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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

QTDT family-based results for tag-SNPs plotted against FSIQ, VIQ, and PIQ for young (A) and adult (B)cohorts.
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Figure 2: QTDT family-based results for tag-SNPs plotted against FSIQ, VIQ, and PIQ for young (A) and adult (B)cohorts.

Mentions: Two 5'UTR SNPs, previously reported, showed the strongest association with IQ, rs2061174 (intron 4) in the adult cohort and rs324650 (intron 5) in the young cohort [8] (see Figure 2). Within-family genetic effects were reflected in an increased IQ of 6.89 (PIQ) points for those individuals carrying the "A" allele of rs2061174 within the adult cohort. individuals in the young cohort bearing the "T" allele of rs324650 showed an increment of 5.30 IQ (VIQ) points (see Tables 3, 4 and 5). Interestingly, the most significant variant in the young cohort, rs324650, is part of a short interspersed repeat (SINE), namely a MIRb (mammalian-wide interspersed repeat) repeat of 160 bp long. The derived "T" allele contained in this repeat seems to be human-specific. In addition this MIRb repeat is also present in non-human primate linages – rhesus (macaca mulatta) and chimpanzee (pan troglodytes) – but not in other mammalian linages. Such an allele-specific effect may reflect that the variant is in LD with the causal allele, or that the "T" allele is directly modifying binding-properties of transcription starting sites (TSS) [38].


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)

QTDT family-based results for tag-SNPs plotted against FSIQ, VIQ, and PIQ for young (A) and adult (B)cohorts.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: QTDT family-based results for tag-SNPs plotted against FSIQ, VIQ, and PIQ for young (A) and adult (B)cohorts.
Mentions: Two 5'UTR SNPs, previously reported, showed the strongest association with IQ, rs2061174 (intron 4) in the adult cohort and rs324650 (intron 5) in the young cohort [8] (see Figure 2). Within-family genetic effects were reflected in an increased IQ of 6.89 (PIQ) points for those individuals carrying the "A" allele of rs2061174 within the adult cohort. individuals in the young cohort bearing the "T" allele of rs324650 showed an increment of 5.30 IQ (VIQ) points (see Tables 3, 4 and 5). Interestingly, the most significant variant in the young cohort, rs324650, is part of a short interspersed repeat (SINE), namely a MIRb (mammalian-wide interspersed repeat) repeat of 160 bp long. The derived "T" allele contained in this repeat seems to be human-specific. In addition this MIRb repeat is also present in non-human primate linages – rhesus (macaca mulatta) and chimpanzee (pan troglodytes) – but not in other mammalian linages. Such an allele-specific effect may reflect that the variant is in LD with the causal allele, or that the "T" allele is directly modifying binding-properties of transcription starting sites (TSS) [38].

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