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.

Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant impairment in social, communicative, and behavioral functioning. A genetic basis for AutD is well established with as many as 10 genes postulated to contribute to its underlying etiology. We have completed a genomic screen and follow‐up analysis to identify potential AutD susceptibility loci. In stage one of the genome screen, 52 multiplex families (two or more AutD affected individuals/family) were genotyped with 352 genetic markers to yield an approximately 10 centimorgan (cM) grid, inclusive of the X chromosome. The selection criterion for follow‐up of interesting regions was a maximum heterogeneity lod score (MLOD) or a maximum nonparametric sib pair lod score (MLS) of at least 1.0. Eight promising regions were identified on chromosomes 2, 3, 7, 15, 18, 19, and X. In the stage two follow‐up study we analyzed an additional 47 multiplex families (total = 99 families). Regions on chromosomes 2, 3, 7, 15, 19, and X remained interesting (MLOD ≥ 1.0) in stage two analysis. The peak lod score regions on chromosomes 2, 7, 15, 19, and X overlap previously reported peak linkage areas. The region on chromosome 3 is unique. © 2001 Wiley‐Liss, Inc.

Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant disturbances in social, communicative, and behavioral functioning. A two-stage genomic screen analysis of 99 families with AutD revealed suggestive evidence for linkage to chromosome 2q (D2S116 nonparametric sib-pair LOD score [MLS] 1.12 at 198 cM). In addition, analysis of linkage disequilibrium for D2S116 showed an allele-specific P value of <.01. Recently, linkage to the same region of 2q was reported in an independent genome screen. This evidence for linkage increased when analysis was restricted to the subset of patients with AutD who had delayed onset (>36 mo) of phrase speech (PSD). We similarly classified our data set of 82 sib pairs with AutD, identifying 45 families with AutD and PSD. Analysis of this PSD subset increased our support for linkage to 2q (MLS 2.86 and HLOD 2.12 for marker D2S116). These data support evidence for a gene on chromosome 2 contributing to risk of AutD, and they suggest that phenotypic homogeneity increases the power to find susceptibility genes for AutD.