Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1–4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1–4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.
Highlights
Mood disorders and schizophrenia are common and disabling conditions in which stressful life events and genetic risk factors are known to contribute to the risk of illness (Murray and Lopez, 1997; Sullivan et al, 2000)
In the current study, no evidence could be found to support an association between genetic variants in HCN1–4 and liability to depression, including measures of neuroticism or extraversion
No evidence was found to support an association between these four hyperpolarization-activated cyclic nucleotide-gated (HCN) channel genes and cognitive impairment, either as main effects or as interacting risk factors with neuroticism
Summary
Mood disorders and schizophrenia are common and disabling conditions in which stressful life events and genetic risk factors are known to contribute to the risk of illness (Murray and Lopez, 1997; Sullivan et al, 2000). Impairment in cognitive function is associated with a variety of psychiatric disorders (Aleman et al, 1999; Austin et al, 2001; Bearden et al, 2001; McIntosh et al, 2005) Cognitive functions such as memory and planning appear to be important and have been shown to contribute significantly to disability, diminished quality of life, and the ability to live independently (Alexopoulos et al, 2000; Dimitris et al, 2000). The relationship of cognitive performance to stress is described by the inverted U-shaped Yerkes–Dodson curve (Yerkes and Dodson, 1908) This relationship is partially mediated by release of dopamine and/or noradrenaline, with downstream effects on cyclic AMP (cAMP) signaling through Gs protein coupled receptors (Wang et al, 2007; Robbins and Arnsten, 2009). These currents, in turn, cause perturbations in neuronal signaling through reduced dendritic summation of incoming currents
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