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

Abstract

Background: Neurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimer's disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome. Methods: DNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals.GWAS analyses applied linear regression models adjusting for relevant covariates. Findings:We identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1. Interpretation:Our study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested 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.

Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning

“…TMEM106B affects neuronal loss 46 and has been convincingly associated with risk for at least two forms of dementias, i.e. fronto-temporal dementia 46 and AD 13,41,47 . CHI3L1 encodes the YKL-40 protein and we and others have previously demonstrated that common and possibly rare variants at this locus represent cis pQTLs of CSF YKL-40.…”

“…Please see Hong et al for a detailed description of the GWAS methods, QC criteria and processing pipeline. 13 For X-chromosome specific methods, see supplementary methods.…”

Epigenetic aging and perceived psychological stress in old age

“…Educational attainment was assessed as education years until highest degree [72]; this information was available for 994 participants. Lastly, we controlled for genetic ancestry by using the first four principal components from a principal component analysis on genome-wide SNP genotyping data [73] generated in the same individuals.…”

A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples

“…shared custom content (Illumina, Inc.) using procedures outlined in Hong et al (29). To compute cis mQTLs (defined as within ±1 Mb of the CpG site) in this dataset we used the matrix eQTL software (30), which performed an additive linear model with sex, genetic PC 1 to 5, and genotyping batch as covariates.…”

“…DNAm data were derived from buccal-swab samples and generated and processed using the same procedures described above. Genome-wide SNP genotyping data were generated from the same samples using the "Global Screening Array" (GSA) with shared custom content (Illumina, Inc.) using procedures outlined in Hong et al (29). To compute cis mQTLs (defined as within ±1 Mb of the CpG site) in this dataset we used the matrix eQTL software (30), which performed an additive linear model with sex, genetic PC 1 to 5, and genotyping batch as covariates.…”