1. ¹Department of Medicine, Center for Human Genetics, IGSP, Duke University Medical Center, Durham, NC, USA
2. ²Center for Human Genetics Research and Department of Molecular Physiology and Biophysics Vanderbilt University Medical Center, Nashville, TN, USA
3. ³Department of Psychiatry, Tufts University/New England Medical Center, Boston, MA, USA

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

Received 9 April 2004; Revised 29 September 2004; Accepted 4 October 2004; Published online 23 November 2004.

Abstract

Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5'-untranslated region (5'-UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Family-based association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5'-UTR repeat (PDT P-value=0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.