Skip to main content
×
Home
    • Aa
    • Aa

A Novel Approach for Pathway Analysis of GWAS Data Highlights Role of BMP Signaling and Muscle Cell Differentiation in Colorectal Cancer Susceptibility

  • Aniket Mishra (a1) and Stuart MacGregor (a1)
Abstract

Genome-wide association studies (GWAS) have revolutionized the field of gene mapping. As the GWAS field matures, it is becoming clear that for many complex traits, a proportion of the missing heritability is attributable to common variants of individually small effect. Detecting these small effects individually can be difficult, and statistical power would be increased if relevant variants could be grouped together for testing. Here, we propose a VEGAS2Pathway approach that aggregates association strength of individual markers into pre-specified biological pathways. It accounts for gene size and linkage disequilibrium between markers using simulations from the multivariate normal distribution. Pathway size is taken into account via a resampling approach. Importantly, since the approach only requires summary data, the method can easily be applied in all GWASs, including meta-analysis, singleton-based, family-based, and DNA-pooling-based designs. This approach is implemented in a user-friendly web page https://vegas2.qimrberghofer.edu.au and a command line tool. The web implementation uses gene-sets from the gene ontology (GO), curated gene-sets from MSigDB (containing canonical pathways and gene-sets from BIOCARTA, REACTOME, KEGG databases), PANTHER, and pathway commons databases, enabling analysis of a wide range of complex traits. We applied this method on a colorectal cancer GWAS meta-analysis data set (10,934 cases, 12,328 controls) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). We report statistically significant enrichment of association signal for the ‘BMP signaling’ and ‘muscle cell differentiation’ pathways, suggesting a possible role for these pathways onto the risk of colorectal cancer.

Copyright
Corresponding author
address for correspondence: Aniket Mishra, Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Brisbane QLD 4006, Australia. E-mail: aniket.mishra@qimrberghofer.edu.au
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

E. L. Alarmo , J. Parssinen , J. M. Ketolainen , K. Savinainen , R. Karhu , & A. Kallioniemi (2009). BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Letters, 275, 3543.

L. A. Brosens , A. van Hattem , L. M. Hylind , C. Iacobuzio-Donahue , K. E. Romans , J. Axilbund , . . . F. M. Giardiello (2007). Risk of colorectal cancer in juvenile polyposis. Gut, 56, 965967.

E. G. Cerami , B. E. Gross , E. Demir , I. Rodchenkov , O. Babur , N. Anwar , . . . C. Sander (2011). Pathway Commons, a web resource for biological pathway data. Nucleic Acids Research, 39, D685–690.

J. F. Chau , D. Jia , Z. Wang , Z. Liu , Y. Hu , X. Zhang , . . . B. Li (2012). A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response. Nature Communications, 3, 836.

H. Chu , H. Luo , H. Wang , X. Chen , P. Li , Y. Bai , . . . G. Zhang (2014). Silencing BMP-2 expression inhibits A549 and H460 cell proliferation and migration. Diagnostic Pathology, 9, 123.

A. De Boeck , P. Pauwels , K. Hensen , J. L. Rummens , W. Westbroek , A. Hendrix , . . . O. De Wever (2013). Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. Gut, 62, 550560.

M. Evangelou , A. Rendon , W. H. Ouwehand , L. Wernisch , & F. Dudbridge (2012). Comparison of methods for competitive tests of pathway analysis. PLoS One, 7, e41018.

N. Fenouille , S. Grosso , S. Yunchao , D. Mary , R. Pontier-Bres , V. Imbert , . . . P. Lagadec (2012). Calpain 2-dependent IkappaBalpha degradation mediates CPT-11 secondary resistance in colorectal cancer xenografts. Journal of Pathology, 227, 118129.

U. Guha , W. A. Gomes , T. Kobayashi , R. G. Pestell , & J. A. Kessler (2002). In vivo evidence that BMP signaling is necessary for apoptosis in the mouse limb. Developmental Biology, 249, 108120.

P. Holmans , E. K. Green , J. S. Pahwa , M. A. Ferreira , S. M. Purcell , P. Sklar , . . . N. Craddock (2009). Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. American Journal of Human Genetics, 85, 1324.

J. R. Howe , F. A. Mitros , & R. W. Summers (1998). The risk of gastrointestinal carcinoma in familial juvenile polyposis. Annals of Surgical Oncology, 5, 751756.

H. S. Jeon , T. Dracheva , S. H. Yang , D. Meerzaman , J. Fukuoka , A. Shakoori , . . . J. Jen (2008). SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-beta homeostasis in lung cancer cells. Cancer Research, 68, 96869692.

S. Jiao , U. Peters , S. Berndt , H. Brenner , K. Butterbach , B. J. Caan , . . . L. Hsu (2014). Estimating the heritability of colorectal cancer. Human Molecular Genetics, 23, 38983905.

T. Kobayashi , K. M. Lyons , A. P. McMahon , & H. M. Kronenberg (2005). BMP signaling stimulates cellular differentiation at multiple steps during cartilage development. Proceedings of the National Academy of Sciences of the United States of America, 102, 1802318027.

L. L. Kodach , E. Wiercinska , N. F. de Miranda , S. A. Bleuming , A. R. Musler , M. P. Peppelenbosch , . . . J. C. Hardwick (2008). The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers. Gastroenterology, 134, 13321341.

