Fine Mapping of Autistic Disorder to Chromosome 15q11-q13 by Use of Phenotypic Subtypes

Abstract

Autistic disorder (AutD) is a complex genetic disease. Available evidence suggests that several genes contribute to the underlying genetic risk for the development of AutD. However, both etiologic heterogeneity and genetic heterogeneity confound the discovery of AutD-susceptibility genes. Chromosome 15q11-q13 has been identified as a strong candidate region on the basis of both the frequent occurrence of chromosomal abnormalities in that region and numerous suggestive linkage and association findings. Ordered-subset analysis (OSA) is a novel statistical method to identify a homogeneous subset of families that contribute to overall linkage at a given chromosomal location and thus to potentially help in the fine mapping and localization of the susceptibility gene within a chromosomal area. For the present analysis, a factor that represents insistence on sameness (IS)--derived from a principal-component factor analysis using data on 221 patients with AutD from the repetitive behaviors/stereotyped patterns domain in the Autism Diagnostic Interview-Revised--was used as a covariate in OSA. Analysis of families sharing high scores on the IS factor increased linkage evidence for the 15q11-q13 region, at the GABRB3 locus, from a LOD score of 1.45 to a LOD score of 4.71. These results narrow our region of interest on chromosome 15 to an area surrounding the gamma-aminobutyric acid-receptor subunit genes, in AutD, and support the hypothesis that the analysis of phenotypic homogeneous subtypes may be a powerful tool for the mapping of disease-susceptibility genes in complex traits.

Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs

“…The 7q linkage result, coupled with literature support for an autism susceptibility gene within 15 cM of the original QTL region, 5,7,10,11,34 prompted us to investigate the possibility of increased heterogeneity in the enlarged sample. Based on the novel work by Shao et al, 20 who described the use of phenotypic subtypes to identify homogeneous subsets of autism families, we applied the OSA approach to the language traits and obtained encouraging results. First, the linkage statistic for the qualitative analysis increased substantially by ranking the families according to the language covariates.…”

“…Investigators have begun to use these autism endophenotypes as covariates in linkage analyses in an attempt to increase both phenotypic and genetic homogeneity of the affected sample. [18][19][20][21] For example, Buxbaum et al 19 reported that most of the linkage evidence for a putative autism susceptibility locus on chromosome 2q was from the families with a language delay. These results were supported in an independent sample of 82 families with autism.…”

“…21 Bradford et al 18 investigated two chromosomes, 7 and 13, and suggested that language-delayed families were responsible for most of the evidence for linkage to autism to these chromosomes. Shao and colleagues 20 applied the Ordered-Subsets Analysis method to a covariate representing 'insistence on sameness' derived from a principal components analysis, and identified a subset of homogeneous families with autism that were responsible for linkage to a previously reported region on 15q11-13.…”

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

“…40,[119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137] Research groups, study design and main findings of linkage studies that reported positive results are summarized in Table 1 for genome-wide linkage and association studies with a qualitative AD phenotype, and in Table 2 for linkage studies with either a quantitative phenotype, a specific qualitative endophenotype, or other specific linkage models. 122,123,127,130,[138][139][140][141][142][143][144][145][146][147][148] From Table 1, it can be seen that linkage has been found in at least two independent studies in regions 2q, 3q25-27, 3p25, 6q14-21, 7q31-36 and 17q11-21.…”

“…144 Orderedsubset analysis regarding the phenotype insistence on sameness has resulted in significant linkage at chromosome 15q11-13. 147 Owing to the disappointing findings regarding the X-chromosome, other approaches have been chosen to elucidate the skewed sex distribution of AD. In two independent samples, two loci on 17q did show significant linkage in male only pairs.…”