注意缺损多动障碍的X染色体基因组扫描分析

Genome-Wide Search for Linkage of Attention Deficit Hyperactivity Disorder(ADHD) to the X Chromosome

注意缺损多动障碍(attention defic it hyperactivity d isorder,ADHD)是儿童期多见行为障碍。男孩发病多于女孩。家系、双生儿和寄养子研究显示该障碍发生具有遗传基础。但是病因尚不清楚。分子遗传学和药理学研究表明ADHD涉及到多巴胺和去甲肾上腺素等神经递质系统,一系列报告发现ADHD与多巴胺D4受体(DRD4)、多巴胺转运体(DAT1)和儿茶酚-O-甲基转移酶(COMT)等基因相关联。以往研究表明ADHD与X染色体上DXS7位点和MAOA基因相关联,而DXS7是紧密连锁于MAO基因。依此假设,应用基因组扫描技术探讨ADHD在X染色体上易感位点。采用TDT方法分析X染色体上48个DNA标志的多态性与中国人群中84个ADHD核心家系间的连锁关系,ADHD诊断依据DSM-Ⅲ-R标准。TDT分析结果观察到如下位点与ADHD相连锁,DXS1214(TDT:χ2=18.1,df=7,P<0.01),DXS8102(TDT:χ2=7.9,df=3,P<0.05),DXS1068(TDT:χ2=21.9,df=9,P<0.01),DXS8015(TDT:χ2=14.6,df=7,P<0.05),DXS1059(TDT:χ2=27.8,df=10,P<0.01)和DXS8088(TDT:χ2=20.4,df=3,P<0.01)。研究资料提示X染色体上Xp11.4-p21和Xq23区域可能存在ADHD的易感基因。

Attention deficit hyperactivity disorder （ADHD） is the most common childhood-onset behavioral disorder. Boys are affected more often than girls. Family, twin and adoption studies have supported a strong genetic basis for the disease. The etiology of this disorder is not clear. Molecular genetic and pharmacological studies suggest the involvement of dopaminergic and noradrenergic neurotransmitter systems in ADHD. Several reports have found associa- tion between ADHD and the dopamine receptor gene DRD-4 ,the dopamine transporter gene DAT1, and the catecholo-methyltransferase gene COMT. Our previous studies showed an association between ADHD and the DXS7 locus, which is closely linked to the MAO gene and the MAOA gene on chromosome X. We therefore screened the genome for ADHD predisposing loci on chromosome X using the gene scan technique. We used transmission/disequilibrium test （TDT） to test for linkage between a VNTR polymorphism from 48 markers of chromosome X and DSM-Ⅲ-R diagnosed ADHD from 84 Chinese nuclear families. TDT analysis revealed linkage between ADHD and loci DXS 1214 （TDT; x^2 = 18.1, dr=7, P〈0.01）, DXS8102 （TDT： x^2=7.9, dr=3, P〈0.05）, DXS1068 （TDT; x^2=21.9, dr=9, P〈0. 01）, DXS8015 （TDT;x^2= 14.6, df=7, P〈0.05）, DXS1059 （TDT. x^2 =27.8, df= 10, P〈0.01） and DXS8088 （TDT：x^2 = 20.4, df= 3, P〈0. 01）. The data indicated that the susceptibility loci for ADHD might reside at chromo- some Xpl 1.4-p21 and Xq23.