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Genetic mapping of habitual substance use, obesity-related traits, responses to mental and physical stress, and heart rate and blood pressure measurements reveals shared genes that are overrepresented in the neural synapse.

Nikpay M, Šeda O, Tremblay J, Petrovich M, Gaudet D, Kotchen TA, Cowley AW, Hamet P - Hypertens. Res. (2012)

Bottom Line: To investigate this hypothesis, we performed genome-wide mapping in 119 multigenerational families from a population in the Saguenay-Lac-St-Jean region with a known founder effect using 58,000 single-nucleotide polymorphisms and 437 microsatellite markers to identify genetic components of the following factors: habitual alcohol, tobacco and coffee use; response to mental and physical stress; obesity-related traits; and heart rate (HR) and blood pressure (BP) measures.Habitual alcohol and/or tobacco users had attenuated HR responses to mental stress compared with non-users, whereas hypertensive individuals had stronger HR and systolic BP responses to mental stress and a higher obesity index than normotensives.In summary, consistent with the observed phenotypic correlations, we found substantial overlap among genomic determinants of these traits in synapse, which supports the notion that the neural synapse may be a shared interface behind substance use, stress, obesity, HR, BP as well as the observed sex- and hypertension-specific genetic differences.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche, Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada.

ABSTRACT
Links between substance use habits, obesity, stress and the related cardiovascular outcomes can be, in part, because of loci with pleiotropic effects. To investigate this hypothesis, we performed genome-wide mapping in 119 multigenerational families from a population in the Saguenay-Lac-St-Jean region with a known founder effect using 58,000 single-nucleotide polymorphisms and 437 microsatellite markers to identify genetic components of the following factors: habitual alcohol, tobacco and coffee use; response to mental and physical stress; obesity-related traits; and heart rate (HR) and blood pressure (BP) measures. Habitual alcohol and/or tobacco users had attenuated HR responses to mental stress compared with non-users, whereas hypertensive individuals had stronger HR and systolic BP responses to mental stress and a higher obesity index than normotensives. Genetic mappings uncovered numerous shared genes among substance use, stress response, obesity and hemodynamic traits, including CAMK4, CNTN4, DLG2, FHIT, GRID2, ITPR2, NOVA1 and PRKCE, forming network of interacting proteins, sharing synaptic function and display higher and patterned expression profiles in brain-related tissues; moreover, pathway analysis of shared genes pointed to long-term potentiation. Subgroup genetic mappings uncovered additional shared synaptic genes, including CAMK4, CNTN5 and DNM3 (hypertension-specific); CNTN4, DNM3, FHIT and ITPR1 (sex-specific), having protein interactions with genes driven from general analysis. In summary, consistent with the observed phenotypic correlations, we found substantial overlap among genomic determinants of these traits in synapse, which supports the notion that the neural synapse may be a shared interface behind substance use, stress, obesity, HR, BP as well as the observed sex- and hypertension-specific genetic differences.

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Gene expression heat map across 65 normal human tissues of the shared genes derived from the general genetic mapping. The shared genes tend to have higher expression and patterned expression profiles in the cluster of brain-related tissues, including the nucleus accumbens, putamen, brain lobes, cerebral cortex, hippocampus and amygdala. The expression values are presented in shades of red (high expression) to blue (low expression). The gene expression values were extracted from the COXPRESdb database.26 A full color version of this figure is available at the Hypertension Research journal online.
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fig2: Gene expression heat map across 65 normal human tissues of the shared genes derived from the general genetic mapping. The shared genes tend to have higher expression and patterned expression profiles in the cluster of brain-related tissues, including the nucleus accumbens, putamen, brain lobes, cerebral cortex, hippocampus and amygdala. The expression values are presented in shades of red (high expression) to blue (low expression). The gene expression values were extracted from the COXPRESdb database.26 A full color version of this figure is available at the Hypertension Research journal online.

Mentions: The family-based association scans identified genes commonly associated (P<0.05) with substance use, obesity, stress responses and hemodynamic traits after correction for multiple testing (Supplementary Table S6). The GRID2, ITPR2, LRP1B and PCM1 genes, identified under the linkage peaks, were also associated with multiple traits (Supplementary Table S5 and S6). Functional annotation indicated that 44% of the identified shared genes have synaptic function (Figure 1 and Supplementary Table S10), and the results of the KEGG pathway analysis of these genes significantly indicated the long-term potentiation (LTP) pathway (P=0.03). Furthermore, the gene expression analysis of the shared genes indicated that these genes are highly expressed and exhibit patterned expression in a cluster of brain-related tissues, including brain lobes, cerebral cortex, amygdala, hippocampus and putamen (Table 2 and Figure 2).


