Dense linkage disequilibrium mapping in the 15q11–q13 maternal expression domain yields evidence for association in autism

Abstract

Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5 0 introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11-q13.

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…220 Similar inconclusive results have been obtained for variants in or close to the AT Pase, class V, type 10C (ATP10C) and the ubiquitin-protein ligase E3A (UBE3A) genes located in the maternal expression domain of chromosome 15q11-13. 212,221,222 Only one study 223 reported an association of D15S122/ hCV2558436 located in the intron at the 5 0 end of UBE3A, which remained significant after correction for multiple testing. This association, however, was not replicated in a bigger sample.…”

“…This association, however, was not replicated in a bigger sample. 222 Taken together, despite the possible role of the neurotransmitter GABA and its receptors in the aetiology of AD, the findings on genetic variants in these receptors are inconclusive to date. The complex organization of chromosome 15q11-q13 with two imprinted regions and areas of high local recombination differing between men and women 217 make it even more difficult to assess genes in this area with regard to their relevance for AD.…”

15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders

“…Chromosome 15q11-13 is one of the genetic loci implicated in autism, as maternal duplications of this region remain one of the most common cytogenetic abnormalities found in cases of idiopathic autism (6). Additional evidence from multiple linkage and association studies suggests 15q11-13 genes are involved in autism (7)(8)(9)(10).…”

A Novel 6.14 Mb Duplication of Chromosome 8p21 in a Patient with Autism and Self Mutilation

“…Cytogenetic abnormalities, consisting of duplications, deletions, translocations, inversions and ring chromosomes have been detected in 5-10% of the patients with autism (Vorstman et al 2006). Among the most frequently reported are abnormalities of chromosome 15, specifically the interval 15q11-q13 (Nurmi et al 2003), 2q37, 5p14-15, several regions on chromosome 7, 11q25, 16q22.3, 18q21.1, 18q23, 22q11.2, 22q13.3 and Xp22.2-p22.3 (Vorstman et al 2006). In addition, copy number variants (CNVs), ranging from a few kilobases to several megabases in size, have been detected in patients with autism (Jacquemont et al 2006;Sebat et al 2007;Hoyer et al 2007;Marshall et al 2008).…”