Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans.
Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.
Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom.
Stela
S
McLachlan
Department of Psychiatry, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, The Leon and Norma Hess Center for Science and Medicine, New York, New York, United States of America.
Claudia
C
Giambartolomei
University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, United Kingdom.
Jon
http://orcid.org/0000-0003-2666-561X
J
White
Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.|Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Pimphen
P
Charoen
MRC Unit for Lifelong Health and Ageing at UCL, London, United Kingdom.
Andrew
A
Wong
Institute of Cardiovascular Science, University College London, London, United Kingdom.
Chris
C
Finan
Genetic Epidemiology Group, Institute of Cardiovascular Science, University College London, London, United Kingdom.|Farr Institute of Health Informatics Research, Department of Epidemiology & Public Health, University College London, London, United Kingdom.
Jorgen
J
Engmann
Genetic Epidemiology Group, Institute of Cardiovascular Science, University College London, London, United Kingdom.
Tina
T
Shah
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Micha
M
Hersch
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Clara
http://orcid.org/0000-0002-2452-8067
C
Podmore
Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.|Population, Policy and Practice, UCL Institute of Child Health, University College London, London, United Kingdom.
Alana
A
Cavadino
Department of Primary Care & Population Health, UCL Institute of Epidemiology & Health Care, University College London, London, United Kingdom.
Barbara J
BJ
Jefferis
Farr Institute of Health Informatics Research, Department of Epidemiology & Public Health, University College London, London, United Kingdom.
Caroline E
CE
Dale
Population, Policy and Practice, UCL Institute of Child Health, University College London, London, United Kingdom.|Centre for Population Health Research, School of Health Sciences and Sansom Institute of Health Research, University of South Australia, Adelaide, Australia.|South Australian Health and Medical Research Institute, Adelaide, Australia.
Elina
E
Hypponen
Department of Primary Care & Population Health, UCL Institute of Epidemiology & Health Care, University College London, London, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
Richard W
RW
Morris
Institute of Health Informatics, University College London, London, United Kingdom.
Juan P
JP
Casas
Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom.|Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, United Kingdom.
Meena
M
Kumari
School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
Yoav
Y
Ben-Shlomo
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
Tom R
TR
Gaunt
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.|Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom.
Fotios
F
Drenos
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, United Kingdom.|Institute of Health Informatics, University College London, London, United Kingdom.
Claudia
C
Langenberg
MRC Unit for Lifelong Health and Ageing at UCL, London, United Kingdom.
Diana
D
Kuh
Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, United Kingdom.
Mika
M
Kivimaki
Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Rico
R
Rueedi
Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Gerard
G
Waeber
Institute of Cardiovascular Science, University College London, London, United Kingdom.|Farr Institute of Health Informatics Research, Department of Epidemiology & Public Health, University College London, London, United Kingdom.
Aroon D
AD
Hingorani
Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom.
Jacqueline F
JF
Price
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom.
Ann P
http://orcid.org/0000-0002-8485-3494
AP
Walker
D000017:ABO Blood-Group System / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004912:Erythrocytes / Q000502:physiology*; D005006:Ethnicity; D005060:Europe; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*
D000017:ABO Blood-Group System