September 29, 2021

Targeted exome screening in synucleinopathy patients to identify rare variants

Isabel Lam, PhD

Additional Authors: Dina Zielinski, Sumaiya Nazeen, Xinyuan Wang, Jian Peng, Vikram Khurana

A substantial component of PD is thought to be heritable, but most of this heritability is currently unexplained. Tremendous advances in genome sequencing promise to uncover variants that account for this “missing heritability”, but challenges remain for identifying rare variants of small effect and combinatorial variants. Rare variants require exceedingly large sample sizes to achieve enough statistical power, and recent human genetic divergence limits the use of replication across populations as a way to validate them. An alternative biological-driven approach to identify rare variants in synucleinopathies is centered on alpha-synuclein protein misfolding. We previously performed a targeted exome sequencing screen in 499 synucleinopathy patients. Together with known AD and PD genes, we sequenced nonoverlapping sets of genetic modulators of alpha-synuclein and beta-amyloid toxicity that had been recovered from genome-wide screens in yeast. When we jointly called rare variants with a cohort of 2570 healthy aged individuals, we found that variants in both beta-amyloid and alpha-synuclein genetic networks were enriched across different synucleinopathies versus controls, as were variants in both known PD and AD genes. In some cases, the same variant was present in patients with distinct neuropathologic diagnosis. Variants that emerged in our targeted exome screening have biological effects, as seen in some instances of altered protein-protein interactions and altered genetic interaction with alpha-synuclein toxicity in yeast. Our data implicate shared genetic drivers across distinct synucleinopathies, and demonstrate convergent genetic networks in beta-amyloid and alpha-synuclein proteinopathies in humans.

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