Network-Based Multiple Sclerosis Pathway Analysis with GWAS Data from 15,000 Cases and 30,000 Controls
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- 作者：International Multiple Sclerosis Genetics Consortium 1&lowast ; sergio.baranzini@ucsf.eduSergio E. Baranzini ; Pouya Khankhanian ; Nikolaos A. Patsopoulos ; Michael Li ; Jim Stankovich ; Chris Cotsapas ; Helle Bach Sø ; ndergaard ; Maria Ban ; Nadia Barizzone ; Laura Bergamaschi ; David Booth ; Dorothea Buck ; Paola Cavalla ; Elisabeth G. Celius ; Manuel Comabella ; Giancarlo Comi ; Alastair Compston ; Isabelle Cournu-Rebeix ; Sandra D&rsquo ; alfonso ; Vincent Damotte ; Lennox Din ; Bé ; né ; dicte Dubois ; Irina Elovaara ; Federica Esposito ; Bertrand Fontaine ; Andre Franke ; An Goris ; Pierre-Antoine Gourraud ; Christiane Graetz ; Franca R. Guerini ; Lé ; na Guillot-Noel ; David Hafler ; Hakon Hakonarson ; Per Hall ; Anders Hamsten ; Hanne F. Harbo ; Bernhard Hemmer ; Jan Hillert ; Anu Kemppinen ; Ingrid Kockum ; Keijo Koivisto ; Malin Larsson ; Mark Lathrop ; Maurizio Leone ; Christina M. Lill ; Fabio Macciardi ; Roland Martin ; Vittorio Martinelli ; Filippo Martinelli-Boneschi ; Jacob L. McCauley ; Kjell-Morten Myhr ; Paola Naldi ; Tomas Olsson ; Annette Oturai ; Margaret A. Pericak-Vance ; Franco Perla ; Mauri Reunanen ; Janna Saarela ; Safa Saker-Delye ; Marco Salvetti ; Finn Sellebjerg ; Per Soelberg Sø ; rensen ; Anne Spurkland ; Graeme Stewart ; Bruce Taylor ; Pentti Tienari ; Juliane Winkelmann ; Wellcome Trust Case Control Consortium 2
- 刊名：The American Journal of Human Genetics
- 出版年：2013
- 出版时间：6 June, 2013
- 年：2013
- 卷：92
- 期：6
- 页码：854-865
- 全文大小：1536 K
文摘
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.