Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms.
BACKGROUND
Schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown.


OBJECTIVE
To prepare the ground for a novel "phenomics" approach, a unique schizophrenia patient database was established by GRAS (Göttingen Research Association for Schizophrenia), designed to allow association of genetic information with quantifiable phenotypes.Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenotype-based genetic association study (PGAS) of GRAS [corrected]


METHODS
Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated.


METHODS
Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany.


METHODS
One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory.


RESULTS
Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in Cplx2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells.


CONCLUSIONS
The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression.
Begemann
Martin
M
Max Planck Institute of Experimental Medicine, Göttingen, Germany.
Grube
Sabrina
S
Papiol
Sergi
S
Malzahn
Dörthe
D
Krampe
Henning
H
Ribbe
Katja
K
Friedrichs
Heidi
H
Radyushkin
Konstantin A
KA
El-Kordi
Ahmed
A
Benseler
Fritz
F
Hannke
Kathrin
K
Sperling
Swetlana
S
Schwerdtfeger
Dayana
D
Thanhäuser
Ivonne
I
Gerchen
Martin F
MF
Ghorbani
Mohammad
M
Gutwinski
Stefan
S
Hilmes
Constanze
C
Leppert
Richard
R
Ronnenberg
Anja
A
Sowislo
Julia
J
Stawicki
Sabina
S
Stödtke
Maren
M
Szuszies
Christoph
C
Reim
Kerstin
K
Riggert
Joachim
J
Eckstein
Fritz
F
Falkai
Peter
P
Bickeböller
Heike
H
Nave
Klaus-Armin
KA
Brose
Nils
N
Ehrenreich
Hannelore
H
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics*; D030541:Databases, Genetic / Q000706:statistics & numerical data; D005260:Female; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D056726:Genetic Association Studies; D005819:Genetic Markers; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology
D033942:Adaptor Proteins, Vesicular Transport; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; C095993:complexin II