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Genes 2014, 5(3), 604-614; doi:10.3390/genes5030604

Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)

1
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
2
Institute for Computing and Information Sciences, Radboud University Nijmegen, P.O. Box 9010, 6500 GL Nijmegen, The Netherlands
3
Department of Child and Adolescent Psychiatry, Erasmus University Medical Center and Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands
4
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
5
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
6
Department of Clinical Genetics, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 9 April 2014 / Revised: 4 July 2014 / Accepted: 10 July 2014 / Published: 22 July 2014
(This article belongs to the Special Issue Grand Celebration: 10th Anniversary of the Human Genome Project)
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Abstract

Attention Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric disorders. Despite high heritability estimates, genome-wide association studies (GWAS) have failed to find significant genetic associations, likely due to the polygenic character of ADHD. Nevertheless, genetic studies suggested the involvement of several processes important for synaptic function. Therefore, we applied a functional gene-set analysis to formally test whether synaptic functions are associated with ADHD. Gene-set analysis tests the joint effect of multiple genetic variants in groups of functionally related genes. This method provides increased statistical power compared to conventional GWAS. We used data from the Psychiatric Genomics Consortium including 896 ADHD cases and 2455 controls, and 2064 parent-affected offspring trios, providing sufficient statistical power to detect gene sets representing a genotype relative risk of at least 1.17. Although all synaptic genes together showed a significant association with ADHD, this association was not stronger than that of randomly generated gene sets matched for same number of genes. Further analyses showed no association of specific synaptic function categories with ADHD after correction for multiple testing. Given current sample size and gene sets based on current knowledge of genes related to synaptic function, our results do not support a major role for common genetic variants in synaptic genes in the etiology of ADHD. View Full-Text
Keywords: complex trait; polygenic; gene network; biological pathway; synapse; GWAS; PGC complex trait; polygenic; gene network; biological pathway; synapse; GWAS; PGC
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Hammerschlag, A.R.; Polderman, T.J.C.; de Leeuw, C.; Tiemeier, H.; White, T.; Smit, A.B.; Verhage, M.; Posthuma, D. Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD). Genes 2014, 5, 604-614.

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