Andrea Ganna
Massachusetts General Hospital
The impact of ultra-rare disruptive mutations in highly constrained genes on human diseases and quantitative traits
Andrea Ganna, Seyedeh M. Zekavat, Kyle Satterstrom, Andrea Byrnes, Giulio Genovese, Mitja Kurki, Joel Ramo, Elmo Saarentaus, Manuel Rivas, Mykyta Artomov, GoT2D consortium, iPSYCH consortium, Jason Flannick, Jose C. Florez, Veikko Salomaa, Aarno Palotie, Christina Hultman, Patrick F. Sullivan, Sekar Kathiresan, Mark J. Daly, Benjamin M. Neale
Disruptive ultra-rare variants in highly constrained genes (URV-LOF-HC) have been associated with higher risk for neurodevelopment disorders and reduced cognition, but the impact across multiple diseases and quantitative traits is unknown. We collected phenotypic information from 74,000 exome-sequenced individuals, 15,000 of those linked with electronic medical records. Carriers of URV-LOF-HC had an increased risk for neurodevelopment disorders, including ADHD (P-value=6.6 x10 ^8), reduced height and HDL cholesterol (P-value < 0.001). We didn’t identify any significant association with later-onset traits, such as coronary heart disease. We performed a phenome-wide scan using manually curated disease definitions obtained from ICD-codes and identified few disorders enriched for URV-LOF-HC (e.g. chronic kidney failure; hazard ratio=1.94, FDR adjusted P-value=0.018). We also observed an overall increase of disease burden among URV-LOF-HC carriers, reflected in a higher number of hospital visits.
