PMID- 21915301
OWN - NLM
STAT- MEDLINE
DCOM- 20120214
LR  - 20220316
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 9
DP  - 2011
TI  - A network-based approach to prioritize results from genome-wide association 
      studies.
PG  - e24220
LID - 10.1371/journal.pone.0024220 [doi]
LID - e24220
AB  - Genome-wide association studies (GWAS) are a valuable approach to understanding 
      the genetic basis of complex traits. One of the challenges of GWAS is the 
      translation of genetic association results into biological hypotheses suitable 
      for further investigation in the laboratory. To address this challenge, we 
      introduce Network Interface Miner for Multigenic Interactions (NIMMI), a 
      network-based method that combines GWAS data with human protein-protein 
      interaction data (PPI). NIMMI builds biological networks weighted by 
      connectivity, which is estimated by use of a modification of the Google PageRank 
      algorithm. These weights are then combined with genetic association p-values 
      derived from GWAS, producing what we call 'trait prioritized sub-networks.' As a 
      proof of principle, NIMMI was tested on three GWAS datasets previously analyzed 
      for height, a classical polygenic trait. Despite differences in sample size and 
      ancestry, NIMMI captured 95% of the known height associated genes within the top 
      20% of ranked sub-networks, far better than what could be achieved by a 
      single-locus approach. The top 2% of NIMMI height-prioritized sub-networks were 
      significantly enriched for genes involved in transcription, signal transduction, 
      transport, and gene expression, as well as nucleic acid, phosphate, protein, and 
      zinc metabolism. All of these sub-networks were ranked near the top across all 
      three height GWAS datasets we tested. We also tested NIMMI on a categorical 
      phenotype, Crohn's disease. NIMMI prioritized sub-networks involved in B- and 
      T-cell receptor, chemokine, interleukin, and other pathways consistent with the 
      known autoimmune nature of Crohn's disease. NIMMI is a simple, user-friendly, 
      open-source software tool that efficiently combines genetic association data with 
      biological networks, translating GWAS findings into biological hypotheses.
FAU - Akula, Nirmala
AU  - Akula N
AD  - Mood and Anxiety Section, Human Genetics Branch, National Institute of Mental 
      Health, National Institutes of Health, Department of Health and Human Services, 
      Bethesda, Maryland, United States of America. akulan@mail.nih.gov
FAU - Baranova, Ancha
AU  - Baranova A
FAU - Seto, Donald
AU  - Seto D
FAU - Solka, Jeffrey
AU  - Solka J
FAU - Nalls, Michael A
AU  - Nalls MA
FAU - Singleton, Andrew
AU  - Singleton A
FAU - Ferrucci, Luigi
AU  - Ferrucci L
FAU - Tanaka, Toshiko
AU  - Tanaka T
FAU - Bandinelli, Stefania
AU  - Bandinelli S
FAU - Cho, Yoon Shin
AU  - Cho YS
FAU - Kim, Young Jin
AU  - Kim YJ
FAU - Lee, Jong-Young
AU  - Lee JY
FAU - Han, Bok-Ghee
AU  - Han BG
CN  - Bipolar Disorder Genome Study (BiGS) Consortium
CN  - Wellcome Trust Case-Control Consortium
FAU - McMahon, Francis J
AU  - McMahon FJ
LA  - eng
GR  - N01-AG-821336/AG/NIA NIH HHS/United States
GR  - R01 MD009164/MD/NIMHD NIH HHS/United States
GR  - 263 MD 821336/MD/NIMHD NIH HHS/United States
GR  - 263 MD 9164 13/MD/NIMHD NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
GR  - N01-AG-916413/AG/NIA NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110906
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Chemokines)
RN  - 0 (Interleukins)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - Chemokines/metabolism
MH  - Crohn Disease/metabolism
MH  - Genome-Wide Association Study/*methods
MH  - Humans
MH  - Interleukins/metabolism
MH  - Protein Binding
MH  - Receptors, Antigen, T-Cell/metabolism
PMC - PMC3168369
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/09/15 06:00
MHDA- 2012/02/15 06:00
PMCR- 2011/09/06
CRDT- 2011/09/15 06:00
PHST- 2011/01/19 00:00 [received]
PHST- 2011/08/08 00:00 [accepted]
PHST- 2011/09/15 06:00 [entrez]
PHST- 2011/09/15 06:00 [pubmed]
PHST- 2012/02/15 06:00 [medline]
PHST- 2011/09/06 00:00 [pmc-release]
AID - PONE-D-11-01931 [pii]
AID - 10.1371/journal.pone.0024220 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(9):e24220. doi: 10.1371/journal.pone.0024220. Epub 2011 Sep 6.