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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; Nomura, Akihiro; Giri, Ayush; Lessard, Samuel; Brody, Jennifer A; Schurmann, Claudia; Pankratz, Nathan; Yanek, Lisa R; Manichaikul, Ani; Pazoki, Raha; Mihailov, Evelin; Hill, W David; Raffield, Laura M; Burt, Amber; Bartz, Traci M; Becker, Diane M; Becker, Lewis C; Boerwinkle, Eric; Bork-Jensen, Jette; Bottinger, Erwin P; O'Donoghue, Michelle L; Crosslin, David R; de Denus, Simon; Dubé, Marie-Pierre; Elliott, Paul; Engström, Gunnar; Evans, Michele K; Floyd, James S; Fornage, Myriam; Gao, He; Greinacher, Andreas; Gudnason, Vilmundur; Hansen, Torben; Harris, Tamara B; Hayward, Caroline; Hernesniemi, Jussi; Highland, Heather M; Hirschhorn, Joel N; Hofman, Albert; Irvin, Marguerite R; Kähönen, Mika; Lange, Ethan; Launer, Lenore J; Lehtimäki, Terho; Li, Jin; Liewald, David C M; Linneberg, Allan René; Liu, Yongmei; Lu, Yingchang; Lyytikäinen, Leo-Pekka; Mägi, Reedik; Mathias, Rasika A; Melander, Olle; Metspalu, Andres; Mononen, Nina; Nalls, Mike A; Nickerson, Deborah A; Nikus, Kjell; O'Donnell, Chris J; Orho-Melander, Marju; Pedersen, Oluf Borbye; Petersmann, Astrid; Polfus, Linda; Psaty, Bruce M; Raitakari, Olli T; Raitoharju, Emma; Richard, Melissa; Rice, Kenneth M; Rivadeneira, Fernando; Rotter, Jerome I; Schmidt, Frank; Smith, Albert Vernon; Starr, John M; Taylor, Kent D; Teumer, Alexander; Thuesen, Betina H; Torstenson, Eric S; Tracy, Russell P; Tzoulaki, Ioanna; Zakai, Neil A; Vacchi-Suzzi, Caterina; van Duijn, Cornelia M; van Rooij, Frank J A; Cushman, Mary; Deary, Ian J; Velez Edwards, Digna R; Vergnaud, Anne-Claire; Wallentin, Lars; Waterworth, Dawn M; White, Harvey D; Wilson, James G; Zonderman, Alan B; Kathiresan, Sekar; Grarup, Niels; Esko, Tõnu; Loos, Ruth J F; Lange, Leslie A; Faraday, Nauder; Abumrad, Nada A; Edwards, Todd L; Ganesh, Santhi K; Auer, Paul L; Johnson, Andrew D; Reiner, Alexander P; Lettre, Guillaume.
In:
American Journal of Human Genetics, Vol. 99, No. 1, 07.07.2016, p. 8-21.
Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
Chami, N, Chen, M-H, Slater, AJ, Eicher, JD, Evangelou, E, Tajuddin, SM, Love-Gregory, L, Kacprowski, T, Schick, UM, Nomura, A, Giri, A, Lessard, S, Brody, JA, Schurmann, C, Pankratz, N, Yanek, LR, Manichaikul, A, Pazoki, R, Mihailov, E, Hill, WD, Raffield, LM, Burt, A, Bartz, TM, Becker, DM, Becker, LC, Boerwinkle, E, Bork-Jensen, J, Bottinger, EP, O'Donoghue, ML, Crosslin, DR, de Denus, S, Dubé, M-P, Elliott, P, Engström, G, Evans, MK, Floyd, JS, Fornage, M, Gao, H, Greinacher, A, Gudnason, V
, Hansen, T, Harris, TB, Hayward, C, Hernesniemi, J, Highland, HM, Hirschhorn, JN, Hofman, A, Irvin, MR, Kähönen, M, Lange, E, Launer, LJ, Lehtimäki, T, Li, J, Liewald, DCM
, Linneberg, AR, Liu, Y, Lu, Y, Lyytikäinen, L-P, Mägi, R, Mathias, RA, Melander, O, Metspalu, A, Mononen, N, Nalls, MA, Nickerson, DA, Nikus, K, O'Donnell, CJ, Orho-Melander, M
, Pedersen, OB, Petersmann, A, Polfus, L, Psaty, BM, Raitakari, OT, Raitoharju, E, Richard, M, Rice, KM, Rivadeneira, F, Rotter, JI, Schmidt, F, Smith, AV, Starr, JM, Taylor, KD, Teumer, A, Thuesen, BH, Torstenson, ES, Tracy, RP, Tzoulaki, I, Zakai, NA, Vacchi-Suzzi, C, van Duijn, CM, van Rooij, FJA, Cushman, M, Deary, IJ, Velez Edwards, DR, Vergnaud, A-C, Wallentin, L, Waterworth, DM, White, HD, Wilson, JG, Zonderman, AB, Kathiresan, S
, Grarup, N, Esko, T, Loos, RJF, Lange, LA, Faraday, N, Abumrad, NA, Edwards, TL, Ganesh, SK, Auer, PL, Johnson, AD, Reiner, AP & Lettre, G 2016, '
Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits',
American Journal of Human Genetics, vol. 99, no. 1, pp. 8-21.
