title: Adrenergic alpha-1 pathway is associated with hypertension among Nigerians in a pathway-focused analysis.
abstract: BACKGROUND
  The pathway-focused association approach offers a hypothesis driven alternative to the agnostic genome-wide association study. Here we apply the pathway-focused approach to an association study of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in 1614 Nigerians with genome-wide data.
  
  
  RESULTS
  Testing of 28 pathways with biological relevance to hypertension, selected a priori, containing a total of 101 unique genes and 4,349 unique single-nucleotide polymorphisms (SNPs) showed an association for the adrenergic alpha 1 (ADRA1) receptor pathway with hypertension (p<0.0009) and diastolic blood pressure (p<0.0007). Within the ADRA1 pathway, the genes PNMT (hypertension P(gene)<0.004, DBP P(gene)<0.004, and SBP P(gene)<0.009, and ADRA1B (hypertension P(gene)<0.005, DBP P(gene)<0.02, and SBP P(gene)<0.02) displayed the strongest associations. Neither ADRA1B nor PNMT could be the sole mediator of the observed pathway association as the ADRA1 pathway remained significant after removing ADRA1B, and other pathways involving PNMT did not reach pathway significance.
  
  
  CONCLUSIONS
  We conclude that multiple variants in several genes in the ADRA1 pathway led to associations with hypertension and DBP. SNPs in ADRA1B and PNMT have not previously been linked to hypertension in a genome-wide association study, but both genes have shown associations with hypertension through linkage or model organism studies. The identification of moderately significant (10(-2)>p>10(-5)) SNPs offers a novel method for detecting the "missing heritability" of hypertension. These findings warrant further studies in similar and other populations to assess the generalizability of our results, and illustrate the potential of the pathway-focused approach to investigate genetic variation in hypertension.
authors.affiliation: Department of Preventive Medicine and Epidemiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, United States of America. nireder@lumc.edu
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Reder
authors.forename: Bamidele O
authors.initials: BO
authors.lastname: Tayo
authors.forename: Babatunde
authors.initials: B
authors.lastname: Salako
authors.forename: Adesola
authors.initials: A
authors.lastname: Ogunniyi
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.forename: Charles
authors.initials: C
authors.lastname: Rotimi
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
mesh_terms: D001794:Blood Pressure / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009549:Nigeria; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C547716:ADRA1B protein, human; D018340:Receptors, Adrenergic, alpha-1