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On the role of NOS1 ex1f-VNTR in ADHD – allelic, subgroup, and meta-analysis

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Author(s)

Heike Weber, S. Kittel-Schneider, J Heupel, L. Weißflog, Lindsey Kent, F. Freudenberg, A. Alttoa, A. Post, S. Herterich, Jan Haavik, Anne Halmøy, Ole Bernt Fasmer, Elisabeth Toverund Landaas, Stefan Johansson, Bru Cormand, Marta Ribasés, Cristina Sánchez-Mora, Josep Antoni Ramos-Quiroga, B. Franke, K-P. Lesch & 1 others Andreas Reif

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Abstract

Attention deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1fVNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association.
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Original languageEnglish
Pages (from-to)445-458
JournalAmerican Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Volume168
Issue number6
Early online date18 Jun 2015
DOIs
Publication statusPublished - Sep 2015

    Research areas

  • Glutamate, Nitric oxide, Association, Adult ADHD, Polymorphism

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