Genome-wide association study identifies two loci influencing plasma neurofilament light levels

Abstract

BackgroundPlasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD.MethodsThis study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model.ResultsThe minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10− 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10− 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018–2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234).ConclusionGWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0364-8) contains supplementary material, which is available to authorized users.

The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta‐analysis

“…Twelve studies compared blood (i.e., plasma and serum) NfL concentration in AD cases and cognitively unimpaired controls [4,9,25,30,42,[47][48][49][50][51][52][53]; however, three of these studies used largely overlapping data from the ADNI database [49,50,53]. To avoid bias, the largest of the three overlapping studies was selected for inclusion in the meta-analysis [53]; thus, 10 studies comparing 471 AD cases to 518 cognitively unimpaired controls were included in the meta-analysis.…”

Variable selection for high‐dimensional partly linear additive Cox model with application to Alzheimer's disease

“…In this section, we apply the method presented in the previous sections to the data arising from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal multicenter study that was launched in 2003 as a public‐private partnership and led by Principal Investigator Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early AD 30‐33 . Here, we are interested in identifying the single nucleotide polymorphisms (SNPs) that have significant effects on the risk of developing AD.…”

“…Also the participants have been divided into three groups based on the levels of their cognitive conditions, cognitively normal, MCI, and AD. In the following, by following the others, 30,32,33 we will focus on the group of the participants with MCI and the time from the baseline visit date to the AD conversion, the failure time of interest. Since the participants were only examined intermittently, the AD conversion thus cannot be observed exactly and is known only to between the last examination time when the AD had not occurred and the first examination time when the AD has already occurred.…”

“…The four covariate are participants' Alzheimer's Disease Assessment Scale Score of 13 items (ADAS13), Rey auditory verbal learning test score of immediate recall (RAVLT.i), functional assessment questionnaire score (FAQ) and MRI volume of middle temporal gyrus (MidTemp). The SNPs were read by Illumina method and to convert SNPs into covariates, by following Li et al, 32 we treated T as the effect allete and coded each SNP as 0, 1, or 2 if it is homozygous without T, heterozygous with T or homozygous with T, respectively.…”

“…On the other hand, it is worth pointing out that most of the previous work only considered a part of the data or performed simplified analyses. For instance, Li et al 30 considered only the demographic and clinical factors and Li et al 32 and Hu et al 33 performed a single SNP analysis.…”