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

Andreas Reif (1) , Trang T Nguyen (1) , Lena Weissflog (1) , Christian Jacob (1) , Marcel Romanos (1) , Tobias J. Renner (1) , Henriette N. Buttenschon (1) , Sarah Kittel-Schneider (1) , Alexandra Gessner (1) , Heike Weber (1) , Maria Neuner (1) , Silke Gross-Lesch (1) , Karin Zamzow (1) , Susanne Kreiker (1) , Susanne Walitza (1) , Jobst Meyer (1) , Christine M. Freitag (1) , Rosa Bosch (1) , Miquel Casas (1) , Nuria Gómez (1) , Marta Ribases (1) , Mònica Bayés (1) , Jan K. Buitelaar (1) , Lambertus A. Kiemeney (1) , J.J. Sandra Kooij (1) , Cees C. Kan (1) , Martine Hoogman (1) , Stefan Johansson (1) , Kaya K. Jacobsen (1) , Per M. Knappskog (1) , Ole B. Fasmer (1) , Philip Asherson (1) , Andreas Warnke (1) , H Grabe (1) , Jessie Mahler (1) , Alexander Teumer (1) , Henry Völzke (1) , Ole Mors (1) , Helmut Schäfer (1) , Josep Antoni Ramos-Quiroga (1) , Bru Cormand (1) , Jan Haavik (1) , Barbara Franke (1) , Klaus-Peter Lesch (1)

1 Mental Health Sciences Unit

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 and 420 controls. Replication samples consisted of 1035 adult ADHD 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 (n=336) or personality disorders (n=622). Twelve 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 towards bipolar disorder (p=0.026) and cluster B personality disorder (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.

Mots clés: Unipolar; Bipolar; Development; Developmental Disorders; Biological Psychiatry; Neurogenetics; Depression; adult ADHD; linkage; genome-wide association study; ras pathway

Andreas Reif, Trang T Nguyen, Lena Weissflog, Christian Jacob, Marcel Romanos, et al.. DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders. Neuropsychopharmacology, 2011, ⟨10.1038/npp.2011.120⟩. ⟨hal-00659513⟩