Abstract
AbstractBackgroundNeurofibrillary tangle (NFT) deposition is a hallmark for neuropathological diagnosis of late‐onset Alzheimer’s disease (LOAD). We were interested in identifying genetic variants associated with NFT burden in brain tissue from participants in the Adult Changes in Thought (ACT) and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) autopsy cohorts.MethodIn ACT, NFT (paired helical filament (PHF)‐tau) is measured using histelide in frontal, temporal and parietal cortex. In ROSMAP, NFT burden is quantified by microscopic examination of silver‐stained slides from hippocampus and midfrontal, midtemporal, inferior parietal, and entorhinal cortex. In each cohort, we used Confirmatory Factor Analysis (CFA) to derive composites for NFT burden. We ran null models adjusting for sex and age at death; residuals were phenotypes for genetic analyses. We ran genome‐wide association studies (GWAS) of NFT burden using 1000G imputed data (NCBI; build 137) from European ancestry participants using Q‐ROADTRIPS which uses an empirical correlation matrix to account for population substructure. We performed meta‐analysis using the adaptively‐weighted Fisher’s method. Due to modest sample size and use of p‐values alone in meta‐analysis, we used conservative criteria for candidate loci, with minor allele frequency (MAF)> 0.05, meta‐analytic p‐value < 5 × 10−8, and p‐value < 0.2 in each cohort. We used generalized linear models for the top SNPs to investigate direction of effects.ResultMean death ages were 89 (ROSMAP, n = 1,225) and 87 (ACT; n = 388); and 66% (ROSMAP) and 53% (ACT) were female. A single factor CFA model fit in ACT. A bi‐factor model with a secondary factor comprising midfrontal, midtemporal, and inferior parietal cortices was needed for ROSMAP. We identified two novel loci at LRP1B (Chr 2: rs10496895; Pmeta = 1.54 × 10−8) and upstream of ZHX2 (Chr 8: rs56258958; Pmeta = 4.9 × 10−8) apart from SNPs near APOE.ConclusionLDL receptor related protein 1B (LRP1B) has restricted expression in human tissues and binds to several extracellular ligands, including fibrinogen and APOE‐ carrying lipoproteins. Zinc‐finger and homeodomain protein 2 (ZHX2) is specifically expressed in neural progenitor cells during cortical neurogenesis. Further functional enrichment analysis is needed to determine whether these novel loci may provide targets for interventions to ameliorate LOAD.
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