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

Hou, Xiao-He; Bi, Yan‐Lin; Tan, Meng-Shan; Xu, Wei; Li, Jieqiong; Shen, Xue‐Ning; Dou, Kai-Xin; Tan, Cheng; Tan, Lan; Initiative, Alzheimer’s Disease Neuroimaging; Yu, Jin‐Tai

doi:10.1016/j.neurobiolaging.2019.05.008

Cited by 32 publications

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“…Seven hundred thirty‐six cognitively normal adults who were northern Han Chinese were derived from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study 16 . Since 2017, CABLE has been an ongoing large‐scale study majorly focused on risk factors and biomarkers of AD in the Chinese Han population.…”

Section: Methodsmentioning

confidence: 99%

Sleep characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study

Tan

et al. 2020

Alzheimer's & Dementia

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Introduction This study tested the self‐reported sleep characteristics associated with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact older adults. Methods The linear and non‐linear regression analyses were conducted in 736 cognitively normal participants (mean [standard deviation; SD] age, 62.3 [10.5] years, range 40 to 88 years, 59% female) who had measurements of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tTau proteins and sleep characteristics, after adjusting for age, gender, education, apolipoprotein E gene (APOE) ε4 status, and general cognition. Results Greater daytime sleepiness was associated with higher CSF indicators of amyloid deposition in female patients. No significant associations were revealed for CSF tTau proteins after Bonferroni correction. A U‐shaped relationship was revealed for nocturnal sleep habits, such that those with insufficient or excessive nocturnal sleep duration had greater CSF biomarkers of amyloid deposition (the reflection range: bedtime: around 10:00 p.m. and sleep duration: 6.0 to 6.5 hours). Discussion These findings consolidated the close relationship between sleep and AD.

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Section: Methodsmentioning

confidence: 99%

Sleep characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study

Tan

et al. 2020

Alzheimer's & Dementia

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“…Our QTL analysis showed that rs7232 was the most significant SNP associated with CSF sTREM2 level. A recent study for Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) cohort (Hou et al, 2019) also reported this association was significant ( p = 0.00106). Moreover, one study showed that rs7232 correlated with atrophy rate of left middle temporal and minor T allele carriers had less loss in the volume of left middle temporal than A allele homozygotes subjects (Ma et al, 2016).…”

Section: Discussionmentioning

confidence: 82%

“…Furthermore, one study reported that MS4A6A expression was significantly correlated to AD-related neurofibrillary pathology and tau phosphorylation (Martiskainen et al, 2015). Additionally, the expression of MS4A6A is highly correlated with the expression of TREM2 in the brain (Hou et al, 2019). For both MS4A6A and TREM2 are mainly expressed on microglia cells in the brain (Darmanis et al, 2015), we speculate that MS4A6A may regulate TREM2 expression and the levels of CSF sTREM2.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Studies for Cerebrospinal Fluid Soluble TREM2 in Alzheimer’s Disease

Liu

2019

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is the most common form of dementia. Rare variants in triggering receptor expressed on myeloid cells 2 (TREM2) have been identified as risk factors for AD. Soluble TREM2 (sTREM2) in the cerebrospinal fluid (CSF) is a potential and novel biomarker of neuroinflammation implicated in the onset and progression of AD. To explore the roles of CSF sTREM2 on the pathogenesis of AD, we performed genome-wide association studies (GWAS) by using the data from Alzheimer’s Disease Neuroimaging Initiative (ADNI). We found CSF sTREM2 levels were elevated with the disease stages, but there was no significant difference between that of AD patients and normal participants. CSF sTREM2 was positively correlated with CSF total tau and phosphorylated-tau levels (ρ > 0.35, p < 1e-06; ρ > 0.32, p < 1e-05, respectively) for all disease states. We identified the most significant CSF sTREM2 related locus was rs7232 (FDR = 3.01e-08), a missense variant in MS4A6A gene of chromosome 11. Moreover, we also detected rs7232 was highly associated with MS4A6A gene expression (FDR = 1.37e-18). In addition, our pathway analysis for our significant GWAS results showed that biological processes for regulation of viruses and immune response were highly overrepresented or enriched. Our study suggests that CSF sTREM2 plays an informative role in AD progression. Moreover, CSF sTREM2 and AD is highly related to viral infections and immune response.

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“…Participants were recruited from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) study. 16 CABLE has been an ongoing study majorly focused on risk factors and biomarkers of neurodegenerative disorders since 2017. Individuals were Han Chinese recruited at Qingdao Municipal Hospital, Shandong Province, China.…”

Section: Cable Studymentioning

confidence: 99%

Associations of sleep characteristics with alpha‐synuclein in cerebrospinal fluid in older adults

Wang

Liu

et al. 2020

Ann Clin Transl Neurol

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Objective: Sleep disorders as a preclinical symptom of synucleinopathies become more prevalent in older adults. Synucleinopathies might be caused by the abnormal aggregation of alpha-synuclein in the brain, which was indicated by alpha-synuclein levels in cerebrospinal fluid (CSF). We aimed to investigate associations of sleep characteristics with CSF alpha-synuclein in older adults. Methods: Our study recruited 536 cognitively intact individuals (aged between 40 and 90 years old) from the Chinese Alzheimer's Biomarker and Lifestyle study. Sleep behaviors were assessed by Pittsburgh Sleep Quality Index and total alpha-synuclein in CSF was measured by enzyme-linked immune-sorbent assay. We used multiple linear and non-linear regression models for research. Results: Significant non-linear associations of CSF alpha-synuclein with sleep time and duration were revealed. Individuals who went to bed and fell asleep too early or late tended to have lower CSF alpha-synuclein (reflection point for time to bed and fall asleep were 10:26 p.m. and 10:40 p.m.). Lower CSF alpha-synuclein was also observed in individuals with either excessive or insufficient sleep duration (reflection point: 7.24 hours). Besides, overall poor sleep quality (b = À0.0621; P = 0.0242), longer sleep latency (b = À0.0415; P = 0.0174) and lower sleep efficiency (b = 0.0036; P = 0.0017) showed linear associations with lower CSF alpha-synuclein. Sleep disturbances and daytime dysfunction were not significantly associated with CSF alpha-synuclein. Interpretation: Poor sleep was associated with lower levels of CSF alpha-synuclein in older adults, which may provide new insight into the prevention of synucleinopathies.

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

Cited by 32 publications

References 36 publications

Sleep characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study

Sleep characteristics and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: The CABLE study

Genome-Wide Association Studies for Cerebrospinal Fluid Soluble TREM2 in Alzheimer’s Disease

Associations of sleep characteristics with alpha‐synuclein in cerebrospinal fluid in older adults

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