1. ¹Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
2. ²Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
3. ³Department of Psychology, Hebrew University and Sara Herzog Memorial Hospital, Jerusalem, Israel
4. ⁴Regional Mental Health Center, Taibe, Israel
5. ⁵Dr Kemal Hospital, Bethlehem, Palestinian Authority, Palestine
6. ⁶Department of Psychiatry, University of Bonn, Germany
7. ⁷Department of Biology, University of Milan, Milan, Italy
8. ⁸Dépt de Génétique Médicale, CHUV-UNIL, Lausanne, Switzerland

Correspondence: Professor B 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 28 February 2006; Revised 2 May 2006; Accepted 2 May 2006; Published online 14 June 2006.

Abstract

Schizophrenia, a severe neuropsychiatric disorder, is believed to involve multiple genetic factors. A significant body of evidence supports a pivotal role for abnormalities of brain development in the disorder. Linkage signals for schizophrenia map to human chromosome 6q. To obtain a finer localization, we genotyped 180 single nucleotide polymorphisms (SNPs) in a young, inbred Arab-Israeli family sample with a limited number of founders. The SNPs were mostly within a 7 Mb region around the strong linkage peak at 136.2 Mb that we had previously mapped. The most significant genetic association with schizophrenia for single SNPs and haplotypes was within a 500 kb genomic region of high linkage disequilibrium (LD) at 135.85 Mb. In a different, outbred, nuclear family sample that was not appropriate for linkage analysis, under-transmitted haplotypes incorporating the same SNPs (but not the individual SNPs) were significantly associated with schizophrenia. The implicated genomic region harbors the Abelson Helper Integration Site 1 (AHI1) gene, which showed the strongest association signal, and an adjacent, primate-specific gene, C6orf217. Mutations in human AHI1 underlie the autosomal recessive Joubert Syndrome with brain malformation and mental retardation. Previous comparative genomic analysis has suggested accelerated evolution of AHI1 in the human lineage. C6orf217 has multiple splice isoforms and is expressed in brain but does not seem to encode a functional protein. The two genes appear in opposite orientations and their regulatory upstream regions overlap, which might affect their expression. Both, AHI1 and C6orf217 appear to be highly relevant candidate genes for schizophrenia.