title: DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders.
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.
authors.affiliation: Department of Psychiatry, University of Würzburg, Würzburg, Germany. reif_a@klinik.uni-wuerzburg.de
authors.forename: Andreas
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authors.lastname: Reif
authors.forename: T Trang
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authors.lastname: Nguyen
authors.forename: Lena
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authors.lastname: Weissflog
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authors.lastname: Gross-Lesch
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authors.lastname: Kreiker
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authors.forename: Miquel
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authors.lastname: Casas
authors.forename: Nuria
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authors.lastname: Gómez
authors.forename: Marta
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authors.lastname: Ribasès
authors.forename: Mónica
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authors.lastname: Bayès
authors.forename: Jan K
authors.initials: JK
authors.lastname: Buitelaar
authors.forename: Lambertus A L M
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authors.lastname: Kiemeney
authors.forename: J J Sandra
authors.initials: JJ
authors.lastname: Kooij
authors.forename: Cees C
authors.initials: CC
authors.lastname: Kan
authors.forename: Martine
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authors.lastname: Hoogman
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.forename: Kaya K
authors.initials: KK
authors.lastname: Jacobsen
authors.forename: Per M
authors.initials: PM
authors.lastname: Knappskog
authors.forename: Ole B
authors.initials: OB
authors.lastname: Fasmer
authors.forename: Phil
authors.initials: P
authors.lastname: Asherson
authors.forename: Andreas
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authors.lastname: Warnke
authors.forename: Hans-Jörgen
authors.initials: HJ
authors.lastname: Grabe
authors.forename: Jessie
authors.initials: J
authors.lastname: Mahler
authors.forename: Alexander
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authors.lastname: Teumer
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Ole N
authors.initials: ON
authors.lastname: Mors
authors.forename: Helmut
authors.initials: H
authors.lastname: Schäfer
authors.forename: Josep Antoni
authors.initials: JA
authors.lastname: Ramos-Quiroga
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.forename: Jan
authors.initials: J
authors.lastname: Haavik
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology / Q000235:genetics*; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D015897:Comorbidity; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010554:Personality Disorders / Q000453:epidemiology / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D025521:Tumor Suppressor Proteins; C468772:DIRAS1 protein, human; D020558:GTP Phosphohydrolases