Cell. 2022 Aug 4;185(16):3041-3055.e25. doi: 10.1016/j.cell.2022.06.036. Epub 2022 Aug 1.
Ryan L Collins 1, Joseph T Glessner 2, Eleonora Porcu 3, Maarja Lepamets 4, Rhonda Brandon 5, Christopher Lauricella 5, Lide Han 6, Theodore Morley 6, Lisa-Marie Niestroj 7, Jacob Ulirsch 8, Selin Everett 9, Daniel P Howrigan 10, Philip M Boone 11, Jack Fu 12, Konrad J Karczewski 10, Georgios Kellaris 13, Chelsea Lowther 12, Diane Lucente 14, Kiana Mohajeri 15, Margit Nõukas 4, Xander Nuttle 12, Kaitlin E Samocha 16, Mi Trinh 17, Farid Ullah 13, Urmo Võsa 18, Epi25 Consortium; Estonian Biobank Research Team; Matthew E Hurles 17, Swaroop Aradhya 5, Erica E Davis 13, Hilary Finucane 10, James F Gusella 9, Aura Janze 5, Nicholas Katsanis 13, Ludmila Matyakhina 5, Benjamin M Neale 10, David Sanders 19, Stephanie Warren 5, Jennelle C Hodge 20, Dennis Lal 21, Douglas M Ruderfer 22, Jeanne Meck 5, Reedik Mägi 18, Tõnu Esko 18, Alexandre Reymond 23, Zoltán Kutalik 24, Hakon Hakonarson 2, Shamil Sunyaev 25, Harrison Brand 26, Michael E Talkowski 27Collaborators, Affiliations expand
Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.
- PMID: 35917817
- DOI: 10.1016/j.cell.2022.06.036