Association of familial autism with imprinted locus on 7q32

Background: A strong genetic component of autism is being approached by linkage analysis, candidate gene association studies, and, most recently, by analysis of copy-number variations and whole-genome associations. Given multiple linkage signals found across the human genome, most findings cannot be replicated on different populations. Linkage to 7q is by far the most robust finding in autism. Recently, linkage signal on 7q32 was replicated in two independent studies including ours.

Objectives: To search for susceptibility genes within the large genetic interval (20 cM ) identified by linkage we performed association analysis of selected candidate genes.

Methods: 350 multiplex autistic families were subjected to transmission disequilibrium test (TDT) analysis.

Results: We detected an association with  ~220 kb interval situated right under the linkage peak. Signals arose from multiple SNPs comprising several haploblocks with the largest one extending  over 100 kb. The associated region contains 5 protein-coding genes, and 4 of which are expressed in the brain. At least 3 of 5 candidate genes are imprinted in human and mouse. Mutations affecting coding sequences/splice sites of 7q32 candidate genes have been searched by sequencing of 100 autists and 100 control individuals.

Conclusions: We identified a new candidate region for autism on 7q32. The associated locus contains several imprinted genes. The involvement of epigenetic component - altered imprinting in autism may explain increasing incidence of the disorder.