1 Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
2 California Pacific Medical Center Research Institute, San Francisco, CA, USA.
Am J Alzheimers Dis Other Demen. 2018 May;33(3):153-165. doi: 10.1177/1533317517739384. Epub 2018 Jan 16.
BACKGROUND/RATIONALE: Experimental studies support the role of neurotransmitter genes in dementia risk, but human studies utilizing single variants in candidate genes have had limited success.
We used the gene-based testing program Versatile Gene-based Association Study to assess whether aggregate variation across 6 neurotransmitter pathways influences risk of cognitive decline in 8159 cognitively normal elderly (≥65 years old) adults from 3 community-based cohorts.
Common genetic variation in GNG4 and KCNQ2 was associated with cognitive decline. In human brain tissue data sets, both GNG4 and KCNQ2 show higher expression in hippocampus relative to other brain regions; GNG4 expression decreases with advancing age. Both GNG4 and KCNQ2 show highest expression in fetal astrocytes.
Genetic variation analyses and gene expression data suggest that GNG4 and KCNQ2 may be associated with cognitive decline in normal aging. Gene-based testing of neurotransmitter pathways may confirm and reveal novel risk genes in future studies of healthy cognitive aging.
背景/原理：实验研究支持神经递质基因在痴呆风险中的作用，但利用候选基因中单变体的人类研究取得的成果有限。
我们使用基于基因的测试程序 Versatile Gene-based Association Study，评估 6 种神经递质通路的总体变异是否会影响来自 3 个基于社区的队列的 8159 名认知正常的老年人（≥65 岁）的认知能力下降风险。
GNG4 和 KCNQ2 的常见遗传变异与认知能力下降有关。在人脑组织数据集，GNG4 和 KCNQ2 在海马体中的表达均高于其他脑区；GNG4 的表达随年龄增长而下降。GNG4 和 KCNQ2 在胎儿星形胶质细胞中的表达最高。
遗传变异分析和基因表达数据表明，GNG4 和 KCNQ2 可能与正常衰老中的认知能力下降有关。对神经递质通路进行基于基因的测试可能会在未来对健康认知衰老的研究中证实并揭示新的风险基因。
