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

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. Never...

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Autores principales: Hammerschlag, Anke R., Polderman, Tinca J. C., de Leeuw, Christiaan, Tiemeier, Henning, White, Tonya, Smit, August B., Verhage, Matthijs, Posthuma, Danielle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198920/
https://www.ncbi.nlm.nih.gov/pubmed/25055203
http://dx.doi.org/10.3390/genes5030604
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author Hammerschlag, Anke R.
Polderman, Tinca J. C.
de Leeuw, Christiaan
Tiemeier, Henning
White, Tonya
Smit, August B.
Verhage, Matthijs
Posthuma, Danielle
author_facet Hammerschlag, Anke R.
Polderman, Tinca J. C.
de Leeuw, Christiaan
Tiemeier, Henning
White, Tonya
Smit, August B.
Verhage, Matthijs
Posthuma, Danielle
author_sort Hammerschlag, Anke R.
collection PubMed
description 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.
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spelling pubmed-41989202014-10-16 Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD) Hammerschlag, Anke R. Polderman, Tinca J. C. de Leeuw, Christiaan Tiemeier, Henning White, Tonya Smit, August B. Verhage, Matthijs Posthuma, Danielle Genes (Basel) Article 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. MDPI 2014-07-22 /pmc/articles/PMC4198920/ /pubmed/25055203 http://dx.doi.org/10.3390/genes5030604 Text en © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Hammerschlag, Anke R.
Polderman, Tinca J. C.
de Leeuw, Christiaan
Tiemeier, Henning
White, Tonya
Smit, August B.
Verhage, Matthijs
Posthuma, Danielle
Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
title Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
title_full Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
title_fullStr Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
title_full_unstemmed Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
title_short Functional Gene-Set Analysis Does Not Support a Major Role for Synaptic Function in Attention Deficit/Hyperactivity Disorder (ADHD)
title_sort functional gene-set analysis does not support a major role for synaptic function in attention deficit/hyperactivity disorder (adhd)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198920/
https://www.ncbi.nlm.nih.gov/pubmed/25055203
http://dx.doi.org/10.3390/genes5030604
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