DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders
DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders
复制标题
DOI：
10.1038/npp.2011.120
复制
发表时间：
2011-10-01
影响因子：
7.6
通讯作者：
Lesch, Klaus-Peter
中科院分区：
文献类型：
--
作者：
Reif, Andreas;Nguyen, T. Trang;Lesch, Klaus-Peter
一些连锁分析表明染色体9q22区域与注意力缺陷/多动障碍（ADHD）有关，ADHD是一种持续到成年的神经发育疾病。该位点包含脑表达的gtp结合ras -样2基因（DIRAS2），被认为调节神经发生。由于DIRAS2是一个定位和功能性ADHD候选基因，我们在600名成人ADHD患者和420名对照患者中进行了一项关联研究。复制样本包括1035名ADHD患者和1381名对照，以及166个有儿童患有ADHD的家庭。考虑到ADHD的高度合并症，我们还调查了双相情感障碍（BD） （n = 336）或人格障碍（pd） （n = 622）患者。分析了DIRAS2结构基因和转录控制区的12个单核苷酸多态性（snp）。4个snp和2个单倍型块显示与ADHD相关的证据，名义p值从p = 0.006到p = 0.05。在成人复制样本中，我们获得了rs1412005和含有启动子区域的风险单倍型的一致效应（p = 0.026）。荟萃分析结果显示rs1412005的显著共同OR为1.12 (p = 0.04)，并证实与启动子风险单倍型相关（OR = 1.45, p = 0.0003）。随后对儿童期ADHD核心家庭的分析再次显示启动子单倍型阻滞与ADHD相关（p = 0.02）。rs1412005也增加了患BD （p = 0.026）和B群PD （p = 0.031）的风险。其他snp与人格得分相关（p = 0.008-0.048）。越来越多的证据表明，DIRAS2启动子区域的遗传变异与ADHD和合并症冲动性障碍的病因有关。神经精神药理学（2011）36,2318-2327；doi: 10.1038 / npp.2011.120;2011年7月13日在线发布
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. Neuropsychopharmacology (2011) 36, 2318-2327; doi:10.1038/npp.2011.120; published online 13 July 2011