Abstract
BackgroundAutism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. However, reported ASD recurrence rates have not demonstrated significantly increased risk to siblings of affected girls. Here, we characterize recurrence patterns in multiplex families from the Autism Genetics Resource Exchange (AGRE) to determine if risk in these families follows a female protective model.MethodsWe assess recurrence rates and quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We consider the first two affected children per family, and one randomly selected autistic twin per pair, as probands. We then compare recurrence rates and phenotypes between males and females and between twin pairs or families with at least one female proband (female-containing (FC)) versus those with only male probands (male-only (MO)).ResultsAmong children born after two probands, we observe significantly higher recurrence in males (47.5%) than in females (21.1%; relative risk, RR = 2.25; adjusted P = 6.22e−08) and in siblings of female (44.3%) versus siblings of male probands (30.4%; RR = 1.46; adj. P = 0.036). This sex-differential recurrence is also robust in dizygotic twin pairs (males = 61.5%, females = 19.1%; RR = 3.23; adj. P = 7.66e−09). Additionally, we find a significant negative relationship between interbirth interval and ASD recurrence that is driven by children in MO families.ConclusionsBy classifying families as MO or FC using two probands instead of one, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, a significant sex difference in risk to children within FC families suggests that female protective mechanisms are still operative in families carrying high genetic risk loads. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk is consistent with a potentially greater contribution from environmental factors in males versus higher genetic risk in affected females and their families. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0004-5) contains supplementary material, which is available to authorized users.
Highlights
Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms
This increased risk for ASD in males compared with females corroborates findings from other studies of recurrence risk in infant siblings [6] as well as in a sample of families from Autism Genetics Resource Exchange (AGRE) and the Interactive Autism Network registry [5]
We observe higher recurrence rates in families with at least one affected female proband as compared with families whose probands are exclusively male; this difference is expected under the sex-differential threshold liability model for ASD
Summary
Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. Autism spectrum disorders are developmental disorders that appear early in life and are defined by impairments in social skills and language abilities, as well as restricted interests and repetitive behaviors [1] These symptoms present heterogeneously, with some autistic children showing severe intellectual disability and poor basic daily living skills, and others with high intelligence and capacity for independence. The heritable or familial component of ASD’s genetic risk architecture, likely to account for more than 50% of genetic risk [15,16], is still poorly understood; family-based genetic linkage and association studies have identified very few replicable risk loci [17,18,19,20,21,22,23,24,25,26]
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