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.

Transcriptome Sequencing of the Anterior Cingulate in Bipolar Disorder: Dysregulation of G Protein-Coupled Receptors

“…DIRAS2 was upregulated by all the three drugs tested, while SSTR2 and SLC7A14 were significantly upregulated by valproate only. Very little is known about the implication of DIRAS2 (DIRAS family, GTP-binding RAS-like 2) in the brain, as it has only been studied in adult attention deficit hyperactivity disorder (37). Neither SLC7A14 (solute carrier family 7, member 14) nor SSTR2 has previously been investigated in bipolar disorder or valproate treatment, but the latter is a G proteincoupled receptor belonging to class 4A that has been implicated in adaptive response to stress (36,38).…”

SLC2A3 single‐nucleotide polymorphism and duplication influence cognitive processing and population‐specific risk for attention‐deficit/hyperactivity disorder

“…The SNP association study was replicated in samples from the IMpACT consortium which was described in detail previously (Franke et al., ; Reif et al., ). The replication sample included aADHD patients and controls of the following origin: The Netherlands ( n cases = 403; n controls = 646), Norway ( n cases = 448; n controls = 581), and Spain ( n cases = 304; n controls = 225).…”

Functional Impact of An ADHD-Associated DIRAS2 Promoter Polymorphism

“…However, a luciferase promoter assay performed in a human cancer cell line only provides limited information of the processes in the human organism. Also, the association of DIRAS2 with aADHD is not only based on the promoter polymorphism as such, but also on the haplotype block containing it (Reif et al, 2011). As this haploblock spans 45 kb, it was not possible to clone the entire region into the luciferase reporter vector to test for expression changes owing to the full risk haplotype.…”

“…The neighboring gene found most likely to be involved in the aetiopathogenesis of ADHD was DIRAS2, because, in contrast to the other neighbor (SYK), it is expressed in the brain (Kontani et al, 2002). On the basis of these reports, we further examined a potential association between tagging SNPs in DIRAS2 and aADHD in a German sample of 600 patients and 420 controls, as well as European replication sample of 1035 patients and 1381 controls (Reif et al, 2011). Four SNPs and two haplotype blocks showed significant results (po0.05) in the German sample.…”