Assessment of Candidate Loci in Neurological diseases

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

We continue to perform an assessment of candidate loci for various diseases, including Alzheimer's disease, frontotemporal dementia, motor neuron diseases, ataxia, Parkinson's disease, and dystonia. This work allows us to parse such families into those with known mutations, and those that should be prioritized for further genetic work aimed at finding new genetic causes of disease, moreover this work allows us to fine map, and to find functional variation at candidate risk loci found through genome wide association. We have performed several studies that aim to define the underlying functional variant at existing risk loci, and to define functional classes of risk genes. Prior to the last period this work has focused on the GBA, TMEM175, SNCA, and lysosomal-linked loci like CTSB. We are currently investigating whether these loci are enriched in specific subtypes of Parkinson's disease like LRRK2-PD and GBA-PD and if these loci contribute to age of disease onset; further, we are examining the consequences of disease linked variability on molecular outcomes in iPSC systems; the molecular readouts include transcriptomics, proteomics, and epigenomics. We recently performed a joint meta-analysis of roughly 49,000 PD cases, 18,000 proxy cases, and 2,450,000 controls from individuals of diverse ancestries and identified 78 genome-wide significant loci and 12 possibly novel loci in a recent preprint (https://doi.org/10.1101/2022.08.04.22278432) to begin to identify loci contributing to PD in non-European populations. Lastly, we are examining the role of structural variability and repeats at known risk loci using an array of structural variant tools in Whole Genome Sequencing data, followed by validation. We will also perform long-read sequencing of PD patient samples to identify large structural variants and other challenging genomic regions in PD genetics that cannot be detected with short-read sequencing.