Autism risk across generations: a population-based study of advancing grandpaternal and paternal age.

IMPORTANCE Advancing paternal age has been linked to autism. OBJECTIVE To further expand knowledge about the association between paternal age and autism by studying the effect of grandfathers' age on childhood autism. DESIGN Population-based, multigenerational, case-control study. SETTING Nationwide multigeneration and patient registers in Sweden. PARTICIPANTS We conducted a study of individuals born in Sweden since 1932. Parental age at birth was obtained for more than 90% of the cohort. Grandparental age at the time of birth of the parent was obtained for a smaller subset (5936 cases and 30 923 controls). MAIN OUTCOME AND MEASURE International Classification of Diseases diagnosis of childhood autism in the patient registry. RESULTS A statistically significant monotonic association was found between advancing grandpaternal age at the time of birth of the parent and risk of autism in grandchildren. Men who had fathered a daughter when they were 50 years or older were 1.79 times (95% CI, 1.35-2.37; P < .001) more likely to have a grandchild with autism, and men who had fathered a son when they were 50 years or older were 1.67 times (95% CI, 1.35-2.37; P < .001) more likely to have a grandchild with autism, compared with men who had fathered children when they were 20 to 24 years old, after controlling for birth year and sex of the child, age of the spouse, family history of psychiatric disorders, highest family educational level, and residential county. A statistically significant monotonic association was also found between advancing paternal age and risk of autism in the offspring. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on grandparental age. CONCLUSIONS AND RELEVANCE Advanced grandparental age was associated with increased risk of autism, suggesting that risk of autism could develop over generations. The results are consistent with mutations and/or epigenetic alterations associated with advancing paternal age.