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Photo: KG Pressfoto

Marju Orho-Melander


Photo: KG Pressfoto

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits


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

Summary, in English

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.


  • Cardiovascular Research - Epidemiology
  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year







American Journal of Human Genetics





Document type

Journal article


Cell Press


  • Cardiac and Cardiovascular Systems



Research group

  • Cardiovascular Research - Epidemiology
  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease


  • ISSN: 0002-9297