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

Gosso FM, de Geus EJ, Polderman TJ, Boomsma DI, Posthuma D, Heutink P - BMC Med. Genet. (2007)

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands. mf.gosso@vumc.nl

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.

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Related in: MedlinePlus

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.
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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.

Mentions: Genotyping success rate was 95.36 (SD = 3.80) among both cohorts. Six tag-SNPs, (rs6957496, rs1424569, rs10488600, rs17494540, rs324582, and rs11773032), although with high genotyping rate, deviated from HWE (P < 0.05) despite a high genotype call rate. One tag-SNP, rs11773032 showed no variation in our population and was thus deleted from further analysis. LD parameters D' and r2 were obtained for all successfully genotyped SNPs. LD blocks were generated applying the algorithm defined by Gabriel et al., 2002 [37] in which confidence bounds on D' are generated if 95% of the information shows "strong LD". By default, this method ignores markers with MAF < 0.05 (see Figure 1 and Table 2).


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

Gosso FM, de Geus EJ, Polderman TJ, Boomsma DI, Posthuma D, Heutink P - BMC Med. Genet. (2007)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2198911&req=5

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.
Mentions: Genotyping success rate was 95.36 (SD = 3.80) among both cohorts. Six tag-SNPs, (rs6957496, rs1424569, rs10488600, rs17494540, rs324582, and rs11773032), although with high genotyping rate, deviated from HWE (P < 0.05) despite a high genotype call rate. One tag-SNP, rs11773032 showed no variation in our population and was thus deleted from further analysis. LD parameters D' and r2 were obtained for all successfully genotyped SNPs. LD blocks were generated applying the algorithm defined by Gabriel et al., 2002 [37] in which confidence bounds on D' are generated if 95% of the information shows "strong LD". By default, this method ignores markers with MAF < 0.05 (see Figure 1 and Table 2).

Bottom Line: 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).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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands. mf.gosso@vumc.nl

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.

Show MeSH
Related in: MedlinePlus