Abstract
Genome-wide association (GWA) studies of complex diseases including coronary heart disease (CHD) challenge investigators attempting to identify relevant genetic variants among hundreds of thousands of markers being tested. A selection strategy based purely on statistical significance will result in many false negative findings after adjustment for multiple testing. Thus, an integrated analysis using information from the learned genetic pathways, molecular functions, and biological processes is desirable. In this study, we applied a customized method, variable set enrichment analysis (VSEA), to the Framingham Heart Study data (404 467 variants, n=6421) to evaluate enrichment of genetic association in 1395 gene sets for their contribution to CHD. We identified 25 gene sets with nominal P<0.01; at least four sets are previously known for their roles in CHD: vascular genesis (GO:0001570), fatty-acid biosynthetic process (GO:0006633), fatty-acid metabolic process (GO:0006631), and glycerolipid metabolic process (GO:0046486). Although the four gene sets include 170 genes, only three of the genes contain a variant ranked among the top 100 in single-variant association tests of the 404 467 variants tested. Significant enrichment for novel gene sets less known for their importance to CHD were also identified: Rac 1 cell-motility signaling pathway (h_rac1 Pathway, P<0.001) and sulfur amino-acid metabolic process (GO:0000096, P<0.001). In summary, we showed that the pathway-based VSEA can help prioritize association signals in GWA studies by identifying biologically plausible targets for downstream searches of genetic variants associated with CHD.
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Acknowledgements
This research is supported in part by the NIH grants HL091028, HL071782, HL094668 and an AHA grant 0855626G. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract no. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278.
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de las Fuentes, L., Yang, W., Dávila-Román, V. et al. Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets. Eur J Hum Genet 20, 1168–1173 (2012). https://doi.org/10.1038/ejhg.2012.66
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DOI: https://doi.org/10.1038/ejhg.2012.66
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