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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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Overview of the identified genes that have synaptic function. Trait nodes are yellow, and gene nodes are green. The edges are colored in a heat scale according to the strength of the association (P-values). A full color version of this figure is available at the Hypertension Research journal online.
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fig1: Overview of the identified genes that have synaptic function. Trait nodes are yellow, and gene nodes are green. The edges are colored in a heat scale according to the strength of the association (P-values). A full color version of this figure is available at the Hypertension Research journal online.

Mentions: The functional annotation of the specific genes derived from the joint linkage and association mapping (Supplementary Table S5) indicated that a number of these genes share functions and interactions. Probing the protein interactions revealed that GRID2, HTR2A, LPHN2, LRP1B, MTPN and NETO1 share interactions with the synaptic protein DLG4 (Figure 3). Furthermore, a search of the synapse databases indicated that the CHRM2, DAB2, GRID2, HTR2A, ITPR2, LPHN2 and NETO1 genes have synaptic function (Figure 1 and Supplementary Table S10).


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)

Overview of the identified genes that have synaptic function. Trait nodes are yellow, and gene nodes are green. The edges are colored in a heat scale according to the strength of the association (P-values). 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

fig1: Overview of the identified genes that have synaptic function. Trait nodes are yellow, and gene nodes are green. The edges are colored in a heat scale according to the strength of the association (P-values). A full color version of this figure is available at the Hypertension Research journal online.
Mentions: The functional annotation of the specific genes derived from the joint linkage and association mapping (Supplementary Table S5) indicated that a number of these genes share functions and interactions. Probing the protein interactions revealed that GRID2, HTR2A, LPHN2, LRP1B, MTPN and NETO1 share interactions with the synaptic protein DLG4 (Figure 3). Furthermore, a search of the synapse databases indicated that the CHRM2, DAB2, GRID2, HTR2A, ITPR2, LPHN2 and NETO1 genes have synaptic function (Figure 1 and Supplementary Table S10).

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