Association between a GABRB3 polymorphism and autism

Abstract

Autistic disorder (OMIM 209850) is a disease with a significant genetic component of a complex nature. 1 Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (15q11-13) have been described in several individuals with autism. 1 For this reason, markers across this region have been screened for evidence of linkage and association, and a marker (155CA-2) in the ␥-aminobutyric acid type-A receptor ␤3 subunit gene (GABRB3) has been associated in one study 2 but not others. [3][4][5] We completed an association analysis with 155CA-2 using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). We also used four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) localized within 150 kb of 155CA-2. The use of multi-allelic TDT (MTDT) (P < 0.002), as well as the TDT (P < 0.004), demonstrated an association between autistic disorder and 155CA-2 in these families. Meiotic segregation distortion could be excluded as a possible cause for these results since no disequilibrium was observed in unaffected siblings. These findings support a role for genetic variants within the GABA receptor gene complex in 15q11-13 in autistic disorder. Molecular Psychiatry ( Autism is a development disorder characterized by impairments in three domains: communication, reciprocal social interactions, and repetitive or stereotyped behaviors and interests (for review see TagerFlusberg et al 1 ). The concordance rate for monozygotic twins is much higher than that of dizygotic twins, which indicates that genetic factors play an important role in the etiology of autism. In addition, family studies indicate that the recurrence risk to siblings, estimated from multiple studies at 1-3%, is profoundly higher than the risk to the general population, which has been estimated at ෂ0.5-2 per 1000. The mode of inheritance of autism appears to be complex; latentclass analyses suggest that 3-10 genes may underlie the disorder, 6 although an interpretation of at least one genome-wide linkage analysis has argued for Ͼ10 genes underlying the disorder. 7 Cytogenetic studies have demonstrated that duplications within the 15q11-q13 region can be associated with autism (for review see Tager-Flusberg et al 1 ). Moreover, symptoms of autism can be associated with both Prader-Willi and Angelman syndromes, both of which involve alterations in the 15q11-q13 region. Because of this, the15q11-q13 region has been examined for genetic linkage to autism. A mapping of nine markers spanning a region of ෂ2 Mb within this region in 132 families demonstrated linkage disequilibrium at a marker within the GABRB3 gene, 155CA-2. 2 An additional locus within GABRB3 that is ෂ150 kb away from 155CA-2 (D15S97) did not demonstrate linkage disequilibrium.A genome-wide scan involving 51 autistic multiplex families demonstrated a broad peak with a LOD score of about 1 over the GABRB3 region. 8 Similarly, multipoint analyses over the region in 63 families demonstrated a peak Z-score of 1.78 in the region, near the marker ...

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.…”

No evidence for significant association between GABA receptor genes in chromosome 15q11–q13 and autism in a Japanese population

“…Two of the studies (Cook et al 1998;Buxbaum et al 2002) observed the association of a microsatellite located in intron 3 of GABRB3 (155CA-2), whereas the other four studies did not replicate the association (Salmon et al 1999;Maestrini et al 1999;Martin et al 2000;Curran et al 2005). Except for 155CA-2, only nominal significant associations were observed with respect to markers located in or around these three GABA receptor genes (Martin et al 2000;Menold et al 2001;McCauley et al 2004;Ashley-Koch et al 2006).…”

La génétique de l’autisme

“…Cependant, bien que cette région soit soumise à empreinte parentale, aucun effet de l'origine parentale de la transmission de ces allèles n'a pu être identifié. D'autres études réalisées depuis ont montré des résultats contradictoires, mais une analyse de l'ensemble de ces résultats révèle un déséquilibre de transmission significatif [34]. D'autres recherches sont donc nécessaires dans cette région du génome afin d'identifier quelles pourraient être les variations nucléotidiques dans le gène GABRB3, ou dans un gène proche, qui augmenteraient la prédisposition au syndrome autistique.…”