Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impacts in excess of 5 million Americans over the age 65 years old. AD disrupts memory and cognitive abilities, and there are currently no effective therapies able to slow or halt its progression. Although environmental and lifestyle factors have been implicated in its pathogenesis, AD is considered a complex disorder with a clear genetic component. Intense genome wide association study (GWAS) efforts through large-scale collaborations have been successful in discovering genetic loci robustly associated with AD beyond the classic APOE locus. However, GWAS only reports genomic signals associated with a given trait and not necessarily the precise localization of culprit genes. As such, over the past ten years, GWAS has not strictly represented a decade of gene target discovery, rather it has simply been a decade of signal discovery. One clear example of this is highlighted by the recent progress in characterizing the FTO locus in obesity. The GWAS signal that resides within an intronic region of FTO has in fact been recently shown to primarily influence the expression of the IRX3 and IRX5 genes nearby rather than the `host' gene itself, suggesting that this variant is in an enhancer embedded in one gene but influencing the expression of others. So a key question remains: is this the case with AD association signals as well? Indeed, we have already addressed the most significant GWAS finding in type 2 diabetes reported to date, namely genetic variation within the transcription factor 7-like 2 (TCF7L2) gene, which the P.I. on this application first described in 2006. Through the use of chromatin conformation capture and CRISPR/Cas9 genome editing techniques, we have evidence that a culprit gene at this locus is ACSL5. Since we already have a dedicated infrastructure in place to conduct such `variant to gene mapping' efforts, including CHOP's established Human Pluripotent Stem Cell core, our team is poised to determine how GWAS- implicated AD loci affect the expression and function of specific genes during neurodegeneration within corresponding topologically associated domains (TADs). The application of `3D Genomics' and CRISPR based techniques in the relevant cellular models of iPSC-derived neural progenitor cells (NPCs) and terminally differentiated neurons is particularly timely, as it will aid in pinpointing causal gene(s) at established AD GWAS signals when combined with `Assay for Transposase Accessible Chromatin sequencing' (ATAC-seq) to ascertain a shortlist of putative causal SNPs, which will almost entirely be non-coding, and that coincide with open chromatin. Only by uncovering the causative genes related to GWAS-identified genetic variants, and understanding how they operate, can we truly translate these high value GWAS reports in to meaningful benefits for patient care.

Public Health Relevance

Genome wide association studies (GWAS) have clearly revolutionized the field of complex disease genetics, where intense efforts by large-scale international collaborations have been successful in discovering key genetic variants robustly associated with Alzheimer's disease (AD). However, GWAS only reports genomic signals associated with a given trait and not necessarily the precise localization of culprit genes. Given the need for `variant to gene mapping', plus the need to expand the collection of public domain genomic data relevant to brain tissue types, we will utilize `3D Genomic' and CRISPR based screens in iPSC-derived neural progenitor cells (NPCs) and terminally differentiated neurons to pinpoint the causal gene(s) at each key AD GWAS-implicated locus.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1)
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Wise, Bradley C
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Children's Hospital of Philadelphia
United States
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