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Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

Chami, Nathalie; Chen, Ming Huei; Slater, Andrew J.; Eicher, John D.; Evangelou, Evangelos; Tajuddin, Salman M.; Love-Gregory, Latisha; Kacprowski, Tim; Schick, Ursula M. and Nomura, Akihiro, et al. (2016) In American Journal of Human Genetics 99(1). p.8-21
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... (More)

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.

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American Journal of Human Genetics
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99
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14 pages
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Cell Press
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  • scopus:84989865856
  • wos:000381616600002
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0002-9297
DOI
10.1016/j.ajhg.2016.05.007
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English
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@article{4ccf07bf-abb5-438c-b7f9-24bb56188e38,
  abstract     = {<p>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<sup>−10</sup> for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p &lt; 3 × 10<sup>−8</sup> 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<sup>−11</sup>) 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 &lt; 8 × 10<sup>−9</sup>). 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 &lt; 8 × 10<sup>−7</sup>). 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.</p>},
  author       = {Chami, Nathalie and Chen, Ming Huei and Slater, Andrew J. and Eicher, John D. and Evangelou, Evangelos and Tajuddin, Salman M. and Love-Gregory, Latisha and Kacprowski, Tim and Schick, Ursula M. and Nomura, Akihiro and Giri, Ayush and Lessard, Samuel and Brody, Jennifer A. and Schurmann, Claudia and Pankratz, Nathan and Yanek, Lisa R. and Manichaikul, Ani and Pazoki, Raha and Mihailov, Evelin and Hill, W. David and Raffield, Laura M. and Burt, Amber and Bartz, Traci M. and Becker, Diane M. and Becker, Lewis C. and Boerwinkle, Eric and Bork-Jensen, Jette and Bottinger, Erwin P. and O'Donoghue, Michelle L. and Crosslin, David R. and de Denus, Simon and Dubé, Marie Pierre and Elliott, Paul and Engström, Gunnar and Evans, Michele K. and Floyd, James S. and Fornage, Myriam and Gao, He and Greinacher, Andreas and Gudnason, Vilmundur and Hansen, Torben and Harris, Tamara B. and Hayward, Caroline and Hernesniemi, Jussi and Highland, Heather M. and Hirschhorn, Joel N. and Hofman, Albert and Irvin, Marguerite R. and Kähönen, Mika and Lange, Ethan and Launer, Lenore J. and Lehtimäki, Terho and Li, Jin and Liewald, David C M and Linneberg, Allan and Liu, Yongmei and Lu, Yingchang and Lyytikäinen, Leo Pekka and Mägi, Reedik and Mathias, Rasika A. and Melander, Olle and Metspalu, Andres and Mononen, Nina and Nalls, Mike A. and Nickerson, Deborah A. and Nikus, Kjell and O'Donnell, Chris J. and Orho-Melander, Marju and Pedersen, Oluf and Petersmann, Astrid and Polfus, Linda and Psaty, Bruce M. and Raitakari, Olli T. and Raitoharju, Emma and Richard, Melissa and Rice, Kenneth M. and Rivadeneira, Fernando and Rotter, Jerome I. and Schmidt, Frank and Smith, Albert Vernon and Starr, John M. and Taylor, Kent D. and Teumer, Alexander and Thuesen, Betina H. and Torstenson, Eric S. and Tracy, Russell P. and Tzoulaki, Ioanna and Zakai, Neil A. and Vacchi-Suzzi, Caterina and van Duijn, Cornelia M. and van Rooij, Frank J A and Cushman, Mary and Deary, Ian J. and Velez Edwards, Digna R. and Vergnaud, Anne Claire and Wallentin, Lars and Waterworth, Dawn M. and White, Harvey D. and Wilson, James G. and Zonderman, Alan B. and Kathiresan, Sekar and Grarup, Niels and Esko, Tõnu and Loos, Ruth J F and Lange, Leslie A. and Faraday, Nauder and Abumrad, Nada A. and Edwards, Todd L. and Ganesh, Santhi K. and Auer, Paul L. and Johnson, Andrew D. and Reiner, Alexander P. and Lettre, Guillaume},
  issn         = {0002-9297},
  language     = {eng},
  month        = {07},
  number       = {1},
  pages        = {8--21},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2016.05.007},
  volume       = {99},
  year         = {2016},
}