Human Molecular Genetics Advance Access originally published online on October 9, 2006
Human Molecular Genetics 2006 15(22):3329-3342; doi:10.1093/hmg/ddl409
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Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia
1 Department of Psychiatry and Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, 800 E. Leigh Street, Richmond, VA 23298, USA, 2 The Department of Psychiatry, The Queens University, Belfast, Northern Ireland, UK, 3 The Health Research Board, Dublin, Ireland, 4 Department of Psychiatry, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, Pennsylvania, USA, 5 Western Australian Institute for Medical Research, Centre for Medical Research and 6 Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, WA, Australia and 7 Department of Psychiatry and 8 Department of Human Genetics, University of North Carolina, Chapel Hill, North Carolina, USA
* To whom correspondence should be addressed. Tel: +1 8048288124; Fax: +1 8048281471; Email: xchen{at}vcu.edu
Received June 16, 2006; Revised August 29, 2006; Accepted October 5, 2006
Chromosome 5q22–33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density Schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case–control sample (657 cases and 414 controls), an Irish parent–proband trio sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes.