ADSP Functional Genomics: from gene, to function to mechanisms and targets

Background: Genetic studies have been highly successful in identifying genetic regions associated with Alzheimer’s disease, and we are now at the exciting juncture of applying this knowledge to understanding disease mechanisms. The ability to generate and mine clinical and omicdata is advancing our understanding of neurodegeneration. The Alzheimer’s Disease Sequencing Project (ADSP) Functional Genomics Consortium (FunGen-AD; https://adsp-fgc.niagads.org/) aims to apply cutting-edge genomics technologies, high-throughput genetic screening and cutting edge disease modeling to understand the functional consequences of genetic susceptibility and resilience to Alzheimer’s Disease, and to identify genetics-guided targets for the prevention, diagnosis, and treatment of Alzheimer’s disease and related dementias (AD/ADRD). Method: The investigators of the FunGen-AD consortium are using multiple approaches, including brain single cell data acquisition, human stem cell modeling and high through put CRISPR-based screens, to understand how AD variants lead to changes across molecular networks, and understand how specific risk variants affect disease in diverse populations. Multi-omic data generated in well characterized cohorts are being used to identify systems-level alterations in and provide insight into the mechanisms underlying genetic variants. Result: The FunGen-AD consortium is organizing and facilitating large collaborative projects. Currently we are working on a xQTL project putting together data from multi-tissue (brain, myeloid cells, CSF and plasma), and multi-omic layers (transcriptomic in bulk and at single cell level, epigenetic, proteomic, and metabolomic). In order to fully understand the biology of AD we recognize that multiple tissues, and -omic layers need to be studied. All the omic data are being processed, harmonized and analyzed using standard pipelines, and mapping on a reference genome and annotation developed by the group. This QTL atlas will be used to perform colocalization and identify the functional genes within AD risk loci, and Mendelian Randomization to identify novel causal genes, proteins and druggable targets. This xQTL project will provide a rich resource of multi-omics datasets, analysis pipelines, and an xQTL atlas for the research community studying AD/ADRD and other complex neurodegenerative traits. Conclusions: In summary, the FunGen-AD consortium is using multidisciplinary and collaborative research approaches to identify genetics-guided targets for the prevention, diagnosis, and treatment of AD/ADRD.