A linkage disequilibrium map of the 1‐Mb 15q12 GABA_A receptor subunit cluster and association to autism

Abstract

Autism is a complex genetic neuropsychiatric condition characterized by deficits in social interaction and language and patterns of repetitive or stereotyped behaviors and restricted interests. Chromosome 15q11.2-q13 is a candidate region for autism susceptibility based on observations of chromosomal duplications in a small percentage of affected individuals and findings of linkage and association. We performed linkage disequilibrium (LD) mapping across a 1-Mb interval containing a cluster of GABA(A) receptor subunit genes (GABRB3, GABRA5, and GABRG3) which are good positional and functional candidates. Intermarker LD was measured for 59 single nucleotide polymorphism (SNP) markers spanning this region, corresponding to an average marker spacing of 17.7 kb(-1). We identified haplotype blocks, and characterized these blocks for common (>5%) haplotypes present in the study population. At this marker resolution, haplotype blocks comprise <50% of the DNA in this region, consistent with a high local recombination rate. Identification of haplotype tag SNPs reduces the overall number of markers necessary to detect all common alleles by only 12%. Individual SNPs and multi-SNP haplotypes were examined for evidence of allelic association to autism, using a dataset of 123 multiplex autism families. Six markers individually, across GABRB3 and GABRA5, and several haplotypes inclusive of those markers, demonstrated nominally significant association. These results are positively correlated with the position of observed linkage. These studies support the existence of one or more autism risk alleles in the GABA(A) receptor subunit cluster on 15q12 and have implications for analysis of LD and association in regions with high local recombination.

An association analysis of candidate genes on chromosome 15 q11–13 and autism spectrum disorder

“…Linkage disequilibrium (LD) analyses were performed by the programme haploview (http:// www.broad.mit.edu/mpg/haploview/) 27 and as others have reported, 12 we found evidence for only a moderate degree of linkage disequilibrium in the region. We used an individual SNP and haplotype analysis programme called weighted haplotype regression (WHAP) http://www.broad.mit.edu/personal/shaun/whap to examine the association between the bi-allelically expressed genes GABRB3 and GABRG3 and the imprinted genes UBE3A and ATP10C.…”

“…More pertinently however, marker rs4906683 is only 12.8 and 13. reported to be associated with autism in a previous report. 12 One limitation to our study is that we tested multiple markers and haplotypes in four candidate genes in this region and because of multiple testing our findings need to be interpreted with caution. Additionally, haplotype-based TDT tests are more subject to bias from Mendelian errors.…”

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

“…[213][214][215][216] Only nominal significant associations of different haplotypes, SNPs or microsatellites located in or around the GABRB3 and the GABRG3 gene have been found in three further studies. 215,[217][218][219] The largest study to date assessing GABA receptor subunit genes found evidence for association of a single SNP in the GABRA4 gene on chromosome 4p with AD, and for interaction effects of this variant with a SNP in the GABRB1 gene on chromosome 4p. No association for SNPs in the GABA receptor genes on chromosome 15 were found.…”

“…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. The UBE3A gene seems not to be relevant for idiopathic AD, which matches the phenotypic differences between Angelman syndrome and AD.…”

“…The most common assessed variants are a deletion/ insertion polymorphism in the transcriptional control region of the SLC6A4 gene with functional effects (5HTTLPR) [227][228][229] and a variable number of tandem repeat in intron 2 (STin2). Several studies have found an association of the short alleles of 5HTTLPR with AD, 217,[230][231][232][233] fewer studies of the long alleles. 234,235 Some studies did not replicate these findings.…”