Associations between the DBH gene, plasma dopamine β-hydroxylase activity and cognitive measures in Han Chinese patients with schizophrenia

Abstract

The dopamine (DA) and norepinephrine (NE) systems modulate cognitive function. Dopamine β-hydroxylase (DβH) converts DA to NE, and its activity is under strong genetic control. This study examines the association of plasma DβH (pDβH) activity, DBH gene polymorphisms (− 1021C > T, rs1611115 and 444G > A, rs1108580) and cognitive deficits in Han Chinese patients with schizophrenia. We assessed pDβH activity and cognitive function using the Verbal Fluency Test (VFT), Trail Making Test (TMT) A-B, Stroop color-word test and Wisconsin Card Sorting Test (WCST) in 200 patients with schizophrenia before and after 8 weeks of antipsychotic treatment (96 patients completed assessments at baseline and post-treatment). We found that rs1611115 was significantly associated with pDβH activity, and there was strong LD between rs1611115 and rs1108580 polymorphisms. Correlation analysis indicated that pDβH activity correlated nominally with improvement in VFT score after 8 weeks antipsychotic treatment. Moreover, there was a significant genotype effect of the rs1108580 on VFT: the VFT score of patients with AA genotype was higher than that of patients with AG/GG genotype either at baseline or the end of 8 weeks after treatment. However, this difference was not observed for rs1611115. Our findings confirm a strong association between genotype at rs1611115 and pDβH activity in Chinese patients with schizophrenia. Our data also suggest the rs1108580 polymorphism may influence some aspects of cognitive function in schizophrenia.

Introduction

Cognitive impairment is a core, stable feature of schizophrenia that limits patient functioning and well-being (Keefe and Harvey, 2012) and associates with poor functional outcome (Fervaha et al., 2014, Kontaxaki et al., 2014). Studies also indicate that cognitive deficits occur prior to the onset of other symptoms of schizophrenia, and generally persist during the course of the illness (Dickerson et al., 2004, Hughes et al., 2003). Almost all individuals diagnosed with schizophrenia have some degree of cognitive impairment (Keefe et al., 2005).

Although the presence and impact of cognitive deficits in individuals with schizophrenia have been widely recognized, the underlying neurobiological mechanisms remain mostly unknown. Metabolic dysfunction in catecholamine neurotransmitters is important in cognitive impairment, and psychopharmacological studies suggest that dopamine receptor antagonists could aggravate the cognitive impairment in patients with schizophrenia (Eisenegger et al., 2014, Nakajima et al., 2013).

Dopamine β-hydroxylase (DβH) is the rate-limiting enzyme for the conversion of dopamine (DA) to norepinephrine (NE) (Condray and Yao, 2011, Friedman et al., 1999), and it may be involved in maintaining the DA/NE balance in the brain. DβH is localized within vesicles of central noradrenergic and adrenergic neurons as well as peripheral noradrenergic (sympathetic) neurons and adrenomedullary neurosecretory cells (Weinshilboum, 1978). Because the DβH enzyme is released from vesicles during sympathetic activity, the enzyme activity and DβH immunoreactive protein can be measured in the serum or plasma (Dunnette and Weinshilboum, 1976, O'Connor et al., 1994, O'Connor et al., 1983).

Plasma DβH activity (​​​​pDßH) is highly heritable and stable trait. While it varies widely across unrelated individuals (Weinshilboum et al., 1973), it is remarkably stable within individuals (Cubells and Zabetian, 2004). Polymorphic variations at the DBH gene, which encodes DβH, have been reported to be associated with cognitive function (Greenwood et al., 2014, Parasuraman et al., 2005). The DBH single nucleotide polymorphism, − 1021C > T (rs1611115), located in the 5′ upstream region of DBH, accounts for 30–50% of the variance in plasma DβH activity across samples from European-American, African-American, and Japanese individuals (Zabetian et al., 2001). In patients with attention-deficit/hyperactivity disorder (ADHD), rs1611115 significantly associated with cognitive function (Kieling et al., 2008). The ins allele, which contains the 19-bp sequence absent in the del allele and associates with higher plasma pDβH (Cubells et al., 2000), corresponded to poorer performance (Hui et al., 2017, Hui et al., 2013). Taken together, these findings suggest a role of DBH gene polymorphisms in cognitive function.

While population genetic data on the DBH gene and pDβH activity have been reported in European Americans (Zabetian et al., 2001), African Americans (Tang et al., 2007, Zabetian et al., 2001), Japanese (Zabetian et al., 2001) and Indian South Asians (Bhaduri and Mukhopadhyay, 2008) samples, no such study has yet been conducted in the Han Chinese population. The possible roles of pDβH activity and DBH polymorphisms in cognitive function and symptomatic severity in schizophrenia also need to be investigated further, in light of the observations that lower cerebrospinal fluid (CSF) levels of DβH associate with better pre-morbid adjustment in schizophrenia (Sternberg et al., 1983, Sternberg et al., 1982, van Kammen et al., 1994), and with better response to first-generation anti-psychotic medications (Sternberg et al., 1983, Sternberg et al., 1982). Therefore, the first aim of the current study was to investigate the association between DBH (rs1611115 and rs1108580) and pDβH activity in Han Chinese patients. The second aim was to examine the association among pDβH activity, DBH genotype and cognitive function in patients with schizophrenia.