LAUSR

In science there are times when the concurrent development of new tools, availability of relevant models, and accessibility to large data sets can coalesce to yield unanticipated conceptual advances. Today, data from genetic studies powered by next-generation sequencing have yielded genetic traits associated with neurodegenerative diseases. Meanwhile, progress in genome engineering tools such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and induced pluripotent stem cell (iPSC) technology has enabled nonbiased functional genomic screens in disease-relevant human cells. This combination of breakthroughs may provide an opportunity where “the stars align” to yield exciting new insights and directions critical to the field of neurodegeneration. Understanding the genetic basis of complex neurodegenerative diseases is critical for developing rational therapeutics. In the past decades, genome-wide association studies (GWASs) of neurodegenerative disorders, along with investigations into rare monogenic forms of these diseases, have greatly expanded our understanding of the genetic factors contributing to these disorders. For instance, the most recent Parkinson’s disease (PD) GWAS identified 90 independent variants for risk and progression across more than 80 genomic regions. Multiple GWASnominated loci overlap with genes that are already implicated in monogenic forms of PD. This convergence reflects a clear etiologic relation between sporadic and familial forms of PD. Therefore, a thorough understanding of how these genetic risk variants contribute to neurodegenerative diseases is becoming a prerequisite for the development of disease-modifying therapeutics. However, it is difficult to apply traditional research paradigms to investigate risk loci associated with complex neurodegenerative diseases. First, in PD alone there are over 90 known GWAS risk loci, and this number is continually increasing. Second, these risk loci are often located outside coding regions and may affect the expression levels of multiple genes. Consequently, a systematic strategy is required to investigate the functions of the multitude of genes potentially affected by risk loci. Moreover, risk variants may exert damaging effects in distinct cell types within different neurodegenerative diseases. For instance, the genes highlighted by PD GWAS are enriched for those highly expressed in neurons in the substantia nigra (SN), whereas the genes highlighted by Alzheimer’s disease GWAS are strongly expressed in immune-related tissues (spleen and liver) and cells types such as microglia. The distinctive transcription features of these GWAShighlighted genes in different cell types validate the need to study risk variants in disease-relevant cells. The elucidation of cell-type-specific gene functions will help to disentangle the contributions of different cell types to the associated disease. In addition, GWAS risk loci do not account for all the genetic factors underlying the disease. Analysis of common genetic variability suggests that only about 22% of the genetic burden for PD is driven by PD GWAS loci, indicating that complementary strategies are needed to identify genetic variability currently not well captured in GWAS, including rare variants of both large and small effects. The recent integration of CRISPR/Cas9-based functional genomics and iPSC technology now enables a © 2022 International Parkinson and Movement Disorder Society