Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations

Karoline Kuchenbaecker; Arthur Gilly; Daniel Suveges; Lorraine Southam; Olga Giannakopoulou; Britt Kilian; Emmanouil Tsafantakis; Maria Karaleftheri; Aliki-Eleni Farmaki; Deepti Gurdasani; Kousik Kundu; Manjinder S Sandhu; John Danesh; Adam Butterworth; Inês Barroso; George Dedoussis; Eleftheria Zeggini

doi:10.1038/s41598-021-04436-9

Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations

Sci Rep. 2022 Jan 21;12(1):1131. doi: 10.1038/s41598-021-04436-9.

Authors

Karoline Kuchenbaecker^{1

2

3}, Arthur Gilly^{4

5}, Daniel Suveges⁴, Lorraine Southam^{4

5

6}, Olga Giannakopoulou^{7

8}, Britt Kilian^{4

9}, Emmanouil Tsafantakis¹⁰, Maria Karaleftheri¹¹, Aliki-Eleni Farmaki^{12

13}, Deepti Gurdasani⁴, Kousik Kundu^{4

14}, Manjinder S Sandhu¹⁵, John Danesh^{4

16

17}, Adam Butterworth^{16

17

18}, Inês Barroso¹⁹, George Dedoussis¹², Eleftheria Zeggini^{4

5}

Affiliations

¹ Division of Psychiatry, University College of London, London, W1T 7NF, UK. k.kuchenbaecker@ucl.ac.uk.
² UCL Genetics Institute, University College London, London, WC1E 6BT, UK. k.kuchenbaecker@ucl.ac.uk.
³ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK. k.kuchenbaecker@ucl.ac.uk.
⁴ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.
⁵ Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
⁷ Division of Psychiatry, University College of London, London, W1T 7NF, UK.
⁸ UCL Genetics Institute, University College London, London, WC1E 6BT, UK.
⁹ The Primary Care Unit, Institute of Public Health, University of Cambridge, Cambridge Biomedical Campus, Box 113, Cambridge, CB2 0SR, UK.
¹⁰ Anogia Medical Centre, 740 51, Anogia, Greece.
¹¹ Echinos Medical Centre, 67300, Echinos, Xanthi, Greece.
¹² Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece.
¹³ MRC Unit for Lifelong Health and Ageing, Institute of Cardiovascular Science, University College London, London, WC1E 7HB, UK.
¹⁴ Department of Haematology, Cambridge Biomedical Campus, University of Cambridge, Long Road, Cambridge, CB2 0PT, UK.
¹⁵ Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.
¹⁶ 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, University of Cambridge, Cambridge, CB1 8RN, UK.
¹⁷ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Wort's Causeway, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK.
¹⁸ Division of Cardiovascular Medicine, British Heart Foundation Centre of Excellence, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
¹⁹ Exeter Centre of Excellence for Diabetes Research (EXCEED), Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

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.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
DNA Mutational Analysis
Erythrocyte Count
Erythrocyte Indices / genetics*
Gene Frequency
Genetic Variation
Genetics, Population*
Genome-Wide Association Study
Greece
Humans
Leukocyte Count
Mutation
Platelet Function Tests
Whole Genome Sequencing
beta-Globins / genetics*

Substances

beta-Globins

Abstract

Publication types

MeSH terms

Substances

Grants and funding