期刊
MOLECULAR PSYCHIATRY
卷 12, 期 4, 页码 376-384出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.mp.4001927
关键词
genome screen; autism; single-nucleotide polymorphisms; extended families
资金
- NCRR NIH HHS [M01 RR-00095] Funding Source: Medline
- NIA NIH HHS [R01 AG20135] Funding Source: Medline
- NINDS NIH HHS [R01 NS36768, R01 NS42165, NS26630] Funding Source: Medline
Autism locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD > 2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p, 11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD = 3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD = 4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.
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