Abstract
Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008–0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.
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Acknowledgements
This study was supported by the DFG (Grant RE1632/1-1, /1-3 and /5 to AR, KFO 125 to AR, CPJ, AW, SW, HS and KPL; SFB 581 to KPL, SFB TRR 58 to AR and KPL; RTG 1252, to AR and KPL; GR 1912/5-1, to HG), BMBF (IZKF Würzburg, 01KS9603, to KPL; IZKF N-27-N, to AR) and the EC (NEWMOOD LSHM-CT-2003-503474, to KPL). The Norwegian part of the study was supported by the Research Council of Norway and the Western Norway Regional Health Authority (Helse Vest). Financial support for the Spanish part of the study was received from ‘Instituto de Salud Carlos III-FIS, Spain’ (PI040524, PI041267), ‘Fundació La Marató de TV3’ (092330/31) and ‘Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR'(2009SGR-00971). MR is a recipient of a ‘Ramón y Cajal’ contract from ‘Ministerio de Ciencia e Innovación’ (Spain). The Dutch part of the project was supported by the Hersenstichting Nederland (Fonds Psychische Gezondheid). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. We thank J Romanos, A Boreatti-Hümmer and M Heine for their dedicated assistance in patient recruitment. T Töpner, N Steigerwald, G Ortega, J Auer, C Gagel, and N Döring are credited for excellent technical assistance. We thank Mariana Nogueira and Montse Corrales for their involvement in the clinical assessment in Spain, M Dolors Castellar and others from the ‘Banc de Sang i Teixits’ (Hospital Vall d'Hebron, Barcelona) for their collaboration in the recruitment of control subjects, and Cristina Sánchez-Mora for her participation in the preparation of DNA samples from patients and controls. We thank Marije Boonstra and Marten Onnink for help with patient inclusion, as well as Marlies Naber and Angelien Heister for DNA handling and genotyping. The Dutch controls were derived from the Nijmegen Biomedical Study. Principal investigators of the Nijmegen Biomedical Study are LALM Kiemeney, M den Heijer, ALM Verbeek, DW Swinkels, and B Franke. Finally, we thank all patients, families, and controls for their participation in this study.
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In the past 3 years, Jan K Buitelaar has been a consultant to/member of advisory board of and/or speaker for Janssen Cilag BV, Eli Lilly, Bristol-Myer Squibb, Organon/Shering Plough, UCB, Shire, Medice and Servier. Sandra Kooij has received research grants from Janssen BV and Shire, and is on the speaker's bureau of Janssen and Eli Lilly. Hans Joergen Grabe has received speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, Servier and travel funds from Janssen-Cilag, Eli Lilly, Novartis, AstraZeneca and the SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. Henry Völzke has received research grants by Sanofi-Aventis and the Siemens AG. Susanne Walitza has received lecture honoraria from Janssen Cilag, Lilly and AstraZeneca. Christine Freitag was on the speakers' bureau for Novartis and Janssen-Cilag during the last 3 years. Helmut Schäfer has received a honorarium for a lecture from the European School of Oncology and has been a member of a Data Safety Monitoring Board of Daiichi Sankyo. Andreas Reif has received a research grant from Astra Zeneca. The remaining authors declare no conflict of interest.
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Reif, A., Nguyen, T., Weißflog, L. et al. DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders. Neuropsychopharmacol 36, 2318–2327 (2011). https://doi.org/10.1038/npp.2011.120
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DOI: https://doi.org/10.1038/npp.2011.120
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