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

Abstract

Introduction:Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods:We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results:We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1.Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

Genome-wide association study of Alzheimer’s disease brain imaging biomarkers and neuropsychological phenotypes in the EMIF-AD Multimodal Biomarker Discovery dataset

“…This study extends previous GWAS analyses from our group utilizing phenotypic data from the EMIF-AD MBD study (Hong et al, 2020; Hong et al, 2021). The overarching goal of this work was to decipher the genetic architecture of AD-related MRI and neuropsychological (endo)phenotypes to better understand AD pathophysiology.…”

“…In our study, we expand earlier work from our group (Hong et al, 2020; Hong et al, 2021) derived from European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample (Bos et al, 2018). Specifically, in two previous GWAS we set out to identify variants underlying variation in several cerebrospinal fluid (CSF) phenotypes, such as levels of CSF Aβ and tau protein (Hong et al, 2020), or neurofilament light (NfL) chain, chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng), which reflect axonal damage, astroglial activation, and synaptic degeneration, respectively (Hong et al, 2021). However, the EMIF-AD MBD dataset features several other quantitative phenotypes, including cross-sectional MRI measurements and cross sectional and longitudinal neuropsychological tests, which are used as outcome traits in the current study.…”

Rare variants in IFFO1, DTNB and NLRC3 associate with Alzheimer’s disease CSF profile of neuronal injury and inflammation

“…CHI3L encodes the YKL-40 protein, which is the primary biomarker loading on the non-AD inflammation PC and was recently identified as a cis-pQTL in a common-variant GWAS in an overlapping set of EMIF-AD MBD and ADNI individuals. [16] In regard to CLU, common and rare variants have been associated with AD and the gene product clusterin has been researched extensively as potential AD biomarker. [47,48] Our results hint at CLU acting mostly via disruption of synaptic functioning, but the results have to be interpreted cautiously in light of non-replication.…”

“…[15] A more recent GWAS on these datasets further identified common-variant associations between TMEM106B and CSF-Nfl and CPOX and CSF-YKL-40. [16] Another study investigated rare variants underlying plasma Aβ using whole-exome sequencing, identifying several exomewide significant genes. [17] With this study, we took a pathway approach by analyzing rare variants in relation to distinct AD-related pathologic processes reflected by six different CSF biomarkers.…”

Genome-Wide Association Study of Alzheimer’s Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery Dataset

“…In our study, we expand earlier work from our group ( Hong et al, 2020 , 2021 ) derived from European Medical Information Framework Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample ( Bos et al, 2018 ). Specifically, in two previous GWAS we set out to identify variants underlying variation in several cerebrospinal fluid (CSF) phenotypes, such as levels of CSF Aβ and tau protein ( Hong et al, 2020 ), or neurofilament light (NfL) chain, chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng), which reflect axonal damage, astroglial activation, and synaptic degeneration, respectively ( Hong et al, 2021 ). However, the EMIF-AD MBD dataset features several other quantitative phenotypes, including cross-sectional MRI measurements and cross-sectional and longitudinal neuropsychological tests, which are used as outcome traits in the current study.…”