A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism.

TitleA linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism.
Publication TypeJournal Article
Year of Publication2004
AuthorsMcCauley, JL, Olson LM, Delahanty R, Amin T, Nurmi EL, Organ EL, Jacobs MM, Folstein SE, Haines JL, Sutcliffe JS
JournalAmerican journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
Date Published2004 Nov 15
KeywordsAlleles, Autistic Disorder, Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 15, Family Health, Female, Gene Frequency, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Male, Multigene Family, Polymorphism, Single Nucleotide, Protein Subunits, Receptors, GABA-A

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.

Alternate JournalAm. J. Med. Genet. B Neuropsychiatr. Genet.