Genome‐Wide Association Study for CSF Aβ42, Tau, and pTau in a Large Multi‐cohort Study to Identify Novel AD Genetic Variants

Abstract

AbstractBackgroundPrevious studies have identified more than 20 genetic loci to be associated with AD risk. These reported loci do not account for all the estimated heritability nor report enough information on the undelaying biological mechanism. Genome‐wide association studies of endophenotypes have identified new loci associated with Alzheimer’s disease. To better understand AD pathology and identify new variants implicated in AD much larger samples size is needed. We conducted a GWAS of Amyloid‐beta (Aβ42) tau, and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) to detect novel variants associated with AD.MethodsAD CSF biomarkers were measured in 7282 individuals from 24 different cohorts. Samples were genotyped using different array technology with stringent quality control standards to each dataset before combining datasets. Minimum call rate for single nucleotide polymorphism (SNP) and individuals was 99.85%. SNPs not in Hardy–Weinberg equilibrium were excluded. X‐chromosome SNPs were analyzed to verify sex identification. Duplicates and cryptic relatedness among samples were tested by pairwise genome‐wide estimates of proportion identity‐by‐descent. PLINK was used to calculate principal component analysis. CSF biomarker levels were log10‐transformed to approximate a normal distribution with the mean standardized to zero for each dataset to account for the variability on the different platforms used to measure proteins levels. One‐stage joint‐GWAS to maximize the power in our analysis. Post‐GWAS analyses Colocalization, Madelian Randomization, LD Score Regression, were implemented to detect colocalization of two potential related signals to detect common causal variant and to evaluate the overlap in genetic architecture of CSF Biomarkers and risk factor for ADResultsThis study represents one of the largest multi‐cohort GWAS analyses on CSF AD biomarkers. Several genome‐wide significant hits were found including APOE. Additional analyses are underway.ConclusionsCSF Aβ42, tau, and ptau are well established AD endophenotypes with a clear genetic association with APOE genotype and AD risk. Genetic studies on endophenotypes provide enough power to detect association with a smaller sample size than case‐control studies helping us to better understand the biological mechanism of the disease. With this study we aim to identify novel variants implicated in AD.