Background: Age at onset (AAO) is a known prognostic indicator for schizophrenia and is hypothesized to correlate with cognition and symptom severity. TCF4 and AKT1 are schizophrenia risk genes involved in cognitive functions. The current study examined the interactive effects of TCF4 and AKT1 variants with gender, family history of psychiatric disorders and ethnicity on the AAO of schizophrenia.
Methods: This study consisted of 322 patients with schizophrenia meeting the DSM-IV criteria. Six single nucleotide polymorphisms (SNPs) of TCF4 (rs12966547, rs8766, rs2958182, rs9960767, rs10401120 and rs17512836) and seven AKT1 SNPs (rs2498804, rs3803304, rs2494732, rs3730358, rs1130214, rs2498784 and rs3803300) were genotyped using the TaqMan® SNP genotyping-based assays method. The relationship of AAO with each variant was investigated using analyses of covariance.
Results: Among the TCF4 variants, rs12966547 (p = 0.024) and rs8766 (p = 0.021) were significantly associated with earlier AAO. We found a lower average AAO in patients with the AA genotype of rs12966547, while the CT genotype of rs8766 was demonstrated to have a protective effect on AAO. For rs8766, there was significant gene × gender interaction (p = 0.012) in influencing AAO. However, these results were not significant after false discovery rate correction. Significant gene × ethnicity interactions were observed to influence AAO (p < 0.05). The Kaplan-Meier curve of the minor AA genotype of rs12966547 displayed a significant trend (p = 0.008) for onset after 19 years of age. Similarly, the minor CC genotype of rs8766 showed a significantly (p = 0.034) lower AAO compared to the TT genotype.
Conclusion: Our analyses suggest that individual risk genotypes may influence the risk of schizophrenia in an age-specific manner.
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