Replication of association between working memory and Reelin, a potential modifier gene in schizophrenia.
BACKGROUND
The challenges in gene identification for psychiatric disorders have awakened interest toward quantitative traits and endophenotypes that are potentially more closely related to the underlying biology and provide more power in the linkage and association analyses. Previously, we successfully replicated schizophrenia linkage on chromosome 7q21-32 in Finnish families and demonstrated that an intragenic short tandem repeat (STR) allele of the regional Reelin (RELN) gene is associated with multiple cognitive traits representing central cognitive functions regarded as valid endophenotypes for schizophrenia.


METHODS
Here, we used an extended sample of 290 Finnish families with schizophrenia and 375 control subjects in an association analysis between 96 SNPs and three STRs in RELN and diagnostic categories, clinical disorder features, as well as central cognitive functions impaired in schizophrenia.


RESULTS
We replicated the original association between RELN intragenic STR allele and working memory in individuals (n = 342) not overlapping with the previous study. This risk allele remained central in the whole study sample by being associated with impaired cognitive functioning and more severe positive and negative symptoms of schizophrenia (p = .0005-.00002). Additionally, multiple SNPs indicated association with the severity of positive symptoms of schizophrenia and together showed potential additive effect on the severity of the symptoms (p = .0000001). However, no significant associations with clinical diagnostic categories emerged.


CONCLUSIONS
The strongest effects on cognitive functions were detected among the affected individuals. We thus propose a particular role for RELN as a modifier gene of the pathogenesis of schizophrenia.
Wedenoja
Juho
J
Institute for Molecular Medicine Finland FIMM, University of Helsinki and National Institute for Health and Welfare, Helsinki, Finland.
Tuulio-Henriksson
Annamari
A
Suvisaari
Jaana
J
Loukola
Anu
A
Paunio
Tiina
T
Partonen
Timo
T
Varilo
Teppo
T
Lönnqvist
Jouko
J
Peltonen
Leena
L
D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008570:Memory, Short-Term; D018895:Microsatellite Repeats; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000091042:Reelin Protein; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D012565:Schizophrenic Psychology; D012697:Serine Endopeptidases / Q000235:genetics*
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; D012697:Serine Endopeptidases