Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis.
Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis.
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中国人群遗传风险因素的鉴定表明免疫系统在阿尔茨海默病发病机制中的作用
DOI：
10.1073/pnas.1715554115
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发表时间：
2018-02-20
影响因子：
11.1
通讯作者：
Alzheimer’s Disease Neuroimaging Initiative
中科院分区：
文献类型：
--
作者：
Zhou X;Chen Y;Mok KY;Zhao Q;Chen K;Chen Y;Hardy J;Li Y;Fu AKY;Guo Q;Ip NY;Alzheimer’s Disease Neuroimaging Initiative
Alzheimer’s disease (AD) is an age-related neurodegenerative disease. Genome-wide association studies predominately focusing on Caucasian populations have identified risk loci and genes associated with AD; the majority of these variants reside in noncoding regions with unclear functions. Here, we report a whole-genome sequencing study for AD in the Chinese population. Other than the APOE locus, we identified common variants in GCH1 and KCNJ15 that show suggestive associations with AD. For these two risk variants, an association with AD or advanced onset of disease can be observed in non-Asian AD cohorts. An association study of risk variants with expression data revealed their modulatory effects on immune signatures, linking the potential roles of these genes with immune-related pathways during AD pathogenesis. Alzheimer’s disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10−14), two common variants, GCH1 (rs72713460, P = 4.36 × 10−5) and KCNJ15 (rs928771, P = 3.60 × 10−6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype–phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
9.8
作者：
Cai N;Bigdeli TB;Kretzschmar WW;Li Y;Liang J;Hu J;Peterson RE;Bacanu S;Webb BT;Riley B;Li Q;Marchini J;Mott R;Kendler KS;Flint J
通讯作者：
Flint J
影响因子：
8.6
作者：
Cobb, Stephanie A.;Wider, Christian;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
5.7
作者：
Guerreiro, Rita;Hardy, John
通讯作者：
Hardy, John