title: Protein interaction-based genome-wide analysis of incident coronary heart disease.
abstract: BACKGROUND
  Network-based approaches may leverage genome-wide association (GWA) analysis by testing for the aggregate association across several pathway members. We aimed to examine if networks of genes that represent experimentally determined protein-protein interactions (PPIs) are enriched in genes associated with risk of coronary heart disease (CHD).
  
  
  RESULTS
  Genome-wide association analyses of approximately ≈700,000 single-nucleotide polymorphisms in 899 incident CHD cases and 1823 age- and sex-matched controls within the Nurses' Health and the Health Professionals Follow-up Studies were used to assign genewise P values. A large database of PPIs was used to assemble 8351 unbiased protein complexes and corresponding gene sets. Superimposed genewise P values were used to rank gene sets based on their enrichment in genes associated with CHD. After correcting for the number of complexes tested, 1 gene set was overrepresented in CHD-associated genes (P=0.002). Centered on the β1-adrenergic receptor gene (ADRB1), this complex included 18 protein interaction partners that have not been identified as candidate loci for CHD. Of the 19 genes in the top complex, 5 are involved in abnormal cardiovascular system physiological features based on knockout mice (4-fold enrichment; Fisher exact test, P=0.006). Ingenuity pathway analysis revealed that canonical pathways, especially related to blood pressure regulation, were significantly enriched in the genes from the top complex.
  
  
  CONCLUSIONS
  The integration of a GWA study with PPI data successfully identifies a set of candidate susceptibility genes for incident CHD that would have been missed in single-marker GWA analysis.
authors: Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. mkjensen@hsph.harvard.edu
authors: Majken K
authors: MK
authors: Jensen
authors: Tune H
authors: TH
authors: Pers
authors: Piotr
authors: P
authors: Dworzynski
authors: Cynthia J
authors: CJ
authors: Girman
authors: Søren
authors: S
authors: Brunak
authors: Eric B
authors: EB
authors: Rimm
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D016022:Case-Control Studies; D003327:Coronary Disease / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: C547787:ADRB1 protein, human; D018342:Receptors, Adrenergic, beta-1