Linkage-Disequilibrium Mapping of Autistic Disorder, with 15q11-13 Markers

Abstract

Autistic disorder is a complex genetic disease. Because of previous reports of individuals with autistic disorder with duplications of the Prader-Willi/Angelman syndrome critical region, we screened several markers across the 15q11-13 region, for linkage disequilibrium. One hundred forty families, consisting predominantly of a child with autistic disorder and both parents, were studied. Genotyping was performed by use of multiplex PCR and capillary electrophoresis. Two children were identified who had interstitial chromosome 15 duplications and were excluded from further linkage-disequilibrium analysis. Use of the multiallelic transmission-disequilibrium test (MTDT), for nine loci on 15q11-13, revealed linkage disequilibrium between autistic disorder and a marker in the gamma-aminobutyric acidA receptor subunit gene, GABRB3 155CA-2 (MTDT 28.63, 10 df, P=.0014). No evidence was found for parent-of-origin effects on allelic transmission. The convergence of GABRB3 as a positional and functional candidate along with the linkage-disequilibrium data suggests the need for further investigation of the role of GABRB3 or adjacent genes in autistic disorder.

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

“…The gamma-aminobutyric acid (GABA) receptor genes located on chromosome 15q11-q13 have received considerable attention, as a study has shown a decreased GABA receptor density in the hippocampus, 209 and a suppressed GABAergic inhibition has been suspected to be aetiologically relevant in AD. 210 Two studies 211,212 found evidence for association of a microsatellite located in intron 3 of the GABRB3 gene (GABRB3 155CA-2), whereas four other studies could not replicate this finding in samples of similar size and power. [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.…”

“…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.…”

Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients

“…7 At baseline, the scores were: BDI, 1279; STAI (added scores), 87721; CFQ, 1675; and SF-36 (added scores), 242777. Nine patients (31%) described a previous psychiatric history and were all included in the study; four patients were taking an antidepressant at baseline and continued with this throughout the treatment.…”

“…The Midwest autistic patients were diagnosed as described previously. 7 Putative missense mutations were identified once each in the NLGN4 gene in four separate autistic patients (Table 1). G99S and K378R were found in unrelated Portuguese patients.…”

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

“…It is approximately 150 kb from the 5 0 microsatellite marker 155C-A and about 120 kb from the 3 0 microsatellite GABRB3, markers for which there is some evidence of association as described above. [9][10][11] These microsatellites are at opposite ends of GABRB3 and this marker lies between the two. Given the poor LD across the entirety of the region, it is unlikely that our marker 5 is reflecting association with these microsatellites.…”