https://doi.org/10.1016/j.ajhg.2016.05.007APA
Chami, N., Chen, M-H., Slater, A. J., Eicher, J. D., Evangelou, E., Tajuddin, S. M., Love-Gregory, L., Kacprowski, T., Schick, U. M., Nomura, A., Giri, A., Lessard, S., Brody, J. A., Schurmann, C., Pankratz, N., Yanek, L. R., Manichaikul, A., Pazoki, R., Mihailov, E., ... Lettre, G. (2016).
Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.
American Journal of Human Genetics,
99(1), 8-21.
https://doi.org/10.1016/j.ajhg.2016.05.007Vancouver
Chami N, Chen M-H, Slater AJ, Eicher JD, Evangelou E, Tajuddin SM et al.
Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.
American Journal of Human Genetics. 2016 Jul 7;99(1):8-21.
https://doi.org/10.1016/j.ajhg.2016.05.007Author
Chami, Nathalie ; Chen, Ming-Huei ; Slater, Andrew J ; Eicher, John D ; Evangelou, Evangelos ; Tajuddin, Salman M ; Love-Gregory, Latisha ; Kacprowski, Tim ; Schick, Ursula M ; Nomura, Akihiro ; Giri, Ayush ; Lessard, Samuel ; Brody, Jennifer A ; Schurmann, Claudia ; Pankratz, Nathan ; Yanek, Lisa R ; Manichaikul, Ani ; Pazoki, Raha ; Mihailov, Evelin ; Hill, W David ; Raffield, Laura M ; Burt, Amber ; Bartz, Traci M ; Becker, Diane M ; Becker, Lewis C ; Boerwinkle, Eric ; Bork-Jensen, Jette ; Bottinger, Erwin P ; O'Donoghue, Michelle L ; Crosslin, David R ; de Denus, Simon ; Dubé, Marie-Pierre ; Elliott, Paul ; Engström, Gunnar ; Evans, Michele K ; Floyd, James S ; Fornage, Myriam ; Gao, He ; Greinacher, Andreas ; Gudnason, Vilmundur ; Hansen, Torben ; Harris, Tamara B ; Hayward, Caroline ; Hernesniemi, Jussi ; Highland, Heather M ; Hirschhorn, Joel N ; Hofman, Albert ; Irvin, Marguerite R ; Kähönen, Mika ; Lange, Ethan ; Launer, Lenore J ; Lehtimäki, Terho ; Li, Jin ; Liewald, David C M ; Linneberg, Allan René ; Liu, Yongmei ; Lu, Yingchang ; Lyytikäinen, Leo-Pekka ; Mägi, Reedik ; Mathias, Rasika A ; Melander, Olle ; Metspalu, Andres ; Mononen, Nina ; Nalls, Mike A ; Nickerson, Deborah A ; Nikus, Kjell ; O'Donnell, Chris J ; Orho-Melander, Marju ; Pedersen, Oluf Borbye ; Petersmann, Astrid ; Polfus, Linda ; Psaty, Bruce M ; Raitakari, Olli T ; Raitoharju, Emma ; Richard, Melissa ; Rice, Kenneth M ; Rivadeneira, Fernando ; Rotter, Jerome I ; Schmidt, Frank ; Smith, Albert Vernon ; Starr, John M ; Taylor, Kent D ; Teumer, Alexander ; Thuesen, Betina H ; Torstenson, Eric S ; Tracy, Russell P ; Tzoulaki, Ioanna ; Zakai, Neil A ; Vacchi-Suzzi, Caterina ; van Duijn, Cornelia M ; van Rooij, Frank J A ; Cushman, Mary ; Deary, Ian J ; Velez Edwards, Digna R ; Vergnaud, Anne-Claire ; Wallentin, Lars ; Waterworth, Dawn M ; White, Harvey D ; Wilson, James G ; Zonderman, Alan B ; Kathiresan, Sekar ; Grarup, Niels ; Esko, Tõnu ; Loos, Ruth J F ; Lange, Leslie A ; Faraday, Nauder ; Abumrad, Nada A ; Edwards, Todd L ; Ganesh, Santhi K ; Auer, Paul L ; Johnson, Andrew D ; Reiner, Alexander P ; Lettre, Guillaume. / Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 1. pp. 8-21.
