Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans

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Abstract
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.
Funding Information
  • Medical Research Council (K013351)
  • Medical Research Council (G0500877)
  • Chief Scientist Office of Scotland (CZQ/1/38)
  • Pfizer plc (Unrestricted Investigator Led Grant)
  • British Heart Foundation (RG/10/12/28456)
  • Medical Research Council (G0000934)
  • Wellcome (068545/Z/02)
  • European Commission Framework Programme 6 (018996)
  • French Ministry of Research
  • British Heart Foundation (RG/08/013/25942)
  • British Heart Foundation (RG/13/16/30528)
  • British Heart Foundation
  • Department of Health Policy Research Programme
  • Medical Research Council
  • British Heart Foundation (RG/98002)
  • Chief Scientist Office of Scotland (CZB/4/672)
  • National Institute on Aging (AG1764406S1)
  • Diabetes UK (10/0003985)
  • Medical Research Council (MC_UU_12019/1)
  • British Heart Foundation (RG/07/008/23674)
  • Stroke Association
  • National Heart, Lung, and Blood Institute (5RO1 HL036310)
  • National Institute on Aging (5RO1AG13196)
  • Agency for Health Care Policy and Research (HS06516)
  • John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health
  • Swiss National Science Founda (33CSCO-122661)
  • GlaxoSmithKline
  • Faculty of Biology and Medicine of Lausanne, Switzerland

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