Pathway analysis in attention deficit hyperactivity disorder: an ensemble approach

Mooney, Michael A., McWeeney, Shannon K., Faraone, Stephen, Hinney, Anke, Hebebrand, Johannes, Nigg, Joel T., Wilmot, Beth, Thapar, Anita ORCID: https://orcid.org/0000-0002-3689-737X, Martin, Joanna ORCID: https://orcid.org/0000-0002-8911-3479, O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862, Williams, Nigel Melville ORCID: https://orcid.org/0000-0003-1177-6931, Anney, Richard ORCID: https://orcid.org/0000-0002-6083-407X, Langley, Kate ORCID: https://orcid.org/0000-0002-2033-2657, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412 and German ADHD GWAS Group 2016. Pathway analysis in attention deficit hyperactivity disorder: an ensemble approach. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 171 (6) , pp. 815-826. 10.1002/ajmg.b.32446

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Abstract

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. Peter Holmans (Schools to be added are MRC Centre for Neuropsychiatric Genetics and Genomics and Psychology.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine Neuroscience and Mental Health Research Institute (NMHRI) Psychology
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Additional Information:	Anita Thapar part of the IMAGE2 Consortium.
Publisher:	Wiley-Blackwell
ISSN:	1552-4841
Date of Acceptance:	7 March 2016
Last Modified:	01 Sep 2023 08:03
URI:	https://orca.cardiff.ac.uk/id/eprint/89100

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