Bibtex
@article{cd99d25647844a2499cc085af2cd3e50,
title = "Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits",
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.",
keywords = "Journal Article",
author = "Nathalie Chami and Ming-Huei Chen and Slater, {Andrew J} and Eicher, {John D} and Evangelos Evangelou and Tajuddin, {Salman M} and Latisha Love-Gregory and Tim Kacprowski and Schick, {Ursula M} and Akihiro Nomura and Ayush Giri and Samuel Lessard and Brody, {Jennifer A} and Claudia Schurmann and Nathan Pankratz and Yanek, {Lisa R} and Ani Manichaikul and Raha Pazoki and Evelin Mihailov and Hill, {W David} and Raffield, {Laura M} and Amber Burt and Bartz, {Traci M} and Becker, {Diane M} and Becker, {Lewis C} and Eric Boerwinkle and Jette Bork-Jensen and Bottinger, {Erwin P} and O'Donoghue, {Michelle L} and Crosslin, {David R} and {de Denus}, Simon and Marie-Pierre Dub{\'e} and Paul Elliott and Gunnar Engstr{\"o}m and Evans, {Michele K} and Floyd, {James S} and Myriam Fornage and He Gao and Andreas Greinacher and Vilmundur Gudnason and Torben Hansen and Harris, {Tamara B} and Caroline Hayward and Jussi Hernesniemi and Highland, {Heather M} and Hirschhorn, {Joel N} and Albert Hofman and Irvin, {Marguerite R} and Mika K{\"a}h{\"o}nen and Ethan Lange and Launer, {Lenore J} and Terho Lehtim{\"a}ki and Jin Li and Liewald, {David C M} and Linneberg, {Allan Ren{\'e}} and Yongmei Liu and Yingchang Lu and Leo-Pekka Lyytik{\"a}inen and Reedik M{\"a}gi and Mathias, {Rasika A} and Olle Melander and Andres Metspalu and Nina Mononen and Nalls, {Mike A} and Nickerson, {Deborah A} and Kjell Nikus and O'Donnell, {Chris J} and Marju Orho-Melander and Pedersen, {Oluf Borbye} and Astrid Petersmann and Linda Polfus and Psaty, {Bruce M} and Raitakari, {Olli T} and Emma Raitoharju and Melissa Richard and Rice, {Kenneth M} and Fernando Rivadeneira and Rotter, {Jerome I} and Frank Schmidt and Smith, {Albert Vernon} and Starr, {John M} and Taylor, {Kent D} and Alexander Teumer and Thuesen, {Betina H} and Torstenson, {Eric S} and Tracy, {Russell P} and Ioanna Tzoulaki and Zakai, {Neil A} and Caterina Vacchi-Suzzi and {van Duijn}, {Cornelia M} and {van Rooij}, {Frank J A} and Mary Cushman and Deary, {Ian J} and {Velez Edwards}, {Digna R} and Anne-Claire Vergnaud and Lars Wallentin and Waterworth, {Dawn M} and White, {Harvey D} and Wilson, {James G} and Zonderman, {Alan B} and Sekar Kathiresan and Niels Grarup and T{\~o}nu Esko and Loos, {Ruth J F} and Lange, {Leslie A} and Nauder Faraday 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 Guillaume Lettre",
note = "Copyright {\textcopyright} 2016 American Society of Human Genetics. All rights reserved.",
year = "2016",
month = jul,
day = "7",
doi = "10.1016/j.ajhg.2016.05.007",
language = "English",
volume = "99",
pages = "8--21",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",
}
RIS
TY - JOUR
T1 - Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits
