Fine-mapping of ZDHHC2 identifies risk variants for schizophrenia in the Han Chinese population

Abstract

Background: ZDHHC2 is a member of the DHHC protein family, mediating palmitoylation of postsynaptic density-95 (PSD-95) and A-kinase-anchoring protein 79/150 (AKAP79/150). Genome-wide association studies (GWASs) have identified ZDHHC2 as a candidate gene for schizophrenia (SCZ). We aimed to fine-map variants of ZDHHC2 conferring risk to SCZ in the Han Chinese population. Methods: Targeted sequencing of whole-exome sequences including untranslated regions (UTRs) along with neighboring regions in 1,827 schizophrenic patients and 1,004 normal controls of Han Chinese origin. Results: A total of 123 variants, including five common and 118 rare variants, were identified. Among common variants, rs73198534, rs530313445, and rs74406481 were significantly associated with SCZ. Nine nonsynonymous rare variants, p.Glu96fs, p.Arg127X, p.Val145Ile, p.Ala177Thr, p.Arg269Gln, p.Asn312His, p.Glu319Lys, p.Gln340X, and p.Ile347Val, identified only in patients; eight are located in the important domains, including two stop-gain variants. The 3D structural analysis and functional prediction revealed that all these eight variants may affect AMPAR expression or function, and influence the synaptic plasticity by regulating the palmitoylation of PSD95 and AKAP79/150. Conclusion: Our results first show strong supportive evidences of the association between the ZDHHC2 and SCZ, and also provide a fine-mapping of variants of this gene in Han Chinese SCZ patients.