TY - JOUR
T1 - Three-cohort targeted gene screening reveals a non-synonymous TRKA polymorphism associated with schizophrenia
AU - van Schijndel, Jessica E
AU - van Loo, Karen M J
AU - van Zweeden, Martine
AU - Djurovic, Srdjan
AU - Andreassen, Ole A
AU - Hansen, Thomas
AU - Werge, Thomas
AU - Kallunki, Pekka
AU - Pedersen, Jan T
AU - Martens, Gerard J M
N1 - Keywords: Adult; Aged; Aged, 80 and over; Case-Control Studies; Chi-Square Distribution; Cohort Studies; Denmark; European Continental Ancestry Group; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Receptor, trkA; Schizophrenia; United States
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
U2 - 10.1016/j.jpsychires.2009.04.006
DO - 10.1016/j.jpsychires.2009.04.006
M3 - Journal article
C2 - 19435634
SN - 0022-3956
VL - 43
SP - 1195
EP - 1199
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
IS - 15
ER -