Biological Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Am J Med Genet B Neuropsychiatr Genet. 2020 Jun;183(4):234-244. doi: 10.1002/ajmg.b.32782. Epub 2020 Mar 19.
Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p < .05) risk SNPs were classified into independent haplotype blocks. All SNPs, including imputed SNPs within these blocks, and haplotypes across each block, were explored for replication of associations in both samples. The potential biological functions of all risk SNPs were predicted using a series of bioinformatics analyses, their regulatory effects on the putamen volumes were tested, and the KTN1 mRNA expression was examined in three independent human putamen tissue samples. We found that fifteen SNPs were nominally associated with ADHD (p < .05) in the first sample, and three of them remained significant even after correction for multiple testing (1.3 × 10 ≤ p ≤ 1.2 × 10 ; α = 2.5 × 10 ). These 15 risk SNPs were located in five haplotype blocks, and 13 SNPs within four of these blocks were associated with ADHD in the second sample. Six haplotypes within these blocks were also significantly (1.2 × 10 ≤ p ≤ .009) associated with ADHD in these samples. These risk variants were located in disease-related transposons and/or transcription-related functional regions. Major alleles of these risk variants significantly increased putamen volumes. Finally, KTN1 mRNA was significantly expressed in putamen across three independent cohorts. We concluded that the KTN1 variants were significantly associated with ADHD. KTN1 may play a functional role in the development of ADHD.
个体注意缺陷多动障碍（ADHD）患者的壳核灰质体积（GMV）减少。KTN1 变体可能调节壳核内的联会蛋白 1 的表达，并影响壳核的结构和功能。我们旨在测试 KTN1 变体可能是 ADHD 的遗传风险因素这一假设。分析了两个独立的基于家系的白种人样本，包括 922 个亲子三体型（共 2757 名受试者，其中 924 名为 ADHD 儿童）和 735 个亲子三体型（共 1383 名受试者，其中 613 名为 ADHD 儿童）。在第一个样本中分析了 ADHD 与总共 143 个 KTN1 SNP 的关联，将名义上显著（p<0.05）的风险 SNP 分类为独立的单倍型块。在两个样本中都探索了所有 SNP，包括这些块内的推断 SNP 和每个块内的单体型，以复制关联。使用一系列生物信息学分析预测所有风险 SNP 的潜在生物学功能，测试它们对壳核体积的调节作用，并在三个独立的人类壳核组织样本中检查 KTN1 mRNA 的表达。我们发现，在第一个样本中，15 个 SNP 与 ADHD 有显著关联（p<0.05），其中 3 个 SNP 在多重检验校正后仍有意义（1.3×10-5≤p≤1.2×10-5；α=2.5×10-5）。这 15 个风险 SNP 位于五个单倍型块中，其中四个块中的 13 个 SNP 与第二个样本中的 ADHD 相关。这些块内的六个单体型也与这些样本中的 ADHD 显著相关（1.2×10-5≤p≤.009）。这些风险变体位于疾病相关的转座子和/或转录相关的功能区域。这些风险变体的主要等位基因显著增加了壳核体积。最后，KTN1 mRNA 在三个独立队列中均在壳核中显著表达。我们得出结论，KTN1 变体与 ADHD 显著相关。KTN1 可能在 ADHD 的发展中发挥功能作用。
