On 14 November, Alexi Nott, Inge Holtman, Nicole Coufal and colleagues reported in the Science journal that genetic risk variants for Alzheimer’s disease (AD) are concentrated in the enhancer regions of microglia, immune cells that reside in the brain. Genome-wide association studies (GWAS) have discovered hundreds of genetic mutations associated with the risk of neurological and psychiatric disorders such as AD, multiple sclerosis and autism. However, the vast majority of these genetic risk variants are located in areas of the human genome that do not encode proteins – also known as ‘non-coding’ areas of the genome. This makes it tricky to understand their function in disease development, as non-coding risk variants may affect the expression of genes that are not in their immediate genetic vicinity. To address this issue, researchers set out to create an atlas of interactions between gene promoters and enhancers, specialised regions of the non-coding genome that dictate the level, localisation and extent of gene expression.
First, the research team isolated the nuclei of microglia, neurons, oligodendrocytes and astrocytes from 6 individuals undergoing surgery for epilepsy treatment. Using advanced next-generation sequencing techniques, they profiled the gene promoters and enhancers that were ‘active’ in each of the different brain cell types. Next, they wanted to map the heritability of genetic risk variants for different neurological and psychological disorders, using GWAS datasets from thousands of individuals. Unlike many of the other disorders analysed, the most heritable AD risk variants were located in the enhancer regions of microglial genes, pointing to the importance of this cell type in the pathogenesis of AD. During gene transcription, epigenetic chromatin ‘loops’ are formed between gene promoters and regulatory regions such as enhancers. Using PLAC-seq (which profiles chromatin ‘loops’) in conjunction with computational fine mapping techniques, researchers were able to identify 41 genes that were strongly associated with AD risk. Of these, 25 were specifically identified in microglia. Interestingly, many of the microglia AD risk genes identified by PLAC-seq were highly connected with risk variants identified in GWAS studies: one of these,BIN1, was directly linked to a risk variant that has the second highest AD risk score afterAPOE. Although the sequencing studies were performed in young, healthy individuals, these results reinforce previous studies suggesting that microglia and neuroinflammation play an important role in the development of AD.
