Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene
2020
Johnathan Cooper-Knock | Sai Zhang | Kevin P. Kenna | Tobias Moll | John P. Franklin | Samantha Allen | Helia Ghahremani Nezhad | Alfredo Iacoangeli | Nancy Y. Yacovzada | Chen Eitan | Eran Hornstein | Eran Ehilak | Petra Celadova | Daniel Bose | Sali Farhan | Simon Fishilevich | Doron Lancet | Karen E. Morrison | Christopher E. Shaw | Ammar Al-Chalabi | Jan H. Veldink | Janine Kirby | Michael P. Snyder | Pamela J. Shaw | Ian Blair | Naomi Wray | Matthew Kiernan | Miguel Mitne Neto | Adriano Chio | Ruben Cauchi | Wim Robberecht | Philip van Damme | Phillippe Corcia | Phillipe Couratier | Orla Hardiman | Russel McLaughlin | Marc Gotkine | Vivan Drory | Nicola Ticozzi | Vincenzo Silani | Jan Veldink | Leonard van den Berg | Mamede de Carvalho | Jesus Mora Pardina | Monica Povedano | Peter Andersen | Markus Wber | Nazli Başak | Ammar Al-Chalabi | Christopher Shaw | Pamela Shaw | Karen Morrison | John Landers | Jonathan Glass
Summary: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.
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