An Alzheimer's disease-associated common regulatory variant in PTK2B has causal effects on microglial function

Genome-wide association studies (GWAS) are revealing an ever-growing number of genetic associations with disease, but identifying and functionally validating the causal variants underlying these associations is very challenging and has only been done for a vanishingly small number of variants. Here we validate a causal single nucleotide polymorphism (SNP) associated with an increased risk of Alzheimer's disease (AD) in an intronic enhancer of the PTK2B gene, by engineering it into human induced pluripotent stem cells (hiPSCs). Upon differentiation to macrophages and microglia, this variant shows effects on chromatin accessibility of the enhancer and increased binding of the transcription factor CEBPB. This variant results in global changes to the transcriptome and phenotype of these cells, as well as a subtle downregulation of PTK2B expression. Expression of interferon gamma responsive genes including chemokine transcripts and their protein products are altered, and chemotaxis of the resulting microglial cells is affected. This variant thus causes disease-relevant transcriptomic and phenotypic changes, and we propose that it acts by altering microglia reactivity, consistent with the role of these cells in progression of AD. ### Competing Interest Statement A.B. is a founder of EnsoCell therapeutics. N.I.P. was an employee of GSK at the time the manuscript was submitted. J.S. was an employee of Illumina at the time the manuscript was submitted.