Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families

Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2-q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n = 1626) allowed replication of linkage on 7q21-32. In a sample of 245 nuclear families (n = 1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n = 861) of the sample showed significant association to RELN variants for traits related to verbal (P = 0.000003) and visual working memory (P = 0.002), memory (P = 0.002) and executive functioning (P = 0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P = 0.0004-0.0000000004), memory (P = 0.02-0.0001) and executive functioning (P = 0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.