Genome-wide association study of cerebrospinal fluid neurofilament light levels in non-demented elders

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.

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

“…15 To the best of our knowledge, our study represents the first bona fide GWAS on these biomarker traits with the exception of two small (n = 133 and n = 265, respectively) CSF protein quantitative trait loci (pQTL) GWAS on YKL-40 in people of Asian descent 34 and a GWAS on NfL in the subset of non-demented elderly from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. 35…”

TMEM106BandCPOXare genetic determinants of cerebrospinal fluid Alzheimer’s disease biomarker levels

“…Finally, we detected very strong and genome-wide significant association between markers in CHI3L1 and CSF levels of YKL-40, representing the only cis pQTL finding in our analyses. To the best of our knowledge, our study is the first bona fide GWAS for all three of these CSF biomarkers with the exception of two small (n = 133 and n = 265) CSF pQTL GWAS on YKL-40 in people of Asian descent 34 and a GWAS on NF-L in non-demented elderly from the the Alzheimer Disease Neuroimaging (ADNI) cohort 35 . Of note, the former study also identified strong and genome-wide significant cis pQTL effects at the CHI3L1 / YKL-40 locus, corroborating our findings.…”

“…To our knowledge, the only other GWAS investigating CSF NF-L was performed on 265 non-demented individuals from the ADNI cohort 35 . These authors highlighted two SNPs (i.e.…”

“…Conversely, variants in TMEM106B were not highlighted as "peak results" in that study. However, apart from the difference in sample size, there were several additional noteworthy differences in the analysis approach used by us and Niu et al 35 (e.g. they did not use genotype imputations to increase their coverage of untyped portions of the genome; in addition to sex and genetic ancestry, they also included age, education years, and APOE e4 status as covariates in the primary GWAS analyses).…”

The Potential of Neurofilament Light as a Biomarker in Alzheimer’s Disease

“…It is suggested that rs465401 and rs460420 may be the regulators of CSF NFL levels. Since rs465401 was most strongly associated with NFL in CSF, further survival analysis of rs465401 showed that rs465401 was associated with the risk of prodromal AD in normal cognitive participants during follow-up and that the risk of clinical progression in normal AA homozygotes was >3 times that of GG homozygotes during follow-up [14].…”