P. H. Lee , C. O'Dushlaine , B. Thomas , & S. M. Purcell (2012). INRICH: interval-based enrichment analysis for genome-wide association studies. Bioinformatics, 28, 17971799.

A. Liberzon , A. Subramanian , R. Pinchback , H. Thorvaldsdottir , P. Tamayo , & J. P. Mesirov (2011). Molecular signatures database (MSigDB) 3.0. Bioinformatics, 27, 17391740.

J. Z. Liu , A. F. McRae , D. R. Nyholt , S. E. Medland , N. R. Wray , K. M. Brown , . . . S. MacGregor (2010). A versatile gene-based test for genome-wide association studies. American Journal of Human Genetics, 87, 139145.

Q. Liu , S. Tomei , M. L. Ascierto , V. De Giorgi , D. Bedognetti , C. Dai , . . . F. M. Marincola (2014). Melanoma NOS1 expression promotes dysfunctional IFN signaling. Journal of Clinical Investigation, 124, 21472159.

A. Mishra , & S. MacGregor (2015). VEGAS2: Software for more flexible gene-based testing. Twin Research and Human Genetics, 18, 8691.

S. Nomura , H. Yoshitomi , S. Takano , T. Shida , S. Kobayashi , M. Ohtsuka , . . . M. Miyazaki (2008). FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer. British Journal of Cancer, 99, 305313.

T. H. Pers , J. M. Karjalainen , Y. Chan , H. J. Westra , A. R. Wood , J. Yang , . . . L. Franke (2015). Biological interpretation of genome-wide association studies using predicted gene functions. Nature Communications, 6, 5890.

U. Peters , S. Bien , & N. Zubair (2015). Genetic architecture of colorectal cancer. Gut, 64, 16231636

U. Peters , S. Jiao , F. R. Schumacher , C. M. Hutter , A. K. Aragaki , J. A. Baron , . . . Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium. (2013). Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis. Gastroenterology, 144, 799807.e24.

M. R. Robinson , N. R. Wray , & P. M. Visscher (2014). Explaining additional genetic variation in complex traits. Trends in Genetics, 30, 124132.

C. F. Schaefer , K. Anthony , S. Krupa , J. Buchoff , M. Day , T. Hannay , & K. H. Buetow (2009). PID: The pathway interaction database. Nucleic Acids Research, 37, D674–679.

A. V. Segre , DIAGRAM Consortium, MAGIC investigators Groop, L., V. K. Mootha , M. J. Daly , & D. Altshuler (2010). Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet, 6, e1001058.

P. D. Thomas , M. J. Campbell , A. Kejariwal , H. Mi , B. Karlak , R. Daverman , . . . A. Narechania (2003). PANTHER: a library of protein families and subfamilies indexed by function. Genome Research, 13, 21292141.

K. L. Thu , N. Radulovich , D. D. Becker-Santos , L. A. Pikor , A. Pusic , W. W. Lockwood , . . . M. S. Tsao (2014). SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/beta-catenin signaling. Oncogene, 33, 279288.

K. Wang , M. Li , & H. Hakonarson (2010). Analysing biological pathways in genome-wide association studies. Nature Reviews Genetics, 11, 843854.

K. Wang , H. Zhang , S. Kugathasan , V. Annese , J. P. Bradfield , R. K. Russell , . . . H. Hakonarson (2009). Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn disease. American Journal of Human Genetics, 84, 399405.

L. Wang , P. Jia , R. D. Wolfinger , X. Chen , & Z. Zhao (2011). Gene set analysis of genome-wide association studies: Methodological issues and perspectives. Genomics, 98, 18.

G. L. Wojcik , W. H. Kao , & P. Duggal (2015). Relative performance of gene- and pathway-level methods as secondary analyses for genome-wide association studies. BMC Genetics, 16, 34.

J. Yamaguchi , S. Nagayama , A. Chino , A. Sakata , N. Yamamoto , Y. Sato , . . . M. Arai (2014). Identification of coding exon 3 duplication in the BMPR1A gene in a patient with juvenile polyposis syndrome. Japanese Journal of Clinical Oncology, 44, 10041008.

J. Yang , T. Ferreira , A. P. Morris , S. E. Medland , A. T. C. Genetic Investigation of , D. I. G. Replication , . . . P. M. Visscher (2012). Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nature Genetics, 44, 369375.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Twin Research and Human Genetics
  • ISSN: 1832-4274
  • EISSN: 1839-2628
  • URL: /core/journals/twin-research-and-human-genetics
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Type Description Title
UNKNOWN
Supplementary Materials

Mishra and MacGregor supplementary material S3
Supplementary Table

 Unknown (57 KB)
57 KB
UNKNOWN
Supplementary Materials

Mishra and MacGregor supplementary material S2
Supplementary Table

 Unknown (74 KB)
74 KB
UNKNOWN
Supplementary Materials

Mishra and MacGregor supplementary material S1
Supplementary Table

 Unknown (49 KB)
49 KB
WORD
Supplementary Materials

Mishra and MacGregor supplementary material S4
Mishra and MacGregor supplementary material

 Word (56 KB)
56 KB

Metrics

Full text views

Total number of HTML views: 47
Total number of PDF views: 124 *
Loading metrics...

Abstract views

Total abstract views: 760 *
Loading metrics...

* Views captured on Cambridge Core between 20th January 2017 - 26th September 2017. This data will be updated every 24 hours.

A correction has been issued for this article: