TY - JOUR
T1 - Pathway analysis in attention deficit hyperactivity disorder
T2 - An ensemble approach
AU - Mooney, Michael A.
AU - McWeeney, Shannon K.
AU - Faraone, Stephen V.
AU - Hinney, Anke
AU - Hebebrand, Johannes
AU - Romanos, Marcel
AU - Warnke, Andreas
AU - Reif, Andreas
AU - Walitza, Susanne
AU - Roeyers, Herbert
AU - Franke, Barbara
AU - Buitelaar, Jan K.
AU - Lesch, Klaus Peter
AU - Kent, Lindsey
AU - Vasquez, Alejandro Arias
AU - Thapar, Anita
AU - Martin, Joanna
AU - O’Donovan, Michael C.
AU - Owen, Michael J.
AU - Williams, Nigel
AU - Holmans, Peter
AU - Langley, Kate
AU - Freitag, Christine
AU - Lambregts-Rommelse, Nanda
AU - Anney, Richard J.L.
AU - Mulligan, Aisling
AU - Rothenberger, Aribert
AU - Steinhausen, Hans Christoph
AU - Gill, Michael
AU - Asherson, Philip
AU - Nguyen, T. Trang
AU - Biederman, Joseph
AU - Doyle, Alysa E.
AU - Romanos, Jasmin
AU - Rivero, Olga
AU - Palmason, Haukur
AU - Meyer, Jobst
AU - Renner, Tobias J.
AU - Albayrak, Özgür
AU - Volckmar, Anna Lena
AU - Dempfle, Astrid
AU - Hoffmann, Per
AU - Cichon, Sven
AU - Nöthen, Markus M.
AU - Schreiber, Stefan
AU - Möbus, Susanne
AU - Wichmann, H. Erich
AU - Herpertz-Dahlmann, Beate
AU - German ADHD GWAS Group
AU - IMAGE2 Consortium
N1 - Funding Information:
Work on this project was supported by the following grants: MH099064 (Drs. Nigg, Wilmot, and Mooney), NIH/NCATS UL1TR000128 (Drs. McWeeney, Mooney and Wilmot), and DFG HE1446/9-1 (Drs. Hinney and Hebebrand). Professor Faraone was supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602805, and NIMH grants R13MH059126 and R01MH094469. Barbara Franke was supported by grants from the Netherlands Organization for Scientific Research (NWO), that is, the NWO Brain & Cognition Excellence Program (grant 433-09-229) and a Vici grant (grant 016-130-669). She also received funding from the European Community's Seventh Framework Programme under grant agreements n°602805 (Aggressotype) and n°602450 (IMAGEMEND), from the European Community's Horizon 2020 Programme under grant agreement n°643051 (MiND), and from the BD2 K Initiative of NIH (grant number U54 EB020403). Andreas Reif was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602805.
Publisher Copyright:
© 2016 Wiley Periodicals, Inc.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Despite a wealth of evidence for the role of genetics in attention deficit hyperactivity disorder (ADHD), specific and definitive genetic mechanisms have not been identified. Pathway analyses, a subset of gene-set analyses, extend the knowledge gained from genome-wide association studies (GWAS) by providing functional context for genetic associations. However, there are numerous methods for association testing of gene sets and no real consensus regarding the best approach. The present study applied six pathway analysis methods to identify pathways associated with ADHD in two GWAS datasets from the Psychiatric Genomics Consortium. Methods that utilize genotypes to model pathway-level effects identified more replicable pathway associations than methods using summary statistics. In addition, pathways implicated by more than one method were significantly more likely to replicate. A number of brain-relevant pathways, such as RhoA signaling, glycosaminoglycan biosynthesis, fibroblast growth factor receptor activity, and pathways containing potassium channel genes, were nominally significant by multiple methods in both datasets. These results support previous hypotheses about the role of regulation of neurotransmitter release, neurite outgrowth and axon guidance in contributing to the ADHD phenotype and suggest the value of cross-method convergence in evaluating pathway analysis results. © 2016 Wiley Periodicals, Inc.
AB - Despite a wealth of evidence for the role of genetics in attention deficit hyperactivity disorder (ADHD), specific and definitive genetic mechanisms have not been identified. Pathway analyses, a subset of gene-set analyses, extend the knowledge gained from genome-wide association studies (GWAS) by providing functional context for genetic associations. However, there are numerous methods for association testing of gene sets and no real consensus regarding the best approach. The present study applied six pathway analysis methods to identify pathways associated with ADHD in two GWAS datasets from the Psychiatric Genomics Consortium. Methods that utilize genotypes to model pathway-level effects identified more replicable pathway associations than methods using summary statistics. In addition, pathways implicated by more than one method were significantly more likely to replicate. A number of brain-relevant pathways, such as RhoA signaling, glycosaminoglycan biosynthesis, fibroblast growth factor receptor activity, and pathways containing potassium channel genes, were nominally significant by multiple methods in both datasets. These results support previous hypotheses about the role of regulation of neurotransmitter release, neurite outgrowth and axon guidance in contributing to the ADHD phenotype and suggest the value of cross-method convergence in evaluating pathway analysis results. © 2016 Wiley Periodicals, Inc.
KW - ADHD
KW - GWAS
KW - pathway analyses
U2 - 10.1002/ajmg.b.32446
DO - 10.1002/ajmg.b.32446
M3 - Article
SN - 1552-4841
VL - 171
SP - 815
EP - 826
JO - American Journal of Medical Genetics Part B-neuropsychiatric Genetics
JF - American Journal of Medical Genetics Part B-neuropsychiatric Genetics
IS - 6
ER -