ZDHHC8 as a candidate gene for schizophrenia: Analysis of a putative functional intronic marker in case-control and family-based association studies

Background: The chromosome 22q11 region is proposed as a major candidate locus for susceptibility genes to schizophrenia. Recently, the gene ZDHHC8 encoding a putative palmitoyltransferase at 22q11 was proposed to increase liability to schizophrenia based on both animal models and human association studies by significant over-transmission of allele rs175174A in female, but not male subjects with schizophrenia. Methods: Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we examined rs175174 in 204 German proband-parent triads and in an independent case-control study (schizophrenic cases: n = 433; controls: n = 186). Results: In the triads heterozygous parents transmitted allele G preferentially to females, and allele A to males (heterogeneity chi(2) = 4.43; p = 0.035). The case-control sample provided no further evidence for overall or gender-specific effects regarding allele and genotype frequency distributions. Conclusion: The findings on rs175174 at ZDHHC8 are still far from being conclusive, but evidence for sexual dimorphism is moderate, and our data do not support a significant genetic contribution of rs175174 to the aetiopathogenesis of schizophrenia.