Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Psychiatry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Genes (Basel). 2021 May 26;12(6):815. doi: 10.3390/genes12060815.
Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. Yet little is known about its genetic basis. To examine the association of common single nucleotide polymorphisms with cerebral atherosclerosis severity, we conducted a genomewide association study (GWAS) using data collected as part of two community-based cohort studies in the United States, the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Both studies enroll older individuals and exclude participants with signs of dementia at baseline. From our analysis of 1325 participants of European ancestry who had genotype and neuropathologically assessed cerebral atherosclerosis measures available, we found a novel locus for cerebral atherosclerosis in . The locus comprises eight SNPs, including two independent significant SNPs: rs6664221 ( = -0.27, 95% CI = (-0.35, -0.19), = 1.29 × 10) and rs10881463 ( = -0.20, 95% CI = (-0.27, -0.13), = 3.40 × 10). We further found that the SNPs may influence cerebral atherosclerosis by regulating brain protein expression of CNOT3. CNOT3 is a subunit of CCR4-NOT, which has been shown to be a master regulator of mRNA stability and translation and an important complex for cholesterol homeostasis. In summary, we identify a novel genetic locus for cerebral atherosclerosis and a potential mechanism linking this variation to cerebral atherosclerosis progression. These findings offer insights into the genetic effects on cerebral atherosclerosis.
脑动脉粥样硬化是中风的主要原因，也是痴呆的重要原因。然而，人们对其遗传基础知之甚少。为了研究常见单核苷酸多态性与脑动脉粥样硬化严重程度的关联，我们进行了一项全基因组关联研究（GWAS），该研究的数据来自美国的两项基于社区的队列研究，即宗教秩序研究（ROS）和拉什记忆与衰老项目（MAP）。这两项研究都招募了老年人，并排除了基线时有痴呆迹象的参与者。在对 1325 名具有基因型和神经病理学评估的欧洲血统参与者进行分析后，我们在 中发现了一个新的脑动脉粥样硬化位点。该基因座由 8 个 SNP 组成，包括两个独立的显著 SNP：rs6664221（ = -0.27，95%CI = (-0.35，-0.19)， = 1.29 × 10）和 rs10881463（ = -0.20，95%CI = (-0.27，-0.13)， = 3.40 × 10）。我们进一步发现，这些 SNP 可能通过调节 CNOT3 的脑蛋白表达来影响脑动脉粥样硬化。CNOT3 是 CCR4-NOT 的一个亚基，已被证明是 mRNA 稳定性和翻译的主要调节剂，也是胆固醇稳态的重要复合物。总之，我们确定了一个新的脑动脉粥样硬化遗传位点，以及一种将这种变异与脑动脉粥样硬化进展联系起来的潜在机制。这些发现为脑动脉粥样硬化的遗传效应提供了新的见解。
