Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia.
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.
Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Nijmegen Centre for Molecular Life Sciences (NCMLS), Faculty of Science, Radboud University Nijmegen, NCMLS RT282, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, The Netherlands.
Jessica E
JE
van Schijndel
Karen M J
KM
van Loo
Martine
M
van Zweeden
Srdjan
S
Djurovic
Ole A
OA
Andreassen
Thomas
T
Hansen
Thomas
T
Werge
Pekka
P
Kallunki
Jan T
JT
Pedersen
Gerard J M
GJ
Martens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D015331:Cohort Studies; D003718:Denmark; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020917:Receptor, trkA / Q000235:genetics*; D000091042:Reelin Protein; D012559:Schizophrenia / Q000235:genetics*; D014481:United States; D044465:White People
D000091042:Reelin Protein; D020917:Receptor, trkA; C000717127:RELN protein, human