Li-Dong Niu1, Wei Xu1,2, Jie-Qiong Li1, Chen-Chen Tan1, Xi-Peng Cao3, Jintai Yu4, Lan Tan1. 1. Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. 2. College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, China. 3. Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China. 4. Department of Neurology and Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
Abstract
BACKGROUND: Cerebrospinal fluid (CSF) neurofilament light (NFL) is a general biomarker for axonal damage. METHODS: This genome-wide association study (GWAS) consisted of 169 mild cognitive impairment (MCI) subjects and 94 cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Analyses of associations between CSF NFL and genetic polymorphisms were performed using an additive genetic model. The novel single nucleotide polymorphisms (SNPs) identified by GWAS were further examined for their correlation with other AD-related phenotypes at baseline and during follow-up using multiple linear regression model and mixed effects model respectively. Survival analysis was performed to evaluate the respective risks of progression from CN to prodromal AD and from MCI to AD among populations with different genotypes. RESULTS: Two novel SNPs (rs465401 and rs460420), both near the ADAMTS1 gene on chromosome 21, showed genome-wide significant associations with CSF NFL. The minor allele (A) of rs465401 was also associated with higher CSF total tau (t-tau) levels, lower amyloid-β (Aβ) levels as well as greater longitudinal change in both Aβ and t-tau among the CN group. Furthermore, the Cox proportional hazards models showed increased risks for prodromal AD among the cognitive normal AA homozygotes. CONCLUSIONS: We found that two SNPs (rs465401 and rs460420) were associated with CSF NFL in non-demented elders. The associations identified in this study may make the SNPs and ADAMTS1 ideal candidates for future genetic studies on aging and neurodegenerative disorders. 2019 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Cerebrospinal fluid (CSF) neurofilament light (NFL) is a general biomarker for axonal damage. METHODS: This genome-wide association study (GWAS) consisted of 169 mild cognitive impairment (MCI) subjects and 94 cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Analyses of associations between CSF NFL and genetic polymorphisms were performed using an additive genetic model. The novel single nucleotide polymorphisms (SNPs) identified by GWAS were further examined for their correlation with other AD-related phenotypes at baseline and during follow-up using multiple linear regression model and mixed effects model respectively. Survival analysis was performed to evaluate the respective risks of progression from CN to prodromal AD and from MCI to AD among populations with different genotypes. RESULTS: Two novel SNPs (rs465401 and rs460420), both near the ADAMTS1 gene on chromosome 21, showed genome-wide significant associations with CSF NFL. The minor allele (A) of rs465401 was also associated with higher CSF total tau (t-tau) levels, lower amyloid-β (Aβ) levels as well as greater longitudinal change in both Aβ and t-tau among the CN group. Furthermore, the Cox proportional hazards models showed increased risks for prodromal AD among the cognitive normal AA homozygotes. CONCLUSIONS: We found that two SNPs (rs465401 and rs460420) were associated with CSF NFL in non-demented elders. The associations identified in this study may make the SNPs and ADAMTS1 ideal candidates for future genetic studies on aging and neurodegenerative disorders. 2019 Annals of Translational Medicine. All rights reserved.
Entities:
Keywords:
Alzheimer’s disease (AD); Genome-wide association study (GWAS); a disintegrin-like and metalloproteinase with thrombospondin type 1 motif (ADAMTS1); neurofilament light (NFL)
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