Pathway-based Approaches for Analysis of Genomewide Association Studies

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2007 Oct 30

PMID 17966091

Citations 513

Authors

Kai Wang

Mingyao Li

Maja Bucan

Affiliations

Soon will be listed here.

Abstract

Published genomewide association (GWA) studies typically analyze and report single-nucleotide polymorphisms (SNPs) and their neighboring genes with the strongest evidence of association (the "most-significant SNPs/genes" approach), while paying little attention to the rest. Borrowing ideas from microarray data analysis, we demonstrate that pathway-based approaches, which jointly consider multiple contributing factors in the same pathway, might complement the most-significant SNPs/genes approach and provide additional insights into interpretation of GWA data on complex diseases.

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References

Marino M, Valenti O, Conn P . Glutamate receptors and Parkinson's disease: opportunities for intervention. Drugs Aging. 2003; 20(5):377-97. DOI: 10.2165/00002512-200320050-00006. View

Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N . Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst. 2004; 96(6):434-42. PMC: 7713993. DOI: 10.1093/jnci/djh075. View

Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita K, Itoh M, Kawashima S . From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res. 2005; 34(Database issue):D354-7. PMC: 1347464. DOI: 10.1093/nar/gkj102. View

Lefebvre T, Guinez C, Dehennaut V, Beseme-Dekeyser O, Morelle W, Michalski J . Does O-GlcNAc play a role in neurodegenerative diseases?. Expert Rev Proteomics. 2005; 2(2):265-75. DOI: 10.1586/14789450.2.2.265. View

Espinosa B, ZENTENO R, Mena R, Robitaille Y, Zenteno E, Guevara J . O-Glycosylation in sprouting neurons in Alzheimer disease, indicating reactive plasticity. J Neuropathol Exp Neurol. 2001; 60(5):441-8. DOI: 10.1093/jnen/60.5.441. View

Freimer N, Sabatti C . Human genetics: variants in common diseases. Nature. 2007; 445(7130):828-30. DOI: 10.1038/nature05568. View

Curtis R, Oresic M, Vidal-Puig A . Pathways to the analysis of microarray data. Trends Biotechnol. 2005; 23(8):429-35. DOI: 10.1016/j.tibtech.2005.05.011. View

Zaykin D, Zhivotovsky L . Ranks of genuine associations in whole-genome scans. Genetics. 2005; 171(2):813-23. PMC: 1456777. DOI: 10.1534/genetics.105.044206. View

Gottesman M, Ambudkar S . Overview: ABC transporters and human disease. J Bioenerg Biomembr. 2002; 33(6):453-8. DOI: 10.1023/a:1012866803188. View

10.

Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C . Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720):385-9. PMC: 1512523. DOI: 10.1126/science.1109557. View

11.

Reiner A, Yekutieli D, Benjamini Y . Identifying differentially expressed genes using false discovery rate controlling procedures. Bioinformatics. 2003; 19(3):368-75. DOI: 10.1093/bioinformatics/btf877. View

12.

Lee G, Bendayan R . Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharm Res. 2004; 21(8):1313-30. DOI: 10.1023/b:pham.0000036905.82914.8e. View

13.

Ashburner M, Ball C, Blake J, Botstein D, Butler H, Cherry J . Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000; 25(1):25-9. PMC: 3037419. DOI: 10.1038/75556. View

14.

Peer I, de Bakker P, Maller J, Yelensky R, Altshuler D, Daly M . Evaluating and improving power in whole-genome association studies using fixed marker sets. Nat Genet. 2006; 38(6):663-7. DOI: 10.1038/ng1816. View

15.

Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science. 1996; 273(5281):1516-7. DOI: 10.1126/science.273.5281.1516. View

16.

Fung H, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A . Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 2006; 5(11):911-6. DOI: 10.1016/S1474-4422(06)70578-6. View

17.

Mootha V, Lindgren C, Eriksson K, Subramanian A, Sihag S, Lehar J . PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003; 34(3):267-73. DOI: 10.1038/ng1180. View

18.

Maraganore D, de Andrade M, Lesnick T, Strain K, Farrer M, Rocca W . High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet. 2005; 77(5):685-93. PMC: 1271381. DOI: 10.1086/496902. View

19.

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

20.

Wigginton J, Cutler D, Abecasis G . A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005; 76(5):887-93. PMC: 1199378. DOI: 10.1086/429864. View