DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders

Andreas Reif*, T. Trang Nguyen, Lena Weiflog, Christian P. Jacob, Marcel Romanos, Tobias J. Renner, Henriette N. Buttenschon, Sarah Kittel-Schneider, Alexandra Gessner, Heike Weber, Maria Neuner, Silke Gross-Lesch, Karin Zamzow, Susanne Kreiker, Susanne Walitza, Jobst Meyer, Christine M. Freitag, Rosa Bosch, Miquel Casas, Nuria GómezMarta Ribasès, Mónica Bayès, Jan K. Buitelaar, Lambertus A.L.M. Kiemeney, J. J.Sandra Kooij, Cees C. Kan, Martine Hoogman, Stefan Johansson, Kaya K. Jacobsen, Per M. Knappskog, Ole B. Fasmer, Phil Asherson, Andreas Warnke, Hans Jörgen Grabe, Jessie Mahler, Alexander Teumer, Henry Völzke, Ole N. Mors, Helmut Schäfer, Josep Antoni Ramos-Quiroga, Bru Cormand, Jan Haavik, Barbara Franke, Klaus Peter Lesch

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2318-2327
Number of pages10
JournalNeuropsychopharmacology
Volume36
Issue number11
DOIs
Publication statusPublished - 1 Jan 2011
Externally publishedYes

Cite this

Reif, A., Nguyen, T. T., Weiflog, L., Jacob, C. P., Romanos, M., Renner, T. J., ... Lesch, K. P. (2011). DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders. Neuropsychopharmacology, 36(11), 2318-2327. https://doi.org/10.1038/npp.2011.120