Objective: We encountered two Japanese siblings who had Hermansky–Pudlak syndrome (HPS) and major mental disorders (schizophrenia and major depression) as well. As it is known that HPS is caused by a local mutation in one of the human genes, named HPS1 to HPS8 and PLDN (HPS9), encoding subunit proteins involved in endosomal trafficking pathways, here, we report the mutation causing the siblings disease and a case–control association study of schizophrenia using polymorphisms of a gene to be screened in the mutation analysis.
Methods: We analyzed three HPS-causing genes, HPS1, HPS4, and HPS7, to identify a genetic mutation involved in the siblings. A case–control association study of nine tagging single-nucleotide polymorphisms of the entire genetic region of the HPS4 gene resulting from the screening in the siblings was carried out for schizophrenic patients (n=422) and controls (n=578).
Results: The two patients with HPS were homozygous for nonsense mutation (T/T) for the c.541C>T (rs119471022) in the HPS4 gene, which is mapped to human chromosome 22q12.1. The same nonsense mutation existed in the heterozygous state (C/T) in their mother and in two other siblings. The genotypic distribution of rs9608491 (C/T) in intron 4 showed a trend toward an association with schizophrenia as indicated by a corrected P-value of 0.053 controlling for multiple testing. Haplotype analyses showed that two of two-locus haplotypes, and all of three-locus, four-locus, and five-locus haplotypes, as they share rs9608491, yielded significant evidence for association with schizophrenia as shown by the following omnibus P-values. When rs4822724, rs61276843, rs9608491, rs713998, and rs2014410, five haplotype tagging single-nucleotide polymorphisms, are assigned serial numerals (1, 2, 3, 4, and 5), the omnibus P-values for the resulting haplotypes were P=0.0039 for 2-3, P=0.0142 for 3-4, P=0.0083 for 1-2-3, P=0.0187 for 2-3-4, P=0.0191 for 3-4-5, P=0.0270 for 1-2-3-4, P=0.0246 for 2-3-4-5, and 0.0261 for 1-2-3-4-5.
Conclusion: These results suggest that the HPS4 gene confers a susceptibility to schizophrenia.