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Genetic studies of Alzheimer's disease risk implicate clearance of lipid rich debris in myeloid cells
Author(s) -
Novikova Gloriia,
T.C.W. Julia,
Marcora Edoardo,
Kapoor Manav,
Renton Alan E.,
Efthymiou Anastasia M.,
Abud Edsel M.,
Bendl Jaroslav M.,
Cheng Haoxiang M.,
Fullard John F.,
Roussos Panos,
Poon Wayne W.,
Hao Ke,
Goate Alison M.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.040601
Subject(s) - genome wide association study , epigenomics , biology , transcriptome , enhancer , mendelian randomization , genetics , trem2 , genetic association , candidate gene , myeloid , induced pluripotent stem cell , disease , gene , computational biology , immunology , cell , gene expression , single nucleotide polymorphism , embryonic stem cell , medicine , pathology , myeloid cells , genetic variants , genotype , dna methylation
Background Genome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Earlier pathway analyses have implicated lipid metabolism, immune response and endocytosis. Method We used LDscore regression to determine the epigenomic annotations enriched for AD risk variants. We then integrated AD GWAS signals with epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. Result We show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia. Using summary‐data based Mendelian Randomization nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the APOE locus we used genome editing to generate isogenic human induced pluripotent stem cells (hiPSC) combined with transcriptomics to demonstrate dyshomeostasis of lipid metabolism in APOE44 glial cells from. Conclusion Combined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD.