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Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

2022; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/s42003-022-03408-7

2399-3642

Kavita Praveen, Lee Dobbyn, Lauren Gurski, Ariane Ayer, Jeffrey Staples, Shawn Mishra, Yu Bai, Alexandra Kaufman, Arden Moscati, Christian Benner, Esteban Chen, Siying Chen, А. В. Попов, Janell Smith, Lance J. Adams, Jackie Blank, Dale L. Bodian, Derek Boris, Adam H. Buchanan, David J. Carey, Ryan Colonie, F. Daniel Davis, Dustin N. Hartzel, Melissa Kelly, H. Lester Kirchner, Joseph B. Leader, David H. Ledbetter, J. Neil Manus, Christa Lese Martin, Raghu Metpally, Michelle N. Meyer, Tooraj Mirshahi, Matthew T. Oetjens, Thomas N. Person, Christopher D. Still, Natasha T. Strande, Amy C. Sturm, Jen Wagner, Marc S. Williams, Aris Baras, Michael Cantor, Giovanni Coppola, Andrew Deubler, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Katia Karalis, Katherine Siminovitch, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, John D. Overton, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Boris Boutkov, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, Jeffrey G. Reid, William Salerno, Jeffrey Staples, Nilanjana Banerjee, Michael Cantor, Dadong Li, Deepika Sharma, Ashish Yadav, Alessandro Di Gioia, Sahar Gelfman, Esteban Chen, Jason Mighty, Michelle G. LeBlanc, Lyndon J. Mitnaul, Joe Burns, Giovanni Coppola, Aris N. Economides, David Frendewey, Scott F. Gallagher, John Lee, John Keilty, Christos A. Kyratsous, Lynn E. Macdonald, Adam T. Palermo, Kavita Praveen, Leah R. Sabin, Jonathon P. Whitton, Brian Zambrowicz, Sarah Deng, Geoff Horwitz, Alejandra King, Jung‐Hoon Sung, Olle Melander, Marcus B. Jones, Jonathan Marchini, Suganthi Balasubramanian, Brian Zambrowicz, Meghan C. Drummond, Aris Baras, Gonçalo R. Abecasis, Manuel A. R. Ferreira, Eli A. Stahl, Giovanni Coppola,

Ear Surgery and Otitis Media

Abstract To better understand the genetics of hearing loss, we performed a genome-wide association meta-analysis with 125,749 cases and 469,497 controls across five cohorts. We identified 53/c loci affecting hearing loss risk, including common coding variants in COL9A3 and TMPRSS3 . Through exome sequencing of 108,415 cases and 329,581 controls, we observed rare coding associations with 11 Mendelian hearing loss genes, including additive effects in known hearing loss genes GJB2 (Gly12fs; odds ratio [OR] = 1.21, P = 4.2 × 10 −11 ) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10 −17 ). We also identified hearing loss associations with rare coding variants in FSCN2 (OR = 1.14, P = 1.9 × 10 −15 ) and KLHDC7B (OR = 2.14, P = 5.2 × 10 −30 ). Our results suggest a shared etiology between Mendelian and common hearing loss in adults. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common disorders where both common and rare variation contribute to risk.