Genome-wide gene-set analysis for identification of pathways associated with alcohol dependence.
It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene-set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol-dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the 'synthesis and degradation of ketone bodies' pathway. Our results also support the potential involvement of the 'neuroactive ligand-receptor interaction' pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence.
Divisions of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. biernacka.joanna@mayo.edu
Joanna M
JM
Biernacka
Jennifer
J
Geske
Gregory D
GD
Jenkins
Colin
C
Colby
David N
DN
Rider
Victor M
VM
Karpyak
Doo-Sup
DS
Choi
Brooke L
BL
Fridley
D000437:Alcoholism / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D030541:Databases, Genetic / Q000706:statistics & numerical data; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007657:Ketone Bodies / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025341:Principal Component Analysis; D011984:Sensory Receptor Cells; D015398:Signal Transduction / Q000235:genetics*
D007657:Ketone Bodies; D008024:Ligands