PMID- 23731539 OWN - NLM STAT- MEDLINE DCOM- 20140109 LR - 20220321 IS - 1537-6605 (Electronic) IS - 0002-9297 (Print) IS - 0002-9297 (Linking) VI - 92 IP - 6 DP - 2013 Jun 6 TI - Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls. PG - 854-65 LID - S0002-9297(13)00180-8 [pii] LID - 10.1016/j.ajhg.2013.04.019 [doi] AB - 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. CI - Copyright (c) 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. CN - International Multiple Sclerosis Genetics Consortium LA - eng GR - R01 NS026799/NS/NINDS NIH HHS/United States GR - R01 NS049477/NS/NINDS NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't DEP - 20130523 PL - United States TA - Am J Hum Genet JT - American journal of human genetics JID - 0370475 SB - IM MH - Case-Control Studies MH - Epistasis, Genetic MH - Genetic Loci MH - Genetic Predisposition to Disease MH - *Genome-Wide Association Study MH - Humans MH - Linkage Disequilibrium MH - Models, Genetic MH - Multiple Sclerosis/*genetics MH - Polymorphism, Single Nucleotide MH - Protein Interaction Maps/*genetics MH - Risk PMC - PMC3958952 FIR - Baranzini, Sergio E IR - Baranzini SE FIR - Khankhanian, Pouya IR - Khankhanian P FIR - Patsopoulos, Nikolaos A IR - Patsopoulos NA FIR - Li, Michael IR - Li M FIR - Stankovich, Jim IR - Stankovich J FIR - Cotsapas, Chris IR - Cotsapas C FIR - Sondergaard, Helle Bach IR - Sondergaard HB FIR - Ban, Maria IR - Ban M FIR - Barizzone, Nadia IR - Barizzone N FIR - Bergamaschi, Laura IR - Bergamaschi L FIR - Booth, David IR - Booth D FIR - Buck, Dorothea IR - Buck D FIR - Cavalla, Paola IR - Cavalla P FIR - Celius, Elisabeth G IR - Celius EG FIR - Comabella, Manuel IR - Comabella M FIR - Comi, Giancarlo IR - Comi G FIR - Compston, Alastair IR - Compston A FIR - Cournu-Rebeix, Isabelle IR - Cournu-Rebeix I FIR - D'alfonso, Sandra IR - D'alfonso S FIR - Damotte, Vincent IR - Damotte V FIR - Din, Lennox IR - Din L FIR - Dubois, Benedicte IR - Dubois B FIR - Elovaara, Irina IR - Elovaara I FIR - Esposito, Federica IR - Esposito F FIR - Fontaine, Bertrand IR - Fontaine B FIR - Franke, Andre IR - Franke A FIR - Goris, An IR - Goris A FIR - Gourraud, Pierre-Antoine IR - Gourraud PA FIR - Graetz, Christiane IR - Graetz C FIR - Guerini, Franca R IR - Guerini FR FIR - Guillot-Noel, Lena IR - Guillot-Noel L FIR - Hafler, David IR - Hafler D FIR - Hakonarson, Hakon IR - Hakonarson H FIR - Hall, Per IR - Hall P FIR - Hamsten, Anders IR - Hamsten A FIR - Harbo, Hanne F IR - Harbo HF FIR - Hemmer, Bernhard IR - Hemmer B FIR - Hillert, Jan IR - Hillert J FIR - Kemppinen, Anu IR - Kemppinen A FIR - Kockum, Ingrid IR - Kockum I FIR - Koivisto, Keijo IR - Koivisto K FIR - Larsson, Malin IR - Larsson M FIR - Lathrop, Mark IR - Lathrop M FIR - Leone, Maurizio IR - Leone M FIR - Lill, Christina M IR - Lill CM FIR - Macciardi, Fabio IR - Macciardi F FIR - Martin, Roland IR - Martin R FIR - Martinelli, Vittorio IR - Martinelli V FIR - Martinelli-Boneschi, Filippo IR - Martinelli-Boneschi F FIR - McCauley, Jacob L IR - McCauley JL FIR - Myhr, Kjell-Morten IR - Myhr KM FIR - Naldi, Paola IR - Naldi P FIR - Olsson, Tomas IR - Olsson T FIR - Oturai, Annette IR - Oturai A FIR - Pericak-Vance, Margaret A IR - Pericak-Vance MA FIR - Perla, Franco IR - Perla F FIR - Reunanen, Mauri IR - Reunanen M FIR - Saarela, Janna IR - Saarela J FIR - Saker-Delye, Safa IR - Saker-Delye S FIR - Salvetti, Marco IR - Salvetti M FIR - Sellebjerg, Finn IR - Sellebjerg F FIR - Sorensen, Per Soelberg IR - Sorensen PS FIR - Spurkland, Anne IR - Spurkland A FIR - Stewart, Graeme IR - Stewart G FIR - Taylor, Bruce IR - Taylor B FIR - Tienari, Pentti IR - Tienari P FIR - Winkelmann, Juliane IR - Winkelmann J FIR - Zipp, Frauke IR - Zipp F FIR - Ivinson, Adrian J IR - Ivinson AJ FIR - Haines, Jonathan L IR - Haines JL FIR - Sawcer, Stephen IR - Sawcer S FIR - Dejager, Philip IR - Dejager P FIR - Hauser, Stephen L IR - Hauser SL FIR - Oksenberg, Jorge R IR - Oksenberg JR EDAT- 2013/06/05 06:00 MHDA- 2014/01/10 06:00 PMCR- 2013/12/06 CRDT- 2013/06/05 06:00 PHST- 2013/02/09 00:00 [received] PHST- 2013/04/04 00:00 [revised] PHST- 2013/04/23 00:00 [accepted] PHST- 2013/06/05 06:00 [entrez] PHST- 2013/06/05 06:00 [pubmed] PHST- 2014/01/10 06:00 [medline] PHST- 2013/12/06 00:00 [pmc-release] AID - S0002-9297(13)00180-8 [pii] AID - 10.1016/j.ajhg.2013.04.019 [doi] PST - ppublish SO - Am J Hum Genet. 2013 Jun 6;92(6):854-65. doi: 10.1016/j.ajhg.2013.04.019. Epub 2013 May 23.