Attention-deficit/hyperactivity disorder in a population isolate: Linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11
Attention-deficit/hyperactivity disorder in a population isolate: Linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11
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DOI：
10.1086/426154
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发表时间：
2004-12-01
影响因子：
9.8
通讯作者：
Muenke, M
中科院分区：
文献类型：
--
作者：
Arcos-Burgos, M;Castellanos, FX;Muenke, M
注意力缺陷/多动障碍 (ADHD [MIM 143465]) 是儿童期最常见的行为障碍。双胞胎、收养、隔离、关联和连锁研究已证实，遗传学在导致 ADHD 易感性方面发挥着重要作用。我们将基于模型和无模型的连锁分析以及谱系不平衡测试应用于对来自遗传分离株的患有 ADHD 的大家族和多代家庭进行全基因组扫描的结果。在这些家庭中，多动症与行为和对立违抗性障碍以及酒精和烟草依赖高度共存。我们在各个家族中发现了与染色体 4q13.2、5q33.3、8q11.23、11q22 和 17p11 标记连锁的证据。应用于这些区域的精细定位导致染色体 4q13.2（D4S3248 处 LODPAL 的两点等位基因共享 LOD 评分 = 4.44）、5q33.3（D5S490 处 LODPAL 的两点等位基因共享 LOD 评分 = 8.22）、11q22（LODPAL 两点等位基因共享 LOD 评分）处的组合家族中存在显着连锁。 = 5.77，D11S1998；多点非参数连锁 [NPL] - log [P 值] = 5.49，类似于 128 cM)，和 17p11（多点 NPL - log [P 值] > 12，类似于 12 cM；多点最大位置得分 2.48 [alpha = 0.10]，类似于 12 cM；来自 LODPAL 的两点等位基因共享 LOD 得分 = 3.73 D17S1159）。此外，在染色体 8q11.23 处发现了暗示性连锁（在 D8S2332 处组合两点 NPL - log [P 值] >3.0）。其中一些区域是新的（4q13.2、5q33.3 和 8q11.23），而其他区域则复制已发表的基因座（11q22 和 17p11）。不同连锁分析方法的结果之间的一致性以及两项独立研究之间数据的复制表明这些基因座确实含有 ADHD 易感基因。
Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL] - log [P value] = 5.49 at similar to128 cM), and 17p11 (multipoint NPL - log [P value] >12 at similar to12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at similar to12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL - log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.