who would incur elevated rates of ASD among their offspring. Currently, there exist no data on second-generation recurrence rates among families affected by ASD. METHODS: We analyzed data from the Swedish National Patient Register and the Multi-Generation Register for a cohort of children born between 2003 and 2012. ASD was ascertained in both the child and parental generations. RESULTS: Among 847,732 children, 13,103 (1.55%) children in the cohort were diagnosed with ASD. Among their maternal/paternal aunts and uncles, 1744 (0.24%) and 1374 (0.18%) were diagnosed with ASD, respectively. Offspring of mothers with a sibling(s) diagnosed with ASD had higher rates of ASD than the general population (relative risk, 3.05; 95% confidence interval, 2.52-3.64), but not more than would be predicted for second-degree relatives within a generation, and only slightly more than was observed for fathers with siblings with ASD (relative risk, 2.08; 95% confidence interval, 1.53-2.67). Models adjusting for temporal trends and for psychiatric history in the parental generation did not alter the results. CONCLUSIONS: These findings establish a robust general estimate of ASD transmission risk for siblings of individuals affected by ASD, the first ever reported. Our findings do not suggest female protective factors as the principal mechanism underlying the male sex bias in ASD.