Evidence for sex-specific risk alleles in autism spectrum disorder

Abstract

We investigated the genetic aspects of the large sex bias in the prevalence of autism spectrum disorder by monitoring changes in linkage when the family set for an affected sibling pair genome scan is subdivided on the basis of the sex of affected children. This produces a significant excess in the total number of linkage peaks (P=1.3 x 10(-8)) and identifies a major male-specific linkage peak at chromosome 17q11 (P<.01). These results suggest that sexual dichotomy is an important factor in the genetics of autism; the same strategy can be used to explore this possibility in other complex disorders that exhibit significant sex biases.

Figure 1

Sex-stratified genome scans, with CIs and highlighted regions. A, Original genome scan based on all families. B and C, The genome scan for MO and FC families, respectively, shown as multicolored lines. The black line represents the sex-stratification–based 95% CI curve; the red sections of the scan curve denote regions where the LOD score exceeds the 95% CI (sex-stratification P<.05), whereas the green portions are within the CI. D, Close-up of the MO family scan in panel B for chromosome 17, with the addition of black lines that show the original genome scan (lowest curve) and the 99% and 99.9% sex-stratification CI curves (upper two curves). E, Close-up of the FC family scan in panel C for chromosome 4, with the addition of black lines that show the original genome scan (lowest curve) and the 99% and 99.9% sex-stratification CI curves (upper two curves).