Genetic mapping of habitual substance use, obesity-related traits, responses to mental and physical stress, and heart rate and blood pressure measurements reveals shared genes that are overrepresented in the neural synapse.

Nikpay M, Šeda O, Tremblay J, Petrovich M, Gaudet D, Kotchen TA, Cowley AW, Hamet P - Hypertens. Res. (2012)

Gene expression heat map across 65 normal human tissues of the shared genes derived from the general genetic mapping. The shared genes tend to have higher expression and patterned expression profiles in the cluster of brain-related tissues, including the nucleus accumbens, putamen, brain lobes, cerebral cortex, hippocampus and amygdala. The expression values are presented in shades of red (high expression) to blue (low expression). The gene expression values were extracted from the COXPRESdb database.26 A full color version of this figure is available at the Hypertension Research journal online.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368234&req=5

fig2: Gene expression heat map across 65 normal human tissues of the shared genes derived from the general genetic mapping. The shared genes tend to have higher expression and patterned expression profiles in the cluster of brain-related tissues, including the nucleus accumbens, putamen, brain lobes, cerebral cortex, hippocampus and amygdala. The expression values are presented in shades of red (high expression) to blue (low expression). The gene expression values were extracted from the COXPRESdb database.26 A full color version of this figure is available at the Hypertension Research journal online.
Mentions: The family-based association scans identified genes commonly associated (P<0.05) with substance use, obesity, stress responses and hemodynamic traits after correction for multiple testing (Supplementary Table S6). The GRID2, ITPR2, LRP1B and PCM1 genes, identified under the linkage peaks, were also associated with multiple traits (Supplementary Table S5 and S6). Functional annotation indicated that 44% of the identified shared genes have synaptic function (Figure 1 and Supplementary Table S10), and the results of the KEGG pathway analysis of these genes significantly indicated the long-term potentiation (LTP) pathway (P=0.03). Furthermore, the gene expression analysis of the shared genes indicated that these genes are highly expressed and exhibit patterned expression in a cluster of brain-related tissues, including brain lobes, cerebral cortex, amygdala, hippocampus and putamen (Table 2 and Figure 2).

Bottom Line: To investigate this hypothesis, we performed genome-wide mapping in 119 multigenerational families from a population in the Saguenay-Lac-St-Jean region with a known founder effect using 58,000 single-nucleotide polymorphisms and 437 microsatellite markers to identify genetic components of the following factors: habitual alcohol, tobacco and coffee use; response to mental and physical stress; obesity-related traits; and heart rate (HR) and blood pressure (BP) measures.Habitual alcohol and/or tobacco users had attenuated HR responses to mental stress compared with non-users, whereas hypertensive individuals had stronger HR and systolic BP responses to mental stress and a higher obesity index than normotensives.In summary, consistent with the observed phenotypic correlations, we found substantial overlap among genomic determinants of these traits in synapse, which supports the notion that the neural synapse may be a shared interface behind substance use, stress, obesity, HR, BP as well as the observed sex- and hypertension-specific genetic differences.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche, Centre hospitalier de l'Université de Montréal, Montréal, Québec, Canada.

ABSTRACT
Links between substance use habits, obesity, stress and the related cardiovascular outcomes can be, in part, because of loci with pleiotropic effects. To investigate this hypothesis, we performed genome-wide mapping in 119 multigenerational families from a population in the Saguenay-Lac-St-Jean region with a known founder effect using 58,000 single-nucleotide polymorphisms and 437 microsatellite markers to identify genetic components of the following factors: habitual alcohol, tobacco and coffee use; response to mental and physical stress; obesity-related traits; and heart rate (HR) and blood pressure (BP) measures. Habitual alcohol and/or tobacco users had attenuated HR responses to mental stress compared with non-users, whereas hypertensive individuals had stronger HR and systolic BP responses to mental stress and a higher obesity index than normotensives. Genetic mappings uncovered numerous shared genes among substance use, stress response, obesity and hemodynamic traits, including CAMK4, CNTN4, DLG2, FHIT, GRID2, ITPR2, NOVA1 and PRKCE, forming network of interacting proteins, sharing synaptic function and display higher and patterned expression profiles in brain-related tissues; moreover, pathway analysis of shared genes pointed to long-term potentiation. Subgroup genetic mappings uncovered additional shared synaptic genes, including CAMK4, CNTN5 and DNM3 (hypertension-specific); CNTN4, DNM3, FHIT and ITPR1 (sex-specific), having protein interactions with genes driven from general analysis. In summary, consistent with the observed phenotypic correlations, we found substantial overlap among genomic determinants of these traits in synapse, which supports the notion that the neural synapse may be a shared interface behind substance use, stress, obesity, HR, BP as well as the observed sex- and hypertension-specific genetic differences.

Show MeSH
Related in: MedlinePlus