Genomic screen and follow‐up analysis for autistic disorder

Abstract

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.

Evidence for multiple loci from a genome scan of autism kindreds

“…The location of this signal overlaps with positive results from analysis from the International Molecular Genetic Study of Autism Consortium (IMGSAC) 16,17,25 and from others. 15,19,23 Thus, our data provides strong support for an autism locus on chromosome 7, both as an individual result, and in conjunction with previous results. Notably missing from our genome scan were signals corresponding to those reported by others on chromosome 2 13,16,17,23,45 and chromosome 17.…”

“…15,19,23 Thus, our data provides strong support for an autism locus on chromosome 7, both as an individual result, and in conjunction with previous results. Notably missing from our genome scan were signals corresponding to those reported by others on chromosome 2 13,16,17,23,45 and chromosome 17. 14,20,24 Gender and linkage analyses Previous work by others suggested that linkage signals on chromosomes 4, 14,20 7, 17 and 17 14,20 were dependent on the gender of the affected individuals in the families.…”

“…The most striking replication is for chromosome 7q, where the IMGSAC finds a strong signal at B133-141 cM 17 on the Rutgers genetic map. Modest evidence for a chromosome 7 locus at this approximate location was also observed in four other linkage analyses, 15,18,19,23 but not in three other studies. 13,12,20 Meta-analyses of genome scan data from a subset of these studies, but not including our data, provides additional evidence for a chromosome 7q autism locus.…”

“…To date, genomewide linkage studies of autism in eight largely nonoverlapping family collections have been published. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] The number of families in these studies ranges from 39 12 to 345 24 families with most kindreds having two affected siblings. While no single region has been unambiguously associated with autism, coincident signals for specific chromosomal regions have been identified in multiple studies.…”

“…While no single region has been unambiguously associated with autism, coincident signals for specific chromosomal regions have been identified in multiple studies. These include 1p (B137-149 cM), 12,19 2q (B177-198 cM), 13,17,22,23 7q (104-145 cM) [15][16][17]25 17q (61 cM) 14,17,21,22 and 19q (B60 cM), 18,23 with the 2q, 7q and 17q regions giving the strongest signals. Numerous candidate gene association studies have also been described but no association finding has been consistently and independently replicated across multiple studies.…”