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KTN1 variants and risk for attention deficit hyperactivity disorder.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics ( IF 1.6 ) Pub Date : 2020-03-19 , DOI: 10.1002/ajmg.b.32782
Xingguang Luo 1, 2 , Xiaoyun Guo 3 , Yunlong Tan 1 , Yong Zhang 4 , Rolando Garcia-Milian 5 , Zhiren Wang 1 , Jing Shi 1 , Ting Yu 1 , Jiawu Ji 6 , Xiaoping Wang 7 , Jianying Xu 8 , Huihao Zhang 9 , Lingjun Zuo 2 , Lu Lu 10 , Kesheng Wang 11 , Chiang-Shan R Li 2
Affiliation  

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 × 10-10  ≤ p ≤ 1.2 × 10-4 ; α = 2.5 × 10-3 ). 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 × 10-7  ≤ 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.

中文翻译:

KTN1 变体和注意力缺陷多动障碍的风险。

患有注意力缺陷多动障碍 (ADHD) 的个体在壳核中表现出灰质体积 (GMV) 减少。KTN1 变体可能调节壳核中激连素 1 的表达并影响壳核的结构和功能。我们的目标是检验 KTN1 变体可能代表 ADHD 遗传风险因素的假设。分析了两个独立的基于家庭的高加索人样本,包括 922 名亲子三人组(共有 2,757 名受试者与 924 名多动症儿童)和 735 名亲子三人组(共有 1,383 名受试者与 613 名多动症儿童)。在第一个样本中分析了 ADHD 与总共 143 个 KTN1 SNP 之间的关联,并将名义显着 (p < .05) 风险 SNP 分类为独立的单倍型块。所有 SNP,包括这些块中的推算 SNP,以及每个块中的单倍型,研究了两个样本中关联的复制。使用一系列生物信息学分析预测了所有风险 SNP 的潜在生物学功能,测试了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了 KTN1 mRNA 表达。我们发现,在第一个样本中,15 个 SNP 在名义上与 ADHD 相关(p < .05),即使经过多次测试校正后,其中三个仍然显着(1.3 × 10-10 ≤ p ≤ 1.2 × 10-4 ;α = 2.5 × 10-3)。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。这些块中的六个单倍型也与这些样本中的 ADHD 显着相关 (1.2 × 10-7 ≤ p ≤ .009)。这些风险变异位于疾病相关的转座子和/或转录相关的功能区域。这些风险变异的主要等位基因显着增加了壳核体积。最后,KTN1 mRNA 在三个独立队列的壳核中显着表达。我们得出结论,KTN1 变体与 ADHD 显着相关。KTN1 可能在 ADHD 的发展中发挥功能作用。
更新日期:2020-03-19
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