1. ¹Center for Human Genetics, Duke University Medical Center, Durham, NC, USA
2. ²Translational Genomics Research Center, Phoenix, AZ, USA
3. ³Department of Neuropsychiatry and Behavioral Science, School of Medicine, University of South Carolina, Columbia, SC, USA
4. ⁴Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence: Dr MA Pericak-Vance, Center for Human Genetics, Duke University Medical Center, 595 LaSalle St, Blg.7540, Box 3445, Durham, NC 27710, USA. E-mail: mpv@chg.duhs.duke.edu

Received 2 August 2006; Revised 19 September 2006; Accepted 24 September 2006; Published online 19 December 2006.

Abstract

Autism is a common neurodevelopmental disorder with a significant genetic component and 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.