Brief report
CHRNA7 haplotypes are associated with impaired attention in euthymic bipolar disorder

https://doi.org/10.1016/j.jad.2011.04.008Get rights and content

Abstract

Background:

Bipolar disorder (BD) patients show a deficit in sustained attention during euthymic periods. This deficit may be relevant for genetic studies in these patients. The α7 cholinergic receptor plays an important role in attentional deficit in humans and animal models. Moreover, there is evidence suggesting the role of the alpha 7 nicotinic cholinergic receptor subunit gene (CHRNA7) in BD susceptibility. The aim of the present study was to investigate the impact of CHRNA7 in sustained attention performance.

Methods:

We studied the association of a promoter variant (− 86 C/T) and three intronic polymorphisms, rs883473, rs6494223 and rs904952, in the non-duplicated region of CHRNA7 with sustained attention in 143 euthymic BD patients (based on DSM-IV criteria) and 101 healthy subjects. Sustained attention was assessed by the degraded stimulus (DS-CPT) version of Continuous Performance Test. Age, gender, years of education and IQ (WAIS vocabulary subtest) were controlled in the analyses as potential confounders.

Results:

Several candidate polymorphisms showed significant associations with different measures of the neuropsychological task for bipolar group. The CTCT haplotype was associated with an improvement in the attentional task performance in the BD group (p  0.025). On the other hand, different low frequency haplotypes showed influence in bipolar attentional performance (p  0.026).

Limitations:

A replication study using larger samples may be required for conclusive results.

Conclusions:

Our results point toward a slight association of CHRNA7 genotypes and haplotypes with sustained attention performance in euthymic patients with BD.

Introduction

In genetic studies, a promising method to resolve the heterogeneity of psychiatric disorders is the examination of endophenotypes (Gottesman and Gould, 2003, Hasler et al., 2006). One of the potential endophenotypes for bipolar disorder (BD) is sustained attention deficit (Ancin et al., 2010b, Bora et al., 2009, Quraishi and Frangou, 2002).

The α7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) plays important roles in chemical and electrical signaling, neurite outgrowth, synaptic plasticity, neuronal death/survival and modulation of cognition (Jones et al., 1999, Zhao et al., 2003).

There is evidence for the role of CHRNA7 in BD (De Luca et al., 2006, Hong et al., 2004). Our group recently reported an association between the non-duplicated region of CHRNA7 and BD (Ancin et al., 2010a). Furthermore, CHRNA7 has already been linked to some neuropsychological and neurophysiological indicators, such as P50 sensory gating deficit (Houy et al., 2004, Leonard et al., 2002, Martin et al., 2007), episodic memory function (Dempster et al. 2006), attention and inhibition (Rigbi et al. 2008). Besides, animal studies support the role of this gene in attention (Hoyle et al., 2006, Young et al., 2007) and working/episodic memory (Fernandes et al. 2006).

Therapeutic research also points to a role of CHRNA7 in cognition. Several α7 agonists (DMXB-A, GTS21, Tropisetron) have shown beneficial effects in cognition (Kitagawa et al., 2003, Martin et al., 2004, Olincy et al., 2006) and sensory gating (Koike et al., 2005). Animal studies have also provided evidence of these effects (Barak et al., 2009, Buccafusco and Terry, 2009, Hajos et al., 2005, Hauser et al., 2009, Haydar et al., 2009).

In the present study, we sought to determine whether the non-duplicated region of CHRNA7 was associated with sustained attention in euthymic bipolar patients and in a control population. As far as we are aware, this is the first study to analyze the possible association of CHRNA7 with sustained attention in bipolar patients.

Section snippets

Participants

Subjects were recruited from the Clínico San Carlos Hospital (Madrid, Spain) and the Virgen de la Luz Hospital (Cuenca, Spain). The sample comprised 244 subjects: 143 diagnosed with Bipolar I (N = 115) or II (N = 28) Disorder (mean age: 44.1 years; 41.2% male) and 101 normal controls (mean age: 42.3 years; 50.5% male), between 18 and 65 years of age. Patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID-I: P). All met DSM-IV criteria for bipolar disorders and were euthymic

Frequency of SNPs and haplotypes

Table 1 shows the case-control analysis in the group of subjects who performed the sustained attention task. − 86 C/T recessive homozygote frequency was low so it was coded using the presence or absence of the T allele in subsequent analysis.

Smoking and CHRNA7

There were no statistical relationships among gene and smoking status/number of cigarettes smoked daily, either in the control or bipolar group.

CPT-DS and CHRNA7

In the bipolar group, regression analysis showed that CT genotype in rs883473 was associated with an improvement in

Discussion

CHRNA7 is a positional and functional candidate gene for BD and its potential endophenotypes. The current study sought to clarify the association between the CHRNA7 gene and attention.

The promoter polymorphism did not show effects in our study. Other studies have documented the relationship between this variant and a deficit in sensory gating (Leonard et al., 2002, Martin et al., 2007), which could be correlated to an attention alteration (Cullum et al., 1993, Erwin et al., 1998, Potter et al.,

Role of funding source

Support for the study was provided by the National Institute of Health Carlos III (FIS Exp. PI030544, FIS No. 060628), the Mutua Madrileña Foundation and the Committee of Castilla la Mancha (Exp: 0316-02). I.A. has received a research grant from the Foundation for Biomedical Research of the Clínico San Carlos Hospital, Madrid (Spain). Those institutions had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision

Conflict of interest

The authors declare no biomedical financial interests or potential conflicts of interest.

Acknowledgements

The authors thank all patients and healthy volunteers for their participation in the study. We would also like to thank Dr Nuechterlein and Dr Asarnow for their computerized version of the DS-CPT.

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