Association between DBH 19 bp insertion/deletion polymorphism and cognition in schizophrenia with and without tardive dyskinesia

Abstract

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), which is involved in increased cognitive impairment. Dopamine beta-hydroxylase (DBH) gene associated with dopamine and norepinephrine systems influences cognition. Schizophrenia with TD have higher DBH activity than those without TD. This study examined whether DBH5′-insertion/deletion (-Ins/Del) polymorphism could influence cognitive function in schizophrenia with and without TD. The presence of DBH5′-Ins/Del polymorphism was determined in 345 schizophrenia with TD and 397 schizophrenia without TD. The Abnormal Involuntary Movement Scale and Repeatable Battery for Assessment of Neuropsychological Status (RBANS) were used to assess TD severity and cognition. The allele and genotype frequencies of DBH5′-Ins/Del polymorphism did not differ between patients with and without TD (both p > 0.05). RBANS total score and subscales did not differ by DBH5′-Ins/Del genotype groups in patients with TD (all p > 0.05). However, attention score significantly differed by DBH5′-Ins/Del genotype groups in those without TD (p < 0.05). Patients without TD who were Del homozygous had significantly lower attention score than those without TD who were Ins alleles (p < 0.05). Immediate memory and attention scores were lower in patients with TD than without TD (both p < 0.05). This study indicated that DBH5′-Ins/Del polymorphism may not play a role in the susceptibility to TD and cognitive deficits in schizophrenia with TD, but it may influence cognitive function in schizophrenia with non-TD. Moreover, schizophrenia with TD experienced greater cognitive deficits than those with non-TD, especially in immediate memory and attention.

Introduction

Long-term antipsychotic treatment for schizophrenia is associated with the development of tardive dyskinesia (TD), a motor syndrome which includes involuntary and hyperkinetic movements (Lohr et al., 2003). Studies have found that schizophrenia with TD experienced greater cognitive impairments than schizophrenia without TD (Wegner et al., 1985a, Wegner et al., 1985b, Waddington and Youssef, 1986, Waddington et al., 1987, Byne et al., 1998). It has been suggested that cognitive impairments may be a risk factor for the development of TD (Wegner et al., 1985a, Wegner et al., 1985b). Another study has suggested that TD is predictive of impaired cognition (Waddington and Youssef, 1986). Moreover, familial and twins studies have shown that genetic factors account for approximately 50% of the variability in memory ability (Bouchard and McGue, 1981, McClearn et al., 1997), approximately 70% of the variability in verbal reasoning skills, and approximately 79% of the variability in abstract reasoning (Benyamin et al., 2005, Johnson et al., 2007). These studies suggested that genetic variants might play an important role in the cognitive deficits of schizophrenia with TD.

The dopamine beta-hydroxylase (DBH) enzyme catalyzes the conversion of dopamine (DA) to norepinephrine (NE) in the adrenergic and noradrenergic neurons in the central nervous system (Ishiguro et al., 1993). Inhibiting DBH activity increases DA levels and decreases NE levels (Robertson et al., 1986), both of which are involved in the cognitive impairments in schizophrenia (Friedman et al., 1999, Braver et al., 1999, Condray and Yao, 2011, Sakurai et al., 2013). A previous study has found an inverse relationship between plasma DBH activity and cognitive deficits in schizophrenia (Bridge et al., 1984). DBH in the prefrontal cortex could be associated with the immediate memory deficits that have been frequently reported in schizophrenia (Tan et al., 2009, Nicoletta et al., 2010, Sandra et al., 2011). Moreover, previous studies have found that DBH is involved in the regulation of mood and attention functions (Hamner and Gold, 1998, Bellgrove et al., 2006). Additional studies have found that schizophrenia with TD is associated with low DBH activity which is under strong DBH genetic control (Weinshiboum, 1978, Jeste et al., 1981, Wagner et al., 1982, Goldin et al., 1982, Kaufman et al., 1986, Oxenstierma et al., 1986, Cubells et al., 2011). These results suggested that cognitive function might be influenced by the DBH gene that encodes the rate-limiting enzyme for the conversion of DA to NE in schizophrenia with TD.

The 4.5 kilobases upstream of the 5′ flank transcriptional start site in the DBH gene contains a 19 nucleotide insertion/deletion (Ins/Del) polymorphism on chromosome 9q34, named the DBH5′-Ins/Del polymorphism. This polymorphism has been reported to be strongly associated with DBH activity (Cubells et al., 2000, Zabetian et al., 2001, Tang and Epstein, 2007). The plasma DBH activity of individuals with DBH5′-Del/Del was only half level of those with DBH5′-Ins/Ins (Cubells et al., 1998). Several studies have found that the DBH5′-Ins/Del polymorphism is associated with cognitive function in elderly women (Togsverd et al., 2007), the average reaction time of response in Chinese Han females (Gong et al., 2011), the attention bias for negative faces in Chinese Han young people (Gong et al., 2013), and post-error slowing in young Caucasian healthy adults (Colzato et al., 2013). These findings suggested that the DBH5′-Ins/Del polymorphism was a functional site which might influence cognitive function in schizophrenia with TD.

Our recent studies found that the DBH5′-Ins/Del polymorphism influenced immediate memory in first-episode schizophrenia and attention in chronic schizophrenia (Hui et al., 2013, Hui et al., 2016). Other studies showed that there was a significant cognitive difference between schizophrenia with and without TD (Waddington et al., 1987, Byne et al., 1998). However, no previous studies have investigated whether the DBH5′-Ins/Del polymorphism influences cognitive function in schizophrenia with and without TD. Therefore, the main aim of this study is to examine the effects of the DBH5′-Ins/Del polymorphism on cognitive function in schizophrenia with and without TD.