Turning GWAS signals into drug targets with scalable CRISPR

Dr. Neville Sanjana, Core Faculty Member at the New York Genome Center and Professor of Biology and Neuroscience at New York University, contributed to Drug Target Review on scalable CRISPR screening approaches. The methods connect noncoding variants with causal genes and potential therapeutic targets. Sanjana said his group develops scalable approaches to target thousands of genes or genomic regions in a single experiment. Genome-wide association studies link variants to disease risk. Sanjana noted that determining which variants are causal and how they act remains difficult, especially since most lie outside protein-coding genes. He said correlation does not equal causation. Sanjana's group developed STING-seq to tackle these limits. The technique pairs CRISPR pooled screens of GWAS variants with single-cell sequencing. It identifies likely causal variants and the genes they modulate. In related work, MultiPerturb-seq measures RNA expression and chromatin accessibility at the same time in single cells. The approach was applied to a rare paediatric brain tumour driven by SWI/SNF dysregulation. ZNHIT1 stood out as a target that restored both gene expression and chromatin state toward normal levels in atypical teratoid rhabdoid tumour cells. Sanjana said the finding supports a reprogramming therapy hypothesis rather than direct cytotoxicity. The research covers oncology, autoimmunity, neural development, neuropsychiatry, metabolic dysfunction and ageing. Other technologies from the lab include OverCITE-seq, CRISPore-seq and MultiPerturb-seq.