INFLUENCE OF GENOME-WIDE ASSOCIATED GENETIC POLYMORPHISMS OF SCHIZOPHRENIA ON THE VERBAL FLUENCY

Background Schizophrenia is a serious psychiatric disorder of multifactorial genesis, which can be associated with serious limitations in everyday life. In addition to environmental factors, genetic factors play a crucial etiological role. In 2014, the Psychiatric Genomics Consortium (PGC) carried out the largest GWAS to date. Significant associations between schizophrenia and 128 linkage-disequilibrium-independent Single-Nucleotide Polymorphisms (SNP) were found in 108 conservatively defined loci (Ripke et al. 2014). A neuropsychological deficit of schizophrenia, which has been widely described in the literature, is a disturbance of verbal fluency. The aim of this study was to examine schizophrenia-associated SNPs for their association with verbal fluency. Methods The PAGES sample includes 1000 schizophrenia patients who were diagnosed according to DSM IV, and 3000 randomly selected psychiatrically healthy controls that performed a multi-stage selection procedure. Verbal fluency was assessed by Regensburg word fluency test (RWT) in a subset of 361 cases and 559 controls. Association analysis was performed applying linear regression using an additive model corrected for affection status, age, education and gender. Results Several SNPs showed nominal significant association with verbal fluency measured with RWT. rs11191419 (BLOC-1 related complex subunit 7, BORCS7) was associated with all tested domains (words, words switch, categories, categories switch), association of rs111294930 (LINC01470) was restricted to categories and categories switch, for both SNPs association was reflected in the same direction of effect in cases and controls. Association in cases only could be detected for rs7523273 (MIR29B2) (all domains) and rs9636107 (transcription factor 4, TCF4) (categories, categories switch), whereas association of rs3849046 (eukaryotic translation termination factor 1, ETF1) (all domains) and rs12826178 (mitochondrial serine hydroxymethyltransferase, SHMT2) (categories and word switch) were restricted to controls. Discussion Though no association survived multiple testing, the nominal associated variations are localized in or near genes showing interesting features. Most genes are involved in regulatory processes either on the transcriptional or translational level: Long non coding RNAs (i.e. LINC01470) and micro RNAs (i.e. MIR29B2) are known to be involved in transcriptional and post-transcriptional regulation of gene expression, ETF1 is involved in termination of mRNA translation and nonsense mediated RNA decay. TCF4 activates transcription. This gene also plays a role in the initiation of neuronal differentiation. Another hit, BORCS7 has been shown to be upregulated during human stem cell differentiation toward neuronal fates in early brain development. The results indicate an influence of schizophrenia risk variants on verbal fluency performance in healthy subjects, thereby implicating an underlying mechanism which might be involved in such deficits in schizophrenia. Functional relevance of the associated SNPs as well as replication in independent samples remains to be determined.