Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations.
Authors
Kuchenbaecker, Karoline
Gilly, Arthur
Suveges, Daniel
Southam, Lorraine
Giannakopoulou, Olga
Kilian, Britt
Tsafantakis, Emmanouil
Karaleftheri, Maria
Farmaki, Aliki-Eleni
Gurdasani, Deepti
Kundu, Kousik
Sandhu, Manjinder S
Barroso, Inês
Dedoussis, George
Zeggini, Eleftheria
Publication Date
2022-01-21Journal Title
Sci Rep
ISSN
2045-2322
Publisher
Springer Science and Business Media LLC
