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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 protein interactions of genes derived from the general, sex-specific and hypertension-specific genetic mappings. The encoded proteins of the genes derived from the general, sex-specific or hypertension-specific genetic mappings share numerous protein interactions. The genes identified through two analyses (e.g., CAMK4) are displayed twice with different colors. A full color version of this figure is available at the Hypertension Research journal online.
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fig3: Overview of the protein interactions of genes derived from the general, sex-specific and hypertension-specific genetic mappings. The encoded proteins of the genes derived from the general, sex-specific or hypertension-specific genetic mappings share numerous protein interactions. The genes identified through two analyses (e.g., CAMK4) are displayed twice with different colors. A full color version of this figure is available at the Hypertension Research journal online.

Mentions: Candidate genes derived from the general (n=76), sex-specific (n=31) and hypertension-specific genetic mappings (n=38) were pooled, and a connectivity diagram was built based on protein interactions. Figure 3 shows an overview of these interactions. Although these genes were derived from different analyses, we found numerous interactions among their encoded proteins. We also checked for the associations of SNPs within the missing genes of the constructed network (Figure 3). In this manner, we identified the following SNPs: rs6938572 (P=0.0006) and rs2327017 (P=0.0003) upstream of the BMP6 gene, which were associated with average sitting DBP; rs2370413 (P=0.0003) and rs2887780 (P=0.0004) inside the CACNA1C gene, which were associated with subscapular skinfold measurements in males and the SBP response to mental stress, respectively; rs10492133 (P=0.0009) inside GRIN2B, which was associated with tobacco use; rs10491321 (P=0.00035) upstream of and rs7705319 (P=0.0006) inside the PPP2CA gene, which were associated with tobacco use; rs953944 (P=0.0007) and rs1029819 (P=0.0008), which were associated with tobacco use, and rs10485912 (P=0.00075), which was associated with overall SBP, inside the MAGI2 gene; rs93059 inside the NFKB1 gene, which was associated with the average sitting HR (P=0.00098) and the DBP response to mental stress (P=0.0006); and SNPs inside the ITPR1 gene, which were associated with (0.0004⩽P⩽0.0007) the BP and SBP response to mental stress.


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 protein interactions of genes derived from the general, sex-specific and hypertension-specific genetic mappings. The encoded proteins of the genes derived from the general, sex-specific or hypertension-specific genetic mappings share numerous protein interactions. The genes identified through two analyses (e.g., CAMK4) are displayed twice with different colors. 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

fig3: Overview of the protein interactions of genes derived from the general, sex-specific and hypertension-specific genetic mappings. The encoded proteins of the genes derived from the general, sex-specific or hypertension-specific genetic mappings share numerous protein interactions. The genes identified through two analyses (e.g., CAMK4) are displayed twice with different colors. A full color version of this figure is available at the Hypertension Research journal online.
Mentions: Candidate genes derived from the general (n=76), sex-specific (n=31) and hypertension-specific genetic mappings (n=38) were pooled, and a connectivity diagram was built based on protein interactions. Figure 3 shows an overview of these interactions. Although these genes were derived from different analyses, we found numerous interactions among their encoded proteins. We also checked for the associations of SNPs within the missing genes of the constructed network (Figure 3). In this manner, we identified the following SNPs: rs6938572 (P=0.0006) and rs2327017 (P=0.0003) upstream of the BMP6 gene, which were associated with average sitting DBP; rs2370413 (P=0.0003) and rs2887780 (P=0.0004) inside the CACNA1C gene, which were associated with subscapular skinfold measurements in males and the SBP response to mental stress, respectively; rs10492133 (P=0.0009) inside GRIN2B, which was associated with tobacco use; rs10491321 (P=0.00035) upstream of and rs7705319 (P=0.0006) inside the PPP2CA gene, which were associated with tobacco use; rs953944 (P=0.0007) and rs1029819 (P=0.0008), which were associated with tobacco use, and rs10485912 (P=0.00075), which was associated with overall SBP, inside the MAGI2 gene; rs93059 inside the NFKB1 gene, which was associated with the average sitting HR (P=0.00098) and the DBP response to mental stress (P=0.0006); and SNPs inside the ITPR1 gene, which were associated with (0.0004⩽P⩽0.0007) the BP and SBP response to mental stress.

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