AU - Chami, Nathalie
AU - Chen, Ming-Huei
AU - Slater, Andrew J
AU - Eicher, John D
AU - Evangelou, Evangelos
AU - Tajuddin, Salman M
AU - Love-Gregory, Latisha
AU - Kacprowski, Tim
AU - Schick, Ursula M
AU - Nomura, Akihiro
AU - Giri, Ayush
AU - Lessard, Samuel
AU - Brody, Jennifer A
AU - Schurmann, Claudia
AU - Pankratz, Nathan
AU - Yanek, Lisa R
AU - Manichaikul, Ani
AU - Pazoki, Raha
AU - Mihailov, Evelin
AU - Hill, W David
AU - Raffield, Laura M
AU - Burt, Amber
AU - Bartz, Traci M
AU - Becker, Diane M
AU - Becker, Lewis C
AU - Boerwinkle, Eric
AU - Bork-Jensen, Jette
AU - Bottinger, Erwin P
AU - O'Donoghue, Michelle L
AU - Crosslin, David R
AU - de Denus, Simon
AU - Dubé, Marie-Pierre
AU - Elliott, Paul
AU - Engström, Gunnar
AU - Evans, Michele K
AU - Floyd, James S
AU - Fornage, Myriam
AU - Gao, He
AU - Greinacher, Andreas
AU - Gudnason, Vilmundur
AU - Hansen, Torben
AU - Harris, Tamara B
AU - Hayward, Caroline
AU - Hernesniemi, Jussi
AU - Highland, Heather M
AU - Hirschhorn, Joel N
AU - Hofman, Albert
AU - Irvin, Marguerite R
AU - Kähönen, Mika
AU - Lange, Ethan
AU - Launer, Lenore J
AU - Lehtimäki, Terho
AU - Li, Jin
AU - Liewald, David C M
AU - Linneberg, Allan René
AU - Liu, Yongmei
AU - Lu, Yingchang
AU - Lyytikäinen, Leo-Pekka
AU - Mägi, Reedik
AU - Mathias, Rasika A
AU - Melander, Olle
AU - Metspalu, Andres
AU - Mononen, Nina
AU - Nalls, Mike A
AU - Nickerson, Deborah A
AU - Nikus, Kjell
AU - O'Donnell, Chris J
AU - Orho-Melander, Marju
AU - Pedersen, Oluf Borbye
AU - Petersmann, Astrid
AU - Polfus, Linda
AU - Psaty, Bruce M
AU - Raitakari, Olli T
AU - Raitoharju, Emma
AU - Richard, Melissa
AU - Rice, Kenneth M
AU - Rivadeneira, Fernando
AU - Rotter, Jerome I
AU - Schmidt, Frank
AU - Smith, Albert Vernon
AU - Starr, John M
AU - Taylor, Kent D
AU - Teumer, Alexander
AU - Thuesen, Betina H
AU - Torstenson, Eric S
AU - Tracy, Russell P
AU - Tzoulaki, Ioanna
AU - Zakai, Neil A
AU - Vacchi-Suzzi, Caterina
AU - van Duijn, Cornelia M
AU - van Rooij, Frank J A
AU - Cushman, Mary
AU - Deary, Ian J
AU - Velez Edwards, Digna R
AU - Vergnaud, Anne-Claire
AU - Wallentin, Lars
AU - Waterworth, Dawn M
AU - White, Harvey D
AU - Wilson, James G
AU - Zonderman, Alan B
AU - Kathiresan, Sekar
AU - Grarup, Niels
AU - Esko, Tõnu
AU - Loos, Ruth J F
AU - Lange, Leslie A
AU - Faraday, Nauder
AU - Abumrad, Nada A
AU - Edwards, Todd L
AU - Ganesh, Santhi K
AU - Auer, Paul L
AU - Johnson, Andrew D
AU - Reiner, Alexander P
AU - Lettre, Guillaume
N1 - Copyright © 2016 American Society of Human Genetics. All rights reserved.
PY - 2016/7/7
Y1 - 2016/7/7
N2 - 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.
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.
KW - Journal Article
U2 - 10.1016/j.ajhg.2016.05.007
DO - 10.1016/j.ajhg.2016.05.007
M3 - Journal article
C2 - 27346685
VL - 99
SP - 8
EP - 21
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -
