Population-scale analysis of common and rare genetic variation associated with hearing loss in adults
Authors: Praveen Kavita , Dobbyn Lee , Gurski Lauren , Ayer Ariane H. , Staples Jeffrey , Mishra Shawn , Bai Yu , Kaufman Alexandra , Moscati Arden , Benner Christian , Chen Esteban , Chen Siying , Popov Alexander , Smith Janell ,   GHS-REGN DiscovEHR collaboration, Adams Lance J. , Blank Jackie , Bodian Dale , Boris Derek , Buchanan Adam , Carey David J. , Colonie Ryan D. , Davis F. Daniel , Hartzel Dustin N. , Kelly Melissa , Kirchner H. Lester , Leader Joseph B. , Ledbetter David H. , Manus J. Neil , Martin Christa L. , Metpally Raghu P. , Meyer Michelle , Mirshahi Tooraj , Oetjens Matthew , Person Thomas Nate , Still Christopher , Strande Natasha , Sturm Amy , Wagner Jen , Williams Marc ,   Regeneron Genetics Center,   RGC Management and Leadership Team, Baras Aris , Cantor Michael , Coppola Giovanni , Deubler Andrew , Economides Aris , Lotta Luca A. , Overton John D. , Reid Jeffrey G. , Shuldiner Alan , Karalis Katia , Siminovitch Katherine ,   Sequencing and Lab Operations, Beechert Christina , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Overton John D. , Schleicher Thomas D. , Padilla Maria Sotiropoulos , Widom Louis , Wolf Sarah E. , Pradhan Manasi , Manoochehri Kia , Ulloa Ricardo H. ,   Genome Informatics, Bai Xiaodong , Balasubramanian Suganthi , Boutkov Boris , Eom Gisu , Habegger Lukas , Hawes Alicia , Khalid Shareef , Krasheninina Olga , Lanche Rouel , Mansfield Adam J. , Maxwell Evan K. , Nafde Mona , O’Keeffe Sean , Orelus Max , Panea Razvan , Polanco Tommy , Rasool Ayesha , Reid Jeffrey G. , Salerno William , Staples Jeffrey C. ,   Clinical Informatics, Banerjee Nilanjana , Cantor Michael , Li Dadong , Sharma Deepika , Yadav Ashish ,   Translational and Analytical Genetics, Di Gioia Alessandro , Gelfman Sahar ,   Research Program Management, Chen Esteban , Mighty Jason , LeBlanc Michelle G. , Mitnaul Lyndon J. ,   Decibel-REGN collaboration,   Collaboration Core Team, Burns Joe , Coppola Giovanni , Economides Aris , Frendewey David , Gallagher Scott , Lee John , Keilty John , Kyratsous Christos , Macdonald Lynn , Palermo Adam T. , Praveen Kavita , Sabin Leah , Whitton Jonathon , Zambrowicz Brian ,   Program Management & Alliance Management, Deng Sarah , Horwitz Geoff , King Alejandra K. , Sung Jung H. , Melander Olle , Jones Marcus B. , Marchini Jonathan , Balasubramanian Suganthi , Zambrowicz Brian , Drummond Meghan C. , Baras Aris , Abecasis Goncalo R. , Ferreira Manuel A. , Stahl Eli A. , Coppola Giovanni 
Published: June 2022

AbstractTo 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.