TY - JOUR T1 - Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. JF - Am J Hum Genet Y1 - 2016 A1 - Chami, Nathalie A1 - Chen, Ming-Huei A1 - Slater, Andrew J A1 - Eicher, John D A1 - Evangelou, Evangelos A1 - Tajuddin, Salman M A1 - Love-Gregory, Latisha A1 - Kacprowski, Tim A1 - Schick, Ursula M A1 - Nomura, Akihiro A1 - Giri, Ayush A1 - Lessard, Samuel A1 - Brody, Jennifer A A1 - Schurmann, Claudia A1 - Pankratz, Nathan A1 - Yanek, Lisa R A1 - Manichaikul, Ani A1 - Pazoki, Raha A1 - Mihailov, Evelin A1 - Hill, W David A1 - Raffield, Laura M A1 - Burt, Amber A1 - Bartz, Traci M A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - O'Donoghue, Michelle L A1 - Crosslin, David R A1 - de Denus, Simon A1 - Dubé, Marie-Pierre A1 - Elliott, Paul A1 - Engström, Gunnar A1 - Evans, Michele K A1 - Floyd, James S A1 - Fornage, Myriam A1 - Gao, He A1 - Greinacher, Andreas A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hernesniemi, Jussi A1 - Highland, Heather M A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Lange, Ethan A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Li, Jin A1 - Liewald, David C M A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mathias, Rasika A A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mononen, Nina A1 - Nalls, Mike A A1 - Nickerson, Deborah A A1 - Nikus, Kjell A1 - O'Donnell, Chris J A1 - Orho-Melander, Marju A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Polfus, Linda A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Raitoharju, Emma A1 - Richard, Melissa A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schmidt, Frank A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thuesen, Betina H A1 - Torstenson, Eric S A1 - Tracy, Russell P A1 - Tzoulaki, Ioanna A1 - Zakai, Neil A A1 - Vacchi-Suzzi, Caterina A1 - van Duijn, Cornelia M A1 - van Rooij, Frank J A A1 - Cushman, Mary A1 - Deary, Ian J A1 - Velez Edwards, Digna R A1 - Vergnaud, Anne-Claire A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Zonderman, Alan B A1 - Kathiresan, Sekar A1 - Grarup, Niels A1 - Esko, Tõnu A1 - Loos, Ruth J F A1 - Lange, Leslie A A1 - Faraday, Nauder A1 - Abumrad, Nada A A1 - Edwards, Todd L A1 - Ganesh, Santhi K A1 - Auer, Paul L A1 - Johnson, Andrew D A1 - Reiner, Alexander P A1 - Lettre, Guillaume AB -

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.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract ER -