Illuminating the APOE Locus with Long-Read Sequencing and Targeted Genomics

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PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a common, progressive, and ultimately fatal brain disease. Currently approved treatments provide only minimal symptomatic benefits and do not stop the disease from progressing. The field is in dire need of novel drug targets which could lead to disease-modifying therapies. The most common genetic risk factor for AD is the ε4 variant of the apolipoprotein E gene (APOE4). The effect of APOE4 varies greatly between people of African ancestry and people of European ancestry. The current study—Illuminating the APOE Locus with Long-Read Sequencing and Targeted Genomics—will apply a new genome sequencing technology (long-read sequencing) to the study of APOE and several other AD-relevant genes including ABCA7. Long-read sequencing will be performed on DNA from roughly 2000 African-Americans with AD and 2000 healthy older African-American control subjects as well as DNA from roughly 5000 European-American AD patients and 5000 European-American controls. A subset of these patients will also have long-read sequencing of these genes’ RNA derived from white blood cells, fibroblasts, or brain tissue. These analyses will help us understand how local genetic variants near the APOE4 variant can alter the type or amount of the APOE4 protein and how this affects risk of AD. Similar analyses will be done on ABCA7 and another 15-20 targeted genes that will be selected just before sequencing begins and following an up-to-date review of the AD genetics literature. In addition to understanding the local variants regulating a gene and the protein it produces, long-read sequencing will be useful in detecting large, damaging genetic mutations that are easily missed with standard whole-genome sequencing. The results will allow for more specific estimates of AD risk in individuals of diverse ancestral backgrounds and will provide novel targets for drug development.