Widespread transposable element dysregulation in human brains with Alzheimer’s disease

Abstract

AbstractBackgroundTransposable elements (TEs), known as “jumping genes” or “viral elements”, constitute approximately 45% of the human genome. However, transposable element (TE) dysregulation of quantitative trait loci (QTL) has not been well‐characterized in human disease, such as Alzheimer’s disease (AD).MethodIn this study, we present the first catalog of transposable element quantitative trait loci (teQTLs) in human brains. By leveraging large‐scale RNA‐sequencing (RNA‐seq), whole‐genome sequencing (WGS), and various QTL data (xQTL) from three brain biobanks with Alzheimer’s disease (AD), we comprehensively characterize TE dysregulation across diverse AD pathobiology, including Tau, amyloid beta, APOE genotypes, and sex differences. We further integrate different types of QTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls to identify AD likely causal genes regulated by brain teQTLs through colocalization analysis. Regulatory roles of brain teQTLs are dissected via long‐range cell type‐specific enhancer‐promoter chromatin interaction maps.ResultJoint‐analysis of WGS and RNA‐seq data identified 77,335 genome‐wide significant TE expression QTLs (teQTLs) in human AD brains. Colocalization analysis of teQTLs with GWAS loci from 278,950 AD cases and 1,780,303 controls identified key AD likely causal genes regulated by brain teQTLs. This identified new AD risk genes, including complement C1q tumor necrosis factor‐related protein 4 (C1QTNF4) and farnesyl‐diphosphate farnesyltransferase 1 (FDFT1). A TE from Plat_L3 subfamily (chr11: 47605296‐47605575) suppressed expression of C1QTNF4 (its nearest gene) via long‐range enhancer‐promoter chromatin interaction in neurons. We identified that a TE from AluSz6 subfamily (chr8: 11834847‐11835127) increased expression of FDFT1 (its nearest gene) via microglia‐specific long‐range chromatin looping. Expression perturbation of FDFT1 and C1QTNF4 were significantly correlated with Braak staging score of AD patients. We further identified that individuals with AD risk allele APOE4 displayed elevated expression of AluSz6 and FDFT1 in patient induced pluripotent stem cells (iPSC)‐derived microglia and superior frontal gyrus (SFG) microglia compared to APOE3 individuals.ConclusionThese findings demonstrate widespread TE dysregulation in human brains and teQTLs offer a useful QTL analytic approach to identify AD risk genes and other complex diseases if broadly applied.