Brief reportCHRNA7 haplotypes are associated with impaired attention in euthymic bipolar disorder
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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2016, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :CHRNA7 (cholinergic receptor nicotinic alpha 7) is involved in cognitive function and synaptic plasticity. A dysfunction of CHRNA7-dependent signaling was reported in bipolar disorder (Thomsen et al., 2011) and variants of this gene were associated with several neuropsychiatric and cognitive phenotypes among which BD and sustained attention performance in patients with BD (Ancin et al., 2010, 2011; Soler-Alfonso et al., 2014). Targeting cholinergic receptor nicotinic alpha 7 (α7 nAChR) is an attractive strategy for the development of new antidepressants.
Long-lasting changes in neural networks to compensate for altered nicotinic input
2015, Biochemical PharmacologyCitation Excerpt :Aberrations in nicotinic signaling, particularly via α7-nAChRs, are also increasingly being linked with neurological disorders, principal among them being schizophrenia [92], Alzheimer’s disease [93,94], and juvenile myoclonic epilepsy [95]. Deletion of human 15q13.3, including the α7-nAChR gene, is associated with autism, mental retardation, epilepsy, bipolar disorder, and intellectual disability [96–108]. Additional evidence suggests that deletion of the α7-nAChR gene alone may be sufficient to cause the majority of the associated clinical features in patients with these disorders [100,101,104,107].
The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function
2015, NeuropharmacologyCitation Excerpt :The expression of α7nAChRs, as measured by [125I]-α-bungarotoxin binding, appears to be increased in hippocampus of bipolar patients (Thomsen et al., 2011). The association of the CHRNA7 gene cluster with bipolar disorder has been supported in multiple studies, including genetic linkage (Turecki et al., 2000), association (Ancin et al., 2011) (Table 2), and in neurobiological studies of the P50 deficit (Leonard et al., 2001; Martin et al., 2007). Patients with bipolar disorder have cognitive deficits involving attention that are similar to patients with schizophrenia (Ancin et al., 2010b).
Cortical parvalbumin GABAergic deficits with α7 nicotinic acetylcholine receptor deletion: Implications for schizophrenia
2014, Molecular and Cellular NeuroscienceCitation Excerpt :Nicotinic receptor mediated neurotransmission has been implicated in many CNS processes including neuronal plasticity, learning and memory as well as in neurological, neurodevelopmental and psychiatric disorders (Dani and Bertrand, 2007; Freedman, 2014; Griguoli and Cherubini, 2012; Lin et al., 2010, 2014; Miwa et al., 2011; Ross et al., 2010; Wallace and Bertrand, 2013). Some of the most powerful evidence comes from genetic studies in which a homozygous microdeletion of human 15q13.3, including the α7 nAChR gene, is associated with cortical circuit disorders including schizophrenia, autism, mental retardation, epilepsy, and intellectual disability (Ancin et al., 2011; Endris et al., 2010; Freedman, 2014; Freedman et al., 1997; Helbig et al., 2009; Hoppman-Chaney et al., 2013; Lepichon et al., 2010; Liao et al., 2011; Miller et al., 2009; Sharp et al., 2008; Shinawi et al., 2009; Spielmann et al., 2011; Yasui et al., 2011). Based on the size and the overlap of deletions in such individuals, loss of the α7 nAChR gene alone appears sufficient to cause the majority of clinical features in such patients (Endris et al., 2010; Hoppman-Chaney et al., 2013; Liao et al., 2011; Shinawi et al., 2009).
Cortical synaptic NMDA receptor deficits in α7 nicotinic acetylcholine receptor gene deletion models: Implications for neuropsychiatric diseases
2014, Neurobiology of DiseaseCitation Excerpt :As the major excitatory neurotransmitters in the CNS, the nicotinic and glutamatergic systems have been implicated in many neurological, neurodevelopmental and neuropsychiatric disorders (Dani and Bertrand, 2007; Traynelis et al., 2010; Waxman and Lynch, 2005). Some of the most powerful evidence for the role of nicotinic receptors comes from genetic studies in which a homozygous microdeletion of human 15q13.3, including the α7 nAChR gene, is associated with disorders including schizophrenia, autism, mental retardation, epilepsy, and intellectual disability (Ancin et al., 2011; Endris et al., 2010; Helbig et al., 2009; Hoppman-Chaney et al., 2013; Lepichon et al., 2010; Liao et al., 2011; Miller et al., 2009; Sharp et al., 2008; Shinawi et al., 2009; Spielmann et al., 2011; Yasui et al., 2011). Based on the size and the overlap of the deletions in different individuals, loss of the α7 nAChR gene alone appears sufficient to cause the majority of clinical features in such patients (Endris et al., 2010; Hoppman-Chaney et al., 2013; Liao et al., 2011; Shinawi et al., 2009).
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These authors contributed equally to the manuscript.