Linkage Disequilibrium at the Angelman Syndrome Gene UBE3A in Autism Families

Nurmi, Erika L.; Bradford, Yuki; Chen, Yi Hui; Hall, Jenifer L.; Arnone, Brenda; Gardiner, Mary Beth; Hutcheson, Holli; Gilbert, John R.; Pericak‐Vance, Margaret A.; Copeland-Yates, Susan A.; Michaelis, Ron C.; Wassink, Thomas H.; Santangelo, Susan L.; Sheffield, Val C.; Piven, Joseph; Folstein, Susan E.; Haines, Jonathan L.; Sutcliffe, James S.

doi:10.1006/geno.2001.6617

Cited by 139 publications

(100 citation statements)

References 43 publications

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“…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.…”

Section: Chromosome 15mentioning

confidence: 99%

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

2006

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Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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Section: Chromosome 15mentioning

confidence: 99%

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

2006

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“…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). In another three studies, no significant association was observed between the genes and autism (Nurmi et al 2001;Ma et al 2005;Kim et al 2006). Thus, the results were inconclusive, and further investigation may be needed to elucidate the problem.…”

Section: Introductionmentioning

confidence: 92%

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

et al. 2007

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The c-aminobutyric acid (GABA) receptor genes GABRB3, GABRA5, and GABRG3 located on chromosome 15q11-q13 have been major candidates for susceptibility genes for autism, a neurodevelopmental disorder with a complex genetic etiology. In this study, we first investigated the association between the GABA receptor genes and autism in a Japanese population by analyzing 11 single nucleotide polymorphisms (SNPs). Intron 3 of GABRB3 was densely mapped because the previous studies observed the association of the microsatellite 155CA-2 located in the region. We observed no significant difference in allelic frequencies or genotypic distributions of the 11 SNPs between patients and controls. A permutation test showed no significant global differences in estimated haplotype frequencies between patients and controls. Analysis after confining the subjects to males showed similar results. Thus, this study provides no positive evidence of an association between the GABA receptor genes and autism in a Japanese population. However, in a SNP (rs3212337) located near the microsatellite 155CA-2, a significant deviation from the HardyWeinberg equilibrium was observed in patients (p = 0.029, corrected for multiple testing). This finding may suggest further studies around the markers for more definitive conclusions.

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“…[34][35][36] Three groups have observed LD at different markers within GABRB3; 30,[37][38][39] however, these findings were not replicated in three independent data sets. [40][41][42] Finally, we have recently reported allelic association in the Collaborative Linkage Study of Austism (CLSA) families at marker D15S122 located at the 5 0 end of UBE3A (42).…”

Section: Introductionmentioning

confidence: 97%

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

et al. 2003

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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.

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Linkage Disequilibrium at the Angelman Syndrome Gene UBE3A in Autism Families

Cited by 139 publications

References 43 publications

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

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

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

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

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