Genome-wide association study identifies Alzheimer's risk variant in MS4A6A influencing cerebrospinal fluid sTREM2 levels

The triggering receptor expressed on myeloid cells 2 (TREM2) gene has been reported to increase the risk of Alzheimer's disease (AD). The soluble TREM2 protein (sTREM2) in cerebrospinal fluid (CSF) was also associated with AD. However, the role of sTREM2 in AD and its genetic modifiers remain u...

Full description

Saved in:
Bibliographic Details
Published in:Neurobiology of aging 2019-12, Vol.84, p.241.e13-241.e20
Main Authors: Hou, Xiao-He, Bi, Yan-Lin, Tan, Meng-Shan, Xu, Wei, Li, Jie-Qiong, Shen, Xue-Ning, Dou, Kai-Xin, Tan, Chen-Chen, Tan, Lan, Yu, Jin-Tai
Format: Article
Language:English
Subjects:
Alzheimer's disease
Genome-wide association study
MS4A6A
TREM2
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The triggering receptor expressed on myeloid cells 2 (TREM2) gene has been reported to increase the risk of Alzheimer's disease (AD). The soluble TREM2 protein (sTREM2) in cerebrospinal fluid (CSF) was also associated with AD. However, the role of sTREM2 in AD and its genetic modifiers remain unclear. We carried out a genome-wide association study for CSF sTREM2 levels using participants from the Alzheimer's Disease Neuroimaging Initiative and validated the significant association in an independent cohort from Chinese Alzheimer's Biomarker and LifestylE study. rs7232 in membrane spanning 4-domains A6A (MS4A6A) gene was associated with CSF sTREM2 levels at genome-wide significance (p = 1.42 × 10−15). The locus influences CSF sTREM2 levels especially in nondemented individuals. And the association was replicable in the validation cohort from Chinese Alzheimer's Biomarker and LifestylE study (p = 0.0106). Besides, the expressions of MS4A6A and TREM2 were correlated in brain regions (p < 2 × 10−16). The findings of our study suggest that the AD risk variant in the MS4A6A gene participates in the regulation of sTREM2. •Minor allele of rs7232 in membrane spanning 4-domains A6A (MS4A6A) gene was associated with higher cerebrospinal fluid soluble TREM2 protein levels.•The locus influences cerebrospinal fluid soluble TREM2 protein levels especially in nondemented individuals.•rs7232 could regulate the expression of MS4A6A in the medulla.•The expression of MS4A6A and TREM2 was correlated in the brain.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2019.05.008