Multiple variants of the DRD3, but not BDNF gene, influence age-at-onset of schizophrenia
Age-at-onset (AAO) of schizophrenia appears to be influenced by various factors including gender and genetics. Males appear to be affected earlier than females and variants of brain-derived neurotrophic factor (BDNF) and of dopamine receptor D3 (DRD3) genes, which are thought to be functionally related, may affect AAO of schizophrenia. However, no study has evaluated multiple single-nucleotide polymorphisms (SNPs) covering these two genes and their effect on AAO of schizophrenia. We report here analyses of 10 and 5 polymorphisms spanning DRD3 and BDNF genes, respectively. Two hundred thirty-eight Caucasian patients (163 men, 75 women) who were diagnosed with schizophrenia before age 40 were included. They were recruited from three clinical sites in North America: the Centre for Addiction and Mental Health in Toronto (Drs GR and JLK, n = 112); Case Western Reserve University in Cleveland, Ohio (Dr HYM, n = 72); Hillside Hospital in Glen Oaks, New York (Dr JAL, n = 54). All four clinicians are highly experienced in schizophrenia assessment. Subjects were recruited based on their diagnoses of schizophrenia according to DSM-III-R or DSM-IV and the availability of AAO data. The AAO was defined as the age when the subject first met DSM criteria for schizophrenia. All SNPs were genotyped using standard ABI TaqMan assay protocols. Genotypes were assigned manually post-amplification on the ABI 7500 Sequence Detection System. No significant differences in genotype and sex distributions between the samples from the three different clinical sites were noted using w tests with SPSS software, allowing the samples to be pooled. Hardy–Weinberg equilibrium was respected for the SNPs reported here. The influence of AAO of schizophrenia was studied by two complementary analyses: analysis of variance was performed for mean AAOs, and survival analysis (Cox proportional hazards model) was used to estimate the effect of gender and genotype on AAO of schizophrenia using SPSS (version 14.0.2). Results for the Cox model were corrected for multiple testing using SNP Spectral Decomposition and SNPSpD software, which take into account the linkage