| Literature DB >> 27346685 |
Nathalie Chami1, Ming-Huei Chen2, Andrew J Slater3, John D Eicher2, Evangelos Evangelou4, Salman M Tajuddin5, Latisha Love-Gregory6, Tim Kacprowski7, Ursula M Schick8, Akihiro Nomura9, Ayush Giri10, Samuel Lessard1, Jennifer A Brody11, Claudia Schurmann12, Nathan Pankratz13, Lisa R Yanek14, Ani Manichaikul15, Raha Pazoki16, Evelin Mihailov17, W David Hill18, Laura M Raffield19, Amber Burt20, Traci M Bartz21, Diane M Becker14, Lewis C Becker22, Eric Boerwinkle23, Jette Bork-Jensen24, Erwin P Bottinger8, Michelle L O'Donoghue25, David R Crosslin26, Simon de Denus27, Marie-Pierre Dubé1, Paul Elliott28, Gunnar Engström29, Michele K Evans5, James S Floyd11, Myriam Fornage30, He Gao28, Andreas Greinacher31, Vilmundur Gudnason32, Torben Hansen24, Tamara B Harris33, Caroline Hayward34, Jussi Hernesniemi35, Heather M Highland36, Joel N Hirschhorn37, Albert Hofman38, Marguerite R Irvin39, Mika Kähönen40, Ethan Lange41, Lenore J Launer33, Terho Lehtimäki42, Jin Li43, David C M Liewald18, Allan Linneberg44, Yongmei Liu45, Yingchang Lu12, Leo-Pekka Lyytikäinen42, Reedik Mägi17, Rasika A Mathias46, Olle Melander29, Andres Metspalu17, Nina Mononen42, Mike A Nalls47, Deborah A Nickerson48, Kjell Nikus49, Chris J O'Donnell50, Marju Orho-Melander29, Oluf Pedersen24, Astrid Petersmann51, Linda Polfus52, Bruce M Psaty53, Olli T Raitakari54, Emma Raitoharju42, Melissa Richard30, Kenneth M Rice21, Fernando Rivadeneira55, Jerome I Rotter56, Frank Schmidt57, Albert Vernon Smith32, John M Starr58, Kent D Taylor56, Alexander Teumer59, Betina H Thuesen60, Eric S Torstenson10, Russell P Tracy61, Ioanna Tzoulaki4, Neil A Zakai62, Caterina Vacchi-Suzzi63, Cornelia M van Duijn16, Frank J A van Rooij16, Mary Cushman62, Ian J Deary18, Digna R Velez Edwards64, Anne-Claire Vergnaud28, Lars Wallentin65, Dawn M Waterworth66, Harvey D White67, James G Wilson68, Alan B Zonderman5, Sekar Kathiresan69, Niels Grarup24, Tõnu Esko70, Ruth J F Loos71, Leslie A Lange19, Nauder Faraday72, Nada A Abumrad6, Todd L Edwards10, Santhi K Ganesh73, Paul L Auer74, Andrew D Johnson2, Alexander P Reiner75, Guillaume Lettre76.
Abstract
Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.Entities:
Mesh：
Substances：
Year: 2016 PMID： 27346685 PMCID： PMC5005438 DOI： 10.1016/j.ajhg.2016.05.007
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025