Scientists identified new risk genes for Neuro-degenerative disorders

Neurodegenerative dementias such as AD and PSP are a major cause of morbidity and mortality worldwide.

Authors used massively parallel reporter assays to screen noncoding variants reported in genome-wide association studies of two neurodegenerative disorders

They used MPRA coupled with CRISPR-based validation to identify  causal genetic variants underlying 2 neurodegenerative conditions- Alzheimers and progressive supranuclear palsy.

They tested the transcriptional regulatory activity of 5706 noncoding single-nucleotide variants, representing 25 significant loci associated with AD and 9 loci associated with PSP.

Identified 320 different functional regulatory variants (frVars) that affect gene expression within 27 of these loci.

AD frVars were enriched within microglial enhancers, whereas PSP frVars were enriched within neuronal enhancers

They also identified and validated multiple risk loci using CRISPR interference/excision, including complement 4 (C4A) and APOC1 in AD and PLEKHM1 and KANSL1 in PSP.

These analyses support a mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk in aggregate through polygenic cell type specific regulatory effects.

Functional regulatory variants implicate distinct transcriptional networks in dementia.

  By Yonatan A. Cooper Noam Teyssier et al Science 2022