Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia

Abstract Schizophrenia is a complex neurodevelopmental disorder that is thought to be induced by an interaction between predisposing genes and environmental stressors. To identify predisposing genetic factors, we performed a targeted (mostly neurodevelopmental) gene approach involving the screening...

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Bibliographic Details
Published in:Journal of psychiatric research 2009-10, Vol.43 (15), p.1195-1199
Main Authors: van Schijndel, Jessica E, van Loo, Karen M.J, van Zweeden, Martine, Djurovic, Srdjan, Andreassen, Ole A, Hansen, Thomas, Werge, Thomas, Kallunki, Pekka, Pedersen, Jan T, Martens, Gerard J.M
Format: Article
Language:English
Subjects:
Adult
Adult and adolescent clinical studies
Aged
Aged, 80 and over
Alleles
Amino acids
Biological and medical sciences
Case-Control Studies
Case-control study
Chi-Square Distribution
Cohort Studies
Denmark
Development
European Continental Ancestry Group
Female
Gene Frequency
Genes
Genetic factors
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Medical sciences
Meta-analysis
Middle Aged
NTRK1 receptor
Polymorphism, Single Nucleotide - genetics
Psychiatry
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Psychoses
Receptor, trkA - genetics
Schizophrenia
Schizophrenia - genetics
Screening
Single-nucleotide polymorphism
United States
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Summary:Abstract Schizophrenia is a complex neurodevelopmental disorder that is thought to be induced by an interaction between predisposing genes and environmental stressors. To identify predisposing genetic factors, we performed a targeted (mostly neurodevelopmental) gene approach involving the screening of 396 selected non-synonymous single-nucleotide polymorphisms (SNPs) in three independent Caucasian schizophrenia case-control cohorts (USA, Denmark and Norway). A meta-analysis revealed ten non-synonymous SNPs that were nominally associated with schizophrenia, nine of which have not been previously linked to the disorder. Risk alleles are in TRKA (rs6336), BARD1 (rs28997576), LAMA5 (rs3810548), DKK2 (rs7037102), NOD2 (rs2066844) and RELN (rs2229860), whereas protective alleles are in NOD2 (rs2066845), NRG1 (rs10503929), ADAM7 (rs13259668) and TNR (rs859427). Following correction for multiple testing, the most attractive candidate for further study concerns SNP rs6336 ( q = 0.12) that causes the substitution of an evolutionarily highly conserved amino acid residue in the kinase domain of the neurodevelopmentally important receptor TRKA. Thus, TRKA signaling may represent a novel susceptibility pathway for schizophrenia.
ISSN:0022-3956
1879-1379
DOI:10.1016/j.jpsychires.2009.04.006