Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures of amyloid-beta (A) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to A42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-A38 and CSF-A40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-A and -tau related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.

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

“…To assess whether and to which degree variation of the three AD CSF biomarkers analyzed in this study show association with "AD-related" phenotypes (using summary statistics from two previously reported large AD case-control GWAS 1,2 ), we initially pursued three different analysis paradigms: i) linkage disequilibrium (LD) score regression as implemented in LDSC software 32 , ii) genetic correlation analyses as implemented in GCTA 33 , and iii) polygenic risk score (PRS) analysis (see methods Table 8). This is in contrast to applying AD GWAS-based PRS to Aβ-related CSF phenotypes in the same EMIF-AD MDB dataset: here, the strongest associations explained nearly 6% of the phenotypic variance (P = 9E-09) 17 , suggesting that the genetic architectures underlying AD risk and variation at CSF NF-L, YKL-40, and Ng in general do not show any substantial overlap.…”

“…For several other variables collected in EMIF-AD MDB, data from ADNI project has served as valuable independent reference, including some analyzed by GWAS (e.g. Hong S et al 17 ). While ADNI investigators are in the process of collecting CSF data for NF-L, YKL-40, and Ng, data available with genetic information at the time of this study only ranged from n=82 to 125 in the whole-genome sequencing (WGS) subset of ADNI, precluding any meaningful GWAS analysis in this setting.…”

“…All participants had provided written consent prior to participation and institutional review board (IRB) approvals for the utilization of the DNA samples in the context of EMIF-AD MBD were obtained by the sample collection sites. A detailed account of the genotyping procedures and subsequent bioinformatic workflows can be found in Hong et al 17 . In brief, a total of 936 DNA samples were sent for genome-wide SNP genotyping using the Infinium Global Screening Array (GSA) with Shared Custom Content (Illumina Inc.).…”

Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics

“…APOE genotype was assessed with two single nucleotide polymorphisms (SNPs) (rs429358, rs7412) that define the ε2, 3, and 4 alleles, using DNA extracted by Cogenics from a 3 ml aliquot of EDTA blood. EMIF-AD MBD samples were genotoyped at the USKH site using the Global Screening Array (Illumina, Inc) (see Hong et al , 2019 for more details on imputation preprocessing). In the ADNI cohort, SNPs were imputed using the 1000 Genomes reference panel, with the use of the Michigan imputation server.…”

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer’s Disease Pathology

“…Furthermore, each individual had genome-wide single nucleotide polymorphism (SNP) genotyping. The details of SNP assays and raw data processing were described in [ 22 ].…”