Genetic Studies Implicate Microglial Function in Alzheimer's Disease Risk
Goate AM1*, Kapoor M1, Raj T1, Renton A1, Efthymiou A1, Hao K1, TCW J1, Poon W2, , Marcora E1
1Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2University of California, Irvine, CA, USA
Genome-wide studies to identify genetic risk factors for Alzheimer's disease (AD) have resulted in the identification of more than thirty loci. While rare variants identified through sequencing or exome arrays identify functional variants in specific genes such as TREM2, ABCA7 and SORL1 genome-wide association studies (GWAS) identify loci but do not pinpoint specific genes. LDScore regression using AD GWAS data has shown an enrichment of AD loci within epigenetic annotations characteristic of myeloid cells (Huang et al., 2017). For example a network of genes regulated by the myeloid transcription factor, PU.1 is more than 50 fold enriched among AD risk loci. Our gene set enrichment analyses using this GWAS data have pinpointed efferocytosis as an important biological function enriched for AD risk genes.
We have used GWAS summary statistics in combination with myeloid cell eQTL data to identify specific risk genes in GWAS loci and determine whether variation in expression levels influences disease risk. This has identified additional candidate loci and pinpointed specific genes in some loci that likely influence genetic risk for AD.
To examine the cell type specific effects of AD risk genotypes on cellular function we are using differential gene expression and pathway analyses of transcriptomic data generated in neurons, astrocytes, microglia and endothelial cells derived from induced pluripotent stem cells. Initial studies have focused on isogenic lines for APOE33 and APOE44. Gene set enrichment analysis (GSEA) identified positive enrichment of cholesterol biosynthesis in astrocytes and a negative enrichment of lysosomal pathways in microglia from APOE44 compared to APOE33 cells. Microglial lysosomal pathways enriched in GSEA are associated with decreased phagosome maturation and autophagic function, resulting in decreased lipid catabolism and increased lipid accumulation in APOE44 cells. Both our genetic and functional data implicate microglial function, specifically in the metabolism of lipids as key pathways in AD risk.
Huang K et al., Nat Neurosci. 2017 Aug;20(8):1052-1061. doi: 10.1038/nn.4587.
J TCW is a NYSCF fellow, this work is supported by funds from JPB Foundation, the Neurodegeneration Consortium and NIH (AG049508, AG054011, AG052411).