Abstract
Using a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs) distributed across the entire 1.5-Mb locus on chromosome 22q11 associated with susceptibilit to schizophrenia1,2, we previously identified two subregions that were consistently associated with the disease3,4. In the distal subregion, we detected an association signal with five neighboring SNPs distributed over a haplotypic block of 80 kb encompassing six known genes4. One of these five SNPs, rs175174, had the strongest association of all 72 SNPs that we tested. Here we show that rs175174 regulates the level of the fully functional transcript by modulating the retention of intron 4 of the gene ZDHHC8, which encodes a putative transmembrane palmitoyltransferase. Zdhhc8-knockout mice had a sexually dimorphic deficit in prepulse inhibition, a gene dosage–dependent decrease in exploratory activity in a new environment and a decreased sensitivity to the locomotor stimulatory effects of the psychomimetic drug dizocilpine (MK801). SNP rs175174 shows differences in transmission distortion between sexes in individuals with schizophrenia. Our results indicate that there is an unexpected connection between impaired palmitate modification of neuronal proteins and the psychiatric phenotypes associated with microdeletions of chromosome 22q11.
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Acknowledgements
We thank J. Keegan, C. Frazier and M. Monsey for technical support; P. Scheiffele for advice; and Y.-J. Chen for help in the initial phases of this project. This study was supported by grants from the US National Institute of Mental Health (to M.K. and J.A.G.) and the New York Academy of Sciences (to J.A.G.). J.A.G. is also the recipient of a McKnight Brain Disorders Award and a Vicente NARSAD Young Investigator.
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Mukai, J., Liu, H., Burt, R. et al. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat Genet 36, 725–731 (2004). https://doi.org/10.1038/ng1375
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DOI: https://doi.org/10.1038/ng1375
