Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Schizophrenia is a complex mental disorder with an unclear biological basis.
• The role of specific gene variants in schizophrenia's complex phenotype is largely unknown.

Purpose of the Study:

• To establish a schizophrenia patient database for a phenomics approach, linking genetic information with quantifiable phenotypes.
• To investigate the complexin 2 gene (CPLX2) in the first phenotype-based genetic association study (PGAS) due to its role in synaptic dysfunction.

Main Methods:

• A case-control study analyzed CPLX2 polymorphisms' contribution to cognitive domains in schizophrenia patients.
• Mechanistic insights were gained by studying CPLX2 in peripheral blood mononuclear cells, Cplx2-null mutant mice, and transfected cells.
• The study involved 1071 schizophrenia patients and 1079 healthy controls, with extensive phenotypic data collection.

Main Results:

• Six single-nucleotide polymorphisms (SNPs) in CPLX2 were strongly associated with current cognition in schizophrenia patients.
• Cplx2-null mutant mice showed cognitive deficits, particularly when combined with a pubertal brain lesion (a "second hit" model).
• A specific SNP (rs3822674) in CPLX2 influenced microRNA-498 binding, gene expression, and was linked to differential CPLX2 expression in blood cells.

Conclusions:

• The PGAS approach successfully identified marker-associated clinical and biological traits in schizophrenia.
• CPLX2 gene variants modulate posttranscriptional gene expression, influencing current cognitive performance in schizophrenia patients.