GWAS have identified 40 loci that are associated with Alzheimer’s disease in European populations, 24 of which are replicated at genome–wide suggestive significance.5,7–9 Functional genomics studies further suggests APOE, CR1, BIN1, TREM2, CLU, SORL1, ADAM10, ABCA7, CD33, SPI1, and PILRA as the likely causal genes in their respective loci.37 Although GWAS have made substantial progress in characterisation of the genetic architecture of Alzheimer’s disease, much work remains to identify the functional genetic variants and biological mechanisms underlying the observed associations of genetic loci with Alzheimer’s disease. This research will require multi–omic datasets from relevant cell types such as microglia, which have been strongly implicated in Alzheimer’s disease pathogenesis.38 Multiethnic GWAS will aid in mapping of specific variants because of divergent genetic variation (panel 3). Research efforts will be also needed to overcome the challenge of obtaining the necessary sample sizes in cell–type–specific datasets, especially if some associations only apply to specific subsets of cells (eg, activated microglia).38 Until functional mapping of GWAS associations are complete, putative gene annotations should be interpreted cautiously.
