Abstract
Large-scale human genetics has transformed Alzheimer’s disease (AD) research. Through coordinated efforts such as the Alzheimer’s Disease Genetics Consortium (ADGC) and the Alzheimer’s Disease Sequencing Project (ADSP), dozens of reproducible risk loci have been identified across diverse populations. ADSP is now generating whole-genome sequence data at unprecedented scale, with an eventual goal of 150,000 genomes integrated with harmonized clinical and functional datasets. As data generation accelerates, interpretation of genetic discoveries has become the central bottleneck.

In this seminar, I will present computational frameworks developed within ADSP to bridge the gap between association and mechanism. These include multi-ancestry meta-analysis and fine-mapping approaches that leverage linkage disequilibrium differences to refine credible sets; integration of rare and structural variants within joint-calling pipelines; and colocalization strategies incorporating eQTL and other quantitative trait locus datasets to prioritize target genes. I will also discuss regulatory annotation tools such as INFERNO and BTS that integrate large collections of functional genomic tracks for context-specific variant interpretation, along with the informatics infrastructure developed within the NIA Genetics of Alzheimer’s Disease Data Storage Site to support genome production, quality control, phenotype harmonization, and scalable coordination across more than 50,000 whole genomes. Together, these efforts illustrate how statistical genetics, functional genomics, and production-scale bioinformatics infrastructure can be integrated to advance mechanistic understanding of complex neurodegenerative disease.

The CCMB Seminar Series (Sponsored by DCMB) is held at Medical Science Unit I - 4B700, each Wednesday, at 4:00 pm EST, on bioinformatics-related topics. Each seminar is presented by an invited guest speaker. These seminars are live-streamed on Zoom.