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Abstract
Haematological traits are linked to cardiovascular, metabolic, infectious and immune disorders, as well as cancer. Here, we examine the role of genetic variation in shaping haematological traits in two isolated Mediterranean populations. Using whole-genome sequencing data at 22× depth for 1457 individuals from Crete (MANOLIS) and 1617 from the Pomak villages in Greece, we carry out a genome-wide association scan for haematological traits using linear mixed models. We discover novel associations (p < 5 × 10–9) of five rare non-coding variants with alleles conferring effects of 1.44–2.63 units of standard deviation on red and white blood cell count, platelet and red cell distribution width. Moreover, 10.0% of individuals in the Pomak population and 6.8% in MANOLIS carry a pathogenic mutation in the Haemoglobin Subunit Beta (HBB) gene. The mutational spectrum is highly diverse (10 different mutations). The most frequent mutation in MANOLIS is the common Mediterranean variant IVS-I-110 (G>A) (rs35004220). In the Pomak population, c.364C>A (“HbO-Arab”, rs33946267) is most frequent (4.4% allele frequency). We demonstrate effects on haematological and other traits, including bilirubin, cholesterol, and, in MANOLIS, height and gestation age. We find less severe effects on red blood cell traits for HbS, HbO, and IVS-I-6 (T>C) compared to other b+ mutations. Overall, we uncover allelic diversity of HBB in Greek isolated populations and find an important role for additional rare variants outside of HBB.
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1 University College of London, Division of Psychiatry, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); UCL Genetics Institute, University College London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382)
2 Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Translational Genomics, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525)
3 Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382)
4 Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Translational Genomics, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948)
5 University College of London, Division of Psychiatry, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); UCL Genetics Institute, University College London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
6 Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, Cambridge Biomedical Campus, The Primary Care Unit, Institute of Public Health, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934)
7 Anogia Medical Centre, Anogia, Greece (GRID:grid.5335.0)
8 Echinos Medical Centre, Echinos, Xanthi, Greece (GRID:grid.5335.0)
9 Harokopio University of Athens, Department of Nutrition and Dietetics, School of Health Science and Education, Athens, Greece (GRID:grid.15823.3d) (ISNI:0000 0004 0622 2843); University College London, MRC Unit for Lifelong Health and Ageing, Institute of Cardiovascular Science, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
10 Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, Department of Haematology, Cambridge Biomedical Campus, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934)
11 University of Cambridge, Department of Medicine, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934)
12 Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Cambridge, The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, Wort’s Causeway, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Wort’s Causeway, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934)
13 University of Cambridge, The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, Wort’s Causeway, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Wort’s Causeway, Strangeways Research Laboratory, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); British Heart Foundation Centre of Excellence, Addenbrooke’s Hospital, Division of Cardiovascular Medicine, Cambridge, UK (GRID:grid.120073.7) (ISNI:0000 0004 0622 5016)
14 University of Exeter, Exeter Centre of Excellence for Diabetes Research (EXCEED), Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK (GRID:grid.8391.3) (ISNI:0000 0004 1936 8024)
15 Harokopio University of Athens, Department of Nutrition and Dietetics, School of Health Science and Education, Athens, Greece (GRID:grid.15823.3d) (ISNI:0000 0004 0622 2843)