Summary: Children whose mothers have a sibling with autism spectrum disorder (ASD) were about three times as likely to be diagnosed with ASD compared with children whose mothers had no siblings with autism. Children whose fathers have one or more siblings diagnosed with ASD were about twice as likely to have an ASD diagnosis. These findings come from a large population study and challenge the hypothesis that females carry a protective effect that reduces ASD risk in their offspring.
Source: NIH/NICHD
A population-based study funded by the National Institutes of Health analyzed nearly 850,000 Swedish children and their family records to estimate how ASD risk is transmitted through maternal and paternal lineages. The researchers report that roughly 3 to 5% of children who have an aunt or uncle with ASD will also be diagnosed with ASD themselves, compared to about 1.5% in the general population. The study also found no strong evidence that children of mothers with a sibling with ASD are at substantially higher risk than children of fathers with a sibling with ASD, a result that calls into question the so-called female protective effect as the main explanation for the higher prevalence of ASD in males.
The study was led by John N. Constantino, M.D., at Washington University in St. Louis, with collaborators in the United States and Sweden. It appears in the journal Biological Psychiatry and was supported by NICHD with additional funding from the National Institute of Mental Health. The analysis draws on comprehensive Swedish national registers that link birth records and family relationships and that allow ASD diagnoses to be ascertained across generations.
Autism spectrum disorder is a complex neurodevelopmental condition that begins in early life and affects social interaction, communication, learning, and behavior. ASD is known to run in families, and many studies have reported that males are diagnosed with ASD at higher rates than females—about three times more often in previous reports. One explanation that has been proposed is a female protective effect: the idea that females may tolerate a greater load of genetic risk factors without developing symptoms themselves, while passing those risks on to their children. If a strong female protective effect were present, siblings of females with ASD—or offspring of women who have a sister with ASD—would be expected to show increased recurrence risk.
In this Swedish cohort of children born between 2003 and 2012, approximately 13,000 children (about 1.5% of the cohort) were diagnosed with ASD. The investigators identified ASD diagnoses among aunts and uncles in the parental generation: 1,744 maternal aunts/uncles (0.24%) and 1,374 paternal aunts/uncles (0.18%) had an ASD diagnosis. Offspring of mothers who had at least one sibling with ASD showed a relative risk of 3.05 (95% confidence interval, 2.52–3.64) compared with the general population. Offspring of fathers with at least one sibling with ASD showed a relative risk of 2.08 (95% confidence interval, 1.53–2.67). These paternal and maternal risk estimates differed from the general population but were not statistically different from each other in a way that would support a strong female-protective mechanism.
The authors note that the observed rates are consistent with what would be expected for second-degree relatives within a generation and that adjusting the models for temporal trends and for parental psychiatric history did not substantially change the results. They also did not find a meaningful difference in risk when comparing offspring of aunts to offspring of uncles, which further weakens the argument that a sex-specific protective effect in females accounts for the male bias in ASD diagnosis.
Alice Kau, Ph.D., of NICHD’s Intellectual and Developmental Disabilities Branch, emphasized the practical value of these results for clinical counseling. The study provides the first population-wide estimate of ASD risk to children of parents who themselves have a sibling with ASD, offering clearer information for families seeking recurrence risk estimates.
About this neuroscience research article
Source:
NIH/NICHD
Media Contacts:
Robert Bock – NIH/NICHD
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The image is in the public domain.
Original Research: “Inherited risk for autism through maternal and paternal lineage.” Bai, D. et al., Biological Psychiatry. DOI: 10.1016/j.biopsych.2020.03.013. (Open access PDF available via the journal.)
Abstract
Inherited risk for autism through maternal and paternal lineage
BACKGROUND: Autism spectrum disorder is strongly familial and shows a skewed male-to-female ratio. The female protective effect hypothesis proposes that common familial liability for ASD may be carried asymptomatically by females, which would predict elevated ASD rates among offspring of sisters of affected individuals. Prior to this study, there were no population-level data on second-generation recurrence rates in families affected by ASD.
METHODS: The investigators used the Swedish National Patient Register and the Multi-Generation Register to study a cohort of children born from 2003 to 2012, with ASD diagnoses ascertained in both the child generation and the parental generation.
RESULTS: Among 847,732 children in the cohort, 13,103 (1.55%) were diagnosed with ASD. Within the parental generation, 1,744 maternal aunts/uncles (0.24%) and 1,374 paternal aunts/uncles (0.18%) had ASD diagnoses. Offspring of mothers with a sibling diagnosed with ASD had an elevated relative risk of ASD (3.05; 95% CI, 2.52–3.64) compared with the general population, while offspring of fathers with a sibling diagnosed with ASD had a relative risk of 2.08 (95% CI, 1.53–2.67). These estimates were consistent with expectations for second-degree familial risk and remained robust after adjustment for temporal trends and parental psychiatric history.
CONCLUSIONS: This study provides a robust population-level estimate of ASD transmission risk through maternal and paternal lineages and does not support a primary role for female protective factors as the main explanation for male-biased ASD prevalence.
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