Abstract
BackgroundThe Hermansky–Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; however, its clinical relevance in schizophrenia remains unknown. The purpose of the present study was to investigate whether HPS4 is associated with cognitive functions in patients with schizophrenia and healthy controls and with the clinical profiles of patients with schizophrenia.MethodsWe investigated the association of variants of HPS4 with clinical symptoms and cognitive function in Japanese patients with schizophrenia (n = 240) and age-matched healthy control subjects (n = 240) with single nucleotide polymorphisms (SNP)- or haplotype-based linear regression. We analyzed five tagging SNPs (rs4822724, rs61276843, rs9608491, rs713998, and rs2014410) of HPS4 and 2–5 locus haplotypes of these five SNPs. The cognitive functions of patients and healthy subjects were evaluated with the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, and the patients were assessed for their symptomatology with the Positive and Negative Symptom Scale (PANSS).ResultsIn patients with schizophrenia, rs713998 was significantly associated with executive function under the dominant genetic model (P = 0.0073). In healthy subjects, there was a significant association between working memory and two individual SNPs under the recessive model (rs9608491: P = 0.001; rs713998: P = 0.0065) and two haplotypes (rs9608491-713998: P = 0.0025; rs61276843-9608491-713998: P = 0.0064). No significant association was found between HPS4 SNPs and PANSS scores or premorbid IQ, as measured by the Japanese version of the National Adult Reading Test.ConclusionsThese findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia.
Highlights
The Hermansky–Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; its clinical relevance in schizophrenia remains unknown
In our previous case–control association study, haplotypes that were composed of five tagging single-nucleotide polymorphisms (SNPs) of HPS4 were found to be significantly associated with schizophrenia, a finding that was revealed by a sliding window approach for 2–5 locus haplotypes, including rs9608491 as an essential single nucleotide polymorphisms (SNP) [17]
Genotyping We focused on genotyping five tagging SNPs in HPS4 because all the haplotypes are composed of these tagging SNPs, with rs9608491 being included as an essential SNP in the sliding window analysis of a window size of 2–5 SNPs, and these have been found to be associated with schizophrenia in our previous case–control study [17]
Summary
The Hermansky–Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; its clinical relevance in schizophrenia remains unknown. Cognitive domains that are impaired in patients with chronic schizophrenia are verbal memory, working memory, motor speed, verbal fluency, attention, and executive function [2,3]. These cognitive domains, working memory and executive function, are. We have reported that two Japanese siblings who suffered from the comorbidity of major mental disorders, schizophrenia and major depression, and HPS harbored a nonsense mutation in HPS4 [17]
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