A Genomic Screen of Autism: Evidence for a Multilocus Etiology

Abstract

We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying </=10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary.

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.…”

“…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.…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Third, twin and family studies have provided compelling evidence for a strong genetic component among autistic individuals (Folstein et al, 2003;Hu-Lince et al, 2005;Vorstman et al, 2006). Multiple genome-wide screens have found evidence for linkage to autism in several chromosomes, including chromosomes 2, 6, 7, 15, 17, 20 and X (International Molecular Genetic Study of Autism Consortium (IMGSAC), 1998, 2001); Barrett et al, 1999;Philippe et al, 1999;Risch et al, 1999;Collaborative Linkage Study of Autism, 2001;Buxbaum et al, 2001;Ylisaukko-oja et al, 2004;Hu-Lince et al, 2005). Likewise, analysis of reported cytogenetic abnormalities (i.e.…”