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 - Nigg, Joel T
AU - Wilmot, Beth
AU - IMAGE2 Consortium
AU - German ADHD GWAS Group
A2 - Steinhausen, Hans-Christoph E.
N1 - © 2016 Wiley Periodicals, Inc.
PY - 2016
Y1 - 2016
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 - Journal Article
U2 - 10.1002/ajmg.b.32446
DO - 10.1002/ajmg.b.32446
M3 - Journal article
C2 - 27004716
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 -