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Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls


Baranzini, SE and Khankhanian, P and Patsopoulos, NA and Li, M and Stankovich, J and Cotsapas, C and Sondergaard, HB and Ban, M and Barizzone, N and Bergamaschi, L and Booth, D and Buck, D and Cavalla, P and Celius, EG and Comabella, M and Comi, G and Compston, A and Cournu-Rebeix, I and D'alfonso, S and Damotte, V and Din, L and Dubois, B and Elovaara, I and Esposito, F and Fontaine, B and Franke, A and Goris, A and Gourraud, PA and Graetz, C and Guerini, FR and Guillot-Noel, L and Hafler, D and Hakonarson, H and Hall, P and Hamsten, A and Harbo, HF and Hemmer, B and Hillert, J and Kemppinen, A and Kockum, I and Koivisto, K and Larsson, M and Lathrop, M and Leone, M and Lill, CM and Macciardi, F and Martin, R and Martinelli, V and Martinelli-Boneschi, F and McCauley, JL and Myhr, KM and Naldi, P and Olsson, T and Oturai, A and Pericak-Vance, MA and Perla, F and Reunanen, M and Saarela, J and Saker-Delye, S and Salvetti, M and Sellebjerg, F and Sorensen, PS and Spurkland, A and Stewart, G and Taylor, B and Tienari, P and Winkelmann, J and Zipp, F and Ivinson, AJ and Haines, JL and Sawcer, S and Dejager, P and Hauser, SL and Oksenberg, JR, Wellcome Trust Case Control Consortium 2, Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls, American Journal of Human Genetics: A Record of Research, Review and Bibliographic Material Relating to Heredity in Man, 92, (6) pp. 854-865. ISSN 0002-9297 (2013) [Refereed Article]

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Copyright Statement

Copyright 2013 The American Society of Human Genetics

DOI: doi:10.1016/j.ajhg.2013.04.019


Multiple sclerosis (MS) is an inflammatory CNS disease with a substantial genetic component, originally mapped to only the human leukocyte antigen (HLA) region. In the last 5 years, a total of seven genome-wide association studies and one meta-analysis successfully identified 57 non-HLA susceptibility loci. Here, we merged nominal statistical evidence of association and physical evidence of interaction to conduct a protein-interaction-network-based pathway analysis (PINBPA) on two large genetic MS studies comprising a total of 15,317 cases and 29,529 controls. The distribution of nominally significant loci at the gene level matched the patterns of extended linkage disequilibrium in regions of interest. We found that products of genome-wide significantly associated genes are more likely to interact physically and belong to the same or related pathways. We next searched for subnetworks (modules) of genes (and their encoded proteins) enriched with nominally associated loci within each study and identified those modules in common between the two studies. We demonstrate that these modules are more likely to contain genes with bona fide susceptibility variants and, in addition, identify several high-confidence candidates (including BCL10, CD48, REL, TRAF3, and TEC). PINBPA is a powerful approach to gaining further insights into the biology of associated genes and to prioritizing candidates for subsequent genetic studies of complex traits.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Stankovich, J (Dr Jim Stankovich)
UTAS Author:Taylor, B (Professor Bruce Taylor)
ID Code:88332
Year Published:2013
Web of Science® Times Cited:111
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-01-29
Last Modified:2017-11-07
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