Case–control study and transmission disequilibrium test provide consistent evidence for association between schizophrenia and genetic variation in the 22q11 gene ZDHHC8

Abstract

Genetic variants in the 22q11 gene ZDHHC8, which encodes a putative transmembrane palmitoyltransferase, has been associated to schizophrenia in family-based linkage disequilibrium (LD) studies. The single nucleotide polymorphism (SNP) rs175174 (A/G), which had the strongest association, has been shown recently to regulate the level of the fully functional transcript by modulating the retention of intron 4 of ZDHHC8. In this work, we genotyped three genetic variants within the ZDHHC8 locus and conducted association studies in both population- and family-based samples of the Han Chinese population. The three polymorphisms spanning approximately 5.5 Kb were detected to be in significant LD. Our results provided compelling supportive evidence for association of the variants within the ZDHHC8 locus with schizophrenia but revealed different risk allele at SNP rs175174. The G allele was significantly more common in cases than in controls (69.47 : 59.96%; P=0.000018) and excess transmission of the same allele was confirmed in the family-based transmission disequilibrium test (transmitted/non-transmitted=87 : 54; P=0.0055). Both sample sets even shared the same risk haplotype with similar frequency. Our current data presents consistent association results obtained from both case-control and family-based samples in a same laboratory under the same experimental condition. Despite the potential genetic heterogeneity, our independent findings further support that the 22q11 region is likely to harbor candidate schizophrenia susceptibility genes.

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Analyses of the associations between the genes of 22q11 deletion syndrome and schizophrenia

“…The biologic effects of this allele on the abundance and function of the enzyme are unknown. Other studies have not confirmed the association of rs175174 with schizophrenia (Faul et al 2005;Glaser et al 2005;Otani et al 2005;Saito et al 2005) or have shown an association of the rs175174G, not the A allele, with schizophrenia (Chen et al 2004b). The role of ZDHHC8 in 22q11DS-schizophrenia is unclear.…”

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

“…326 Subsequent studies have confirmed positive associations between mutations in ZDHHC8 and schizophrenia across a number of racial groups, as well as a sex-related heterogeneity of allele transmission, whereby female patients showed a stronger association between mutations in ZDHHC8 and schizophrenia. 325,327 However, multiple studies have been unable to replicate these findings across various racial groups, although modest evidence of a sex-related heterogeneity of allele transmission has been confirmed. 328,329 Whereas ZDHHC8 is a positional candidate gene, no endophenotypes have been associated with it and, given the inconsistent results, it is difficult to make a conclusive determination about its role in the development of schizophrenia.…”