Rommelse Nanda N J, Arias-Vásquez Alejandro, Altink Marieke E, Buschgens Cathelijne J M, Fliers Ellen, Asherson Philip, Faraone Stephen V, Buitelaar Jan K, Sergeant Joseph A, Oosterlaan Jaap, Franke Barbara
Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, The Netherlands.
Am J Hum Genet. 2008 Jul;83(1):99-105. doi: 10.1016/j.ajhg.2008.06.006.
ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities > 0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores > or = 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders.
注意力缺陷多动障碍（ADHD）的连锁分析结果并非都能得到一致的重复验证，这表明可能需要采用其他方法进行ADHD的连锁分析，例如使用（定量）内表型（与ADHD风险增加相关的可遗传性状）。在国际多中心ADHD遗传学（IMAGE）研究的荷兰子样本中进行了全基因组连锁分析，该子样本包括238名DSM-IV混合型ADHD先证者及其112名受影响和195名未受影响的兄弟姐妹。使用8种遗传力>0.2的候选神经心理学ADHD内表型作为定量性状。此外，还使用了神经心理功能的总体成分得分。总共5407个常染色体单核苷酸多态性（SNP）用于进行基于多点回归的连锁分析。发现了两个全基因组显著连锁信号，一个位于2q21.1染色体上的运动计时（LOD得分：3.944），另一个位于13q12.11染色体上的数字广度（LOD得分：3.959）。在2号染色体短臂、2号染色体长臂、3号染色体短臂、4号染色体长臂、8号染色体长臂、12号染色体短臂、12号染色体长臂、14号染色体长臂和17号染色体上发现了10个提示性连锁信号（LOD得分≥2）。在2q14.3处发现的成分得分提示性连锁信号（LOD得分：2.878）与与运动计时显著连锁的区域重叠。内表型方法可能会提高在ADHD以及可能在其他复杂疾病中检测易感基因座的能力。
