Neurohack C3

Overview

This project focused on using human genetics to identify potential therapeutic targets for motor neuron disease, including ALS. Recent genome-wide association studies had uncovered multiple risk loci associated with motor neuron disease, but the harder question was how to translate those statistical associations into biological mechanisms and actionable drug discovery hypotheses.

As part of the NGV Hunters team, we built a three-part pipeline: first, exploring genetic variation linked to disease longevity; second, using Mendelian Randomization to infer causal relationships between variants, exposures, and outcomes; and third, mapping potential causal genes to drug discovery databases to identify druggable targets.

The analysis combined variant annotation, statistical genetics, and therapeutic target prioritization. We processed genetic variants using tools like VEP and BCFtools, analyzed SNP effects with Mendelian Randomization workflows, generated scatter plots and funnel plots to evaluate instrument validity, and mapped promising genes into drug-protein interaction and ChemBL-style target spaces.

The most interesting part of the project was seeing how biological discovery becomes a systems problem. Variant data alone is not enough. You need annotation pipelines, causal inference methods, pathway analysis, druggability scoring, and biological interpretation all working together to move from “this locus is associated with disease” to “this mechanism might be therapeutically actionable.”

The project won 1st place in the UK DEMON Dementia Network Neurohack Challenge and received a $10K research grant for continued work on Alzheimer’s and motor neuron disease drug repurposing.

Technical Highlights

• Variant annotation with VEP and BCFtools
• Mendelian Randomization for causal inference
• SNP exposure-outcome effect analysis
• Funnel plot validation for genetic instruments
• Drug-target mapping using therapeutic databases
• Pathway and transmembrane region enrichment analysis
• 1st place, DEMON Dementia Network Neurohack Challenge