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Integration of Alzheimer’s disease genetics and myeloid genomics reveals novel disease risk mechanisms
Author(s) -
Novikova Gloriia,
Marcora Edoardo,
Kapoor Manav,
TCW Julia,
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.043897
Subject(s) - biology , genome wide association study , epigenomics , enhancer , genetics , mendelian randomization , candidate gene , locus (genetics) , disease , trem2 , gene , myeloid , computational biology , transcription factor , gene expression , single nucleotide polymorphism , cancer research , medicine , cell , genotype , dna methylation , myeloid cells , pathology , genetic variants
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. Method We used an integrative genomic approach to determine the epigenomic annotations enriched for AD risk variants and applied a summary‐data based Mendelian Randomization 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, 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 MS4A locus we identified a single candidate functional variant within an CTCF binding site, that is predicted to alter chromatin looping and MS4A gene expression. We used human induced pluripotent stem cells (hiPSC)‐derived microglia to provide experimental validation of this putative causal variant. 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.