Imperial College London


Faculty of MedicineSchool of Public Health

Chair in Epidemiology and Public Health Medicine



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Miss Jennifer Wells +44 (0)20 7594 3328




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BibTex format

author = {Chami, N and Chen, MH and Slater, AJ and Eicher, JD and Evangelou, E and Tajuddin, SM and Love-Gregory, L and Kacprowski, T and Schick, UM and Nomura, A and Giri, A and Lessard, S and Brody, JA and Schurmann, C and Pankratz, N and Yanek, LR and Manichaikul, A and Pazoki, R and Mihailov, E and Hill, WD and Raffield, LM and Burt, A and Bartz, TM and Becker, DM and Becker, LC and Boerwinkle, E and Bork-Jensen, J and Bottinger, EP and O'Donoghue, ML and Crosslin, DR and de, Denus S and Dubé, MP and Elliott, P and Engström, G and Evans, MK and Floyd, JS and Fornage, M and Gao, H and Greinacher, A and Gudnason, V and Hansen, T and Harris, TB and Hayward, C and Hernesniemi, J and Highland, HM and Hirschhorn, JN and Hofman, A and Irvin, MR and Kähönen, M and Lange, E and Launer, LJ and Lehtimäki, T and Li, J and Liewald, DC and Linneberg, A and Liu, Y and Lu, Y and Lyytikäinen, LP and Mägi, R and Mathias, RA and Melander, O and Metspalu, A and Mononen, N and Nalls, MA and Nickerson, DA and Nik},
doi = {10.1016/j.ajhg.2016.05.007},
journal = {American Journal of Human Genetics},
pages = {8--21},
title = {Exome genotyping identifies pleiotropic variants associated with red blood cell traits},
url = {},
volume = {99},
year = {2016}

RIS format (EndNote, RefMan)

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.
AU - Chami,N
AU - Chen,MH
AU - Slater,AJ
AU - Eicher,JD
AU - Evangelou,E
AU - Tajuddin,SM
AU - Love-Gregory,L
AU - Kacprowski,T
AU - Schick,UM
AU - Nomura,A
AU - Giri,A
AU - Lessard,S
AU - Brody,JA
AU - Schurmann,C
AU - Pankratz,N
AU - Yanek,LR
AU - Manichaikul,A
AU - Pazoki,R
AU - Mihailov,E
AU - Hill,WD
AU - Raffield,LM
AU - Burt,A
AU - Bartz,TM
AU - Becker,DM
AU - Becker,LC
AU - Boerwinkle,E
AU - Bork-Jensen,J
AU - Bottinger,EP
AU - O'Donoghue,ML
AU - Crosslin,DR
AU - de,Denus S
AU - Dubé,MP
AU - Elliott,P
AU - Engström,G
AU - Evans,MK
AU - Floyd,JS
AU - Fornage,M
AU - Gao,H
AU - Greinacher,A
AU - Gudnason,V
AU - Hansen,T
AU - Harris,TB
AU - Hayward,C
AU - Hernesniemi,J
AU - Highland,HM
AU - Hirschhorn,JN
AU - Hofman,A
AU - Irvin,MR
AU - Kähönen,M
AU - Lange,E
AU - Launer,LJ
AU - Lehtimäki,T
AU - Li,J
AU - Liewald,DC
AU - Linneberg,A
AU - Liu,Y
AU - Lu,Y
AU - Lyytikäinen,LP
AU - Mägi,R
AU - Mathias,RA
AU - Melander,O
AU - Metspalu,A
AU - Mononen,N
AU - Nalls,MA
AU - Nickerson,DA
AU - Nikus,K
AU - O'Donnell,CJ
AU - Orho-Melander,M
AU - Pedersen,O
AU - Petersmann,A
AU - Polfus,L
AU - Psaty,BM
AU - Raitakari,OT
AU - Raitoharju,E
AU - Richard,M
AU - Rice,KM
AU - Rivadeneira,F
AU - Rotter,JI
AU - Schmidt,F
AU - Smith,AV
AU - Starr,JM
AU - Taylor,KD
AU - Teumer,A
AU - Thuesen,BH
AU - Torstenson,ES
AU - Tracy,RP
AU - Tzoulaki,I
AU - Zakai,NA
AU - Vacchi-Suzzi,C
AU - van,Duijn CM
AU - van,Rooij FJ
AU - Cushman,M
AU - Deary,IJ
AU - Velez,Edwards DR
AU - Vergnaud,AC
AU - Wallentin,L
AU - Waterworth,DM
AU - White,HD
AU - Wilson,JG
AU - Zonderman,AB
AU - Kathiresan,S
AU - Grarup,N
AU - Esko,T
AU - Loos,RJ
AU - Lange,LA
AU - Faraday,N
AU - Abumrad,NA
AU - Edwards,TL
AU - Ganesh,SK
AU - Auer,PL
AU - Johnson,AD
AU - Reiner,AP
AU - Lettre,G
DO - 10.1016/j.ajhg.2016.05.007
EP - 21
PY - 2016///
SN - 1537-6605
SP - 8
TI - Exome genotyping identifies pleiotropic variants associated with red blood cell traits
T2 - American Journal of Human Genetics
UR -
UR -
UR -
VL - 99
ER -