Association of the Hermansky–Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects

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.

Hermansky–Pudlak syndrome: Mutation update

“…Of note, the HPS4 missense variant p.His154Arg (c.461A>G) was found homozygous in two Japanese siblings with HPS and mental disorder (schizophrenia and major depression). It was suggested that HPS4 gene single nucleotide polymorphisms variants may be associated with susceptibility to schizophrenia (A. Saito et al, 2013) and/or cognitive function (Kuratomi et al, 2013). However, there are no reports of other HPS‐related BLOC‐3 (HPS1 and HPS4) variants in individuals with HPS to be associated with neurological phenotypes.…”

“… i This variant was found homozygous in two Japanese siblings with HPS and mental disorder (schizophrenia and major depression). It was suggested that HPS4 gene variants are associated with susceptibility to schizophrenia (A. Saito et al, 2013) and/or cognitive function (Kuratomi et al, 2013). …”

Association of genetic variants at 22q11.2 chromosomal region with cognitive performance in Japanese patients with schizophrenia

“…The control subjects were volunteers from among mainly nonprofessional university/hospital staff, unrelated to the patients, and were free of any mental disorders. All subjects lived in the Kanto region of Japan, and some of them had been included in our previous studies (Akiyama et al, 2016; Kuratomi et al, 2013; Saito et al, 2013; Saito et al, 2017). Exclusion criteria included a history of neurological disorder, significant head injury, or substance dependence or abuse with the exception of nicotine.…”

“…The sex ratio between patients and healthy controls was analyzed using a chi-squared test. Age, JART-estimated premorbid IQ, education duration, and BACS z-scores were regarded as continuous variables and were assessed for a normal distribution using a Shapiro–Wilk test, and if appropriate, standardized and normalized across all of the subjects with a mean of zero and SD of one using rank transformation, as described previously (Kuratomi et al, 2013).…”

“…The Brief Assessment of Cognition in Schizophrenia (BACS) is a battery including six major cognitive domains (Keefe et al, 2004). It has been widely used as a portable and acceptable instrument with high reliability to assess the cognitive impairment of subjects with schizophrenia and affective disorder by other research groups (Bralet et al, 2007; Chianetta et al, 2008; Keefe et al, 2004) and ourselves (Akiyama et al, 2016; Kuratomi et al, 2013; Saito et al, 2017). The purpose of this study was to explore if genetic variants at 22q11.2 are associated with cognitive impairment in patients with schizophrenia and bipolar disorder with the latter being added to investigate the disease-specific aspects of our findings, in comparison with controls from the Japanese population.…”