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Comparative Study

DIRAS2 Is Associated With Adult ADHD, Related Traits, and Co-Morbid Disorders

Andreas Reif et al. Neuropsychopharmacology.

Erratum in

  • Neuropsychopharmacology. 2012 Mar;37(4):1076


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.


Figure 1
Figure 1
LD plot of DIRAS2 aligned to the gene structure and the significant SNPs from all samples. Please note that the LD plot is not exactly matched to the SNPs, as precise scaling was not possible: rs9695432 is the last SNP of block 1 while rs1331503 is the first SNP of block 2. rs16906711 is associated with aADHD, cluster C PD, cluster B PD, and Harm Avoidance in PD; rs9695432 with aADHD and personality domains; rs1331503 with aADHD and personality domains; rs2297354 with aADHD and personality domains; rs7848810 with aADHD, cluster B PD, BD, and personality domains; and rs1412005 with aADHD and personality domains.
Figure 2
Figure 2
Forest plot of the rs1412005 T allele for the aADHD case–control association study.
Figure 3
Figure 3
Forest plot of the ACGCTT haplotype for the aADHD case–control association study.

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