1. ¹Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2. ²Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
3. ³St. Mary's Hospital, Catholic University of Korea, Seoul, Korea
4. ⁴Regional Mental Health Center, Taibe, Israel
5. ⁵Center for Genomic Technologies, Hebrew University of Jerusalem, Israel
6. ⁶Dépt de Génétique Médicale, Lausanne-CHUV, Switzerland
7. ⁷Center for Addiction and Mental Health, University of Toronto, Canada

Correspondence: Prof Bernard Lerer, Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah – Hebrew University Medical Center, Ein Karem, Jerusalem 91120, Israel. Tel: +972 2 6777185; Fax: +972 2 6439294; E-mail: lerer@cc.huji.ac.il

Received 17 November 2004; Revised 3 February 2005; Accepted 11 February 2005; Published online 6 April 2005.

Abstract

We previously reported an autosomal scan for schizophrenia susceptibility loci in a systematically recruited sample of Arab Israeli families. The scan detected significant evidence for linkage at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) and a multipoint parametric LOD score of 4.16. In order to refine this finding we typed 42 additional microsatellite markers on chromosome 6q between D6S1570 (99.01 cM from the pter) and D6S281 (190.14 from the pter) in the same sample (average intermarker distance 1.7 cM). In the 23 cM region between D6S1715 and D6S311, markers were more closely spaced (1.1 cM). Multipoint nonparametric and parametric and single point linkage analyses were performed. The peak NPL rose to 4.98 (P=0.00000058) at D6S1626 (136.97 cM), immediately adjacent to D6S292 (NPL 4.98, P=0.00000068), the marker that gave the highest NPL in the original genome scan, under the broad diagnostic category. The putative susceptibility region (NPL-1) was reduced from 12.0 to 4.96 cM. The peak multipoint parametric LOD score was 4.63 at D6S1626 under a dominant genetic model, core diagnostic category and the LOD-1 interval was 2.10 cM. The maximum single point LOD score (3.55, =0.01) was also at D6S1626 (dominant model, core diagnostic category). Increased evidence for linkage in the same sample as in the original genome scan and consistent localization of the linkage peak add further support for the presence of a schizophrenia susceptibility locus at chromosome 6q23. Moreover, the markedly reduced linkage interval greatly improves prospects for identifying a schizophrenia susceptibility gene within the implicated region.