title: Functional gene-set analysis does not support a major role for synaptic function in attention deficit/hyperactivity disorder (ADHD).
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.
authors: 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. a.r.hammerschlag@vu.nl.
authors: Anke R
authors: AR
authors: Hammerschlag
authors: 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. tinca.polderman@vu.nl.
authors: Tinca J C
authors: TJ
authors: Polderman
authors: 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. c.deleeuw@science.ru.nl.
authors: Christiaan
authors: C
authors: de Leeuw
authors: Department of Child and Adolescent Psychiatry, Erasmus University Medical Center and Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. h.tiemeier@erasmusmc.nl.
authors: Henning
authors: H
authors: Tiemeier
authors: Department of Child and Adolescent Psychiatry, Erasmus University Medical Center and Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. t.white@erasmusmc.nl.
authors: Tonya
authors: T
authors: White
authors: 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. guus.smit@vu.nl.
authors: August B
authors: AB
authors: Smit
authors: Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. matthijs.verhage@cncr.vu.nl.
authors: Matthijs
authors: M
authors: Verhage
authors: 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. danielle.posthuma@vu.nl.
authors: Danielle
authors: D
authors: Posthuma