Abstract
Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures.
Highlights
Various lines of basic, “translational” and clinical research suggest that the nicotinic cholinergic system modulates cognitive processes and that it plays an import role in a number of neuropsychiatric disorders such as schizophrenia, Alzheimer’s dementia, addiction and pain [1,2,3,4]
We did not genotype a standard panel of ancestry-informative single nucleotide polymorphisms (SNPs) to control for genetic stratification since we investigated a genetically highly homogeneous sample of subjects with Germany ancestry and because participants were randomly selected from the general population
A genotypeÃsex interaction effect was seen on reaction time: In females the TT genotype was associated with higher reaction times while in males it was associated with lower reaction times
Summary
“translational” and clinical research suggest that the nicotinic cholinergic system modulates cognitive processes and that it plays an import role in a number of neuropsychiatric disorders such as schizophrenia, Alzheimer’s dementia, addiction and pain [1,2,3,4]. One “hot spot” for genetic variation is exon five of the CHRNA4 gene where common synonymous single nucleotide polymorphisms (SNPs) have been the focus of previous research In these previous studies addressing the role of SNPs in the exon 5 or other regions of the CHRNA4 gene in human cognition or neuropsychiatric disorders have by and large either investigated the association of these SNPs with cognitive (endo)phenotypes such as electrophysiological or brain imaging measures [8, 9] in rather small numbers of subjects or with “clinical” measures such as smoking status and related outcome measures in larger cohorts [10, 11]. We did not genotype a standard panel of ancestry-informative SNPs to control for genetic stratification since we investigated a genetically highly homogeneous sample of subjects with Germany ancestry (or from adjacent countries) and because participants were randomly selected from the general population. Follow-up EEG-based sLORETA (N100) analyses: For between-group analyses, standardized current density are corrected for the effects of relevant covariates (age, gender, study site, education) before the residuals were entered into the final sLORETA analyses. We conclude that in our sample, the N100 amplitude at electrode position Cz cannot be explained by association with rare variants
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