Protein interaction-based genome-wide analysis of incident coronary heart disease

TY - JOUR

T1 - Protein interaction-based genome-wide analysis of incident coronary heart disease

AU - Jensen, Majken K

AU - Pers, Tune H

AU - Dworzynski, Piotr

AU - Girman, Cynthia J

AU - Brunak, Søren

AU - Rimm, Eric B

PY - 2011/10

Y1 - 2011/10

N2 - 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). Methods and 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 =1-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.

AB - 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). Methods and 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 =1-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.

KW - Adult

KW - Aged

KW - Animals

KW - Blood Pressure

KW - Case-Control Studies

KW - Coronary Disease

KW - Female

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Incidence

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Protein Interaction Mapping

KW - Receptors, Adrenergic, beta-1

KW - Risk Factors

U2 - 10.1161/CIRCGENETICS.111.960393

DO - 10.1161/CIRCGENETICS.111.960393

M3 - Journal article

C2 - 21880673

SN - 1942-325X

VL - 4

SP - 549

EP - 556

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 5

ER -