Exploring the functional role of the CHRM2 gene in human cognition: results from a dense genotyping and brain expression study

Abstract

Background: The CHRM2 gene, located on the long arm of chromosome 7 (7q31-35), is involved in neuronal excitability, synaptic plasticity and feedback regulation of acetylcholine release, and has been implicated in higher cognitive processing. The aim of this study is the identification of functional (non)coding variants underlying cognitive phenotypic variation.

Methods: We previously reported an association between polymorphisms in the 5'UTR regions of the CHRM2 gene and intelligence.. However, no functional variants within this area have currently been identified. In order to identify the relevant functional variant(s), we conducted a denser coverage of SNPs, using two independent Dutch cohorts, consisting of a children's sample (N = 371 ss; mean age 12.4) and an adult sample (N= 391 ss; mean age 37.6). For all individuals standardized intelligence measures were available. Subsequently, we investigated genotype-dependent CHRM2 gene expression levels in the brain, to explore putative enhancer/inhibition activity exerted by variants within the muscarinic acetylcholinergic receptor.

Results: Using a test of within-family association two of the previously reported variants - rs2061174, and rs324650 - were again strongly associated with intelligence (P < 0.01). A new SNP (rs2350780) showed a trend towards significance. SNP rs324650, is located within a short interspersed repeat (SINE). Although the function of short interspersed repeats remains contentious, recent research revealed potential functionality of SINE repeats in a gene-regulatory context. Gene-expression levels in post-mortem brain material, however were not dependent on rs324650 genotype.

Conclusion: Using a denser coverage of SNPs in the CHRM2 gene, we confirmed the 5'UTR regions to be most interesting in the context of intelligence, and ruled out other regions of this gene. Although no correlation between genomic variants and gene expression was found, it would be interesting to examine allele-specific effects on CHRM2 transcripts expression in much more detail, for example in relation to transcripts specific halve-life and their relation to LTP and memory.

Figure 1

Location of single nucleotide polymorphisms (SNPs) within the CHRM2 gene on chromosome 7 and LD blocks defined by them, respectively. Coding sequence (CDS) is depicted in black. Untranslated exons (Exon 1 till Exon 5) are depicted in grey. SNPs already reported in our previous study (Gosso et al., 2006) are in bold.

Figure 2

QTDT family-based results for tag-SNPs plotted against FSIQ, VIQ, and PIQ for young (A) and adult (B)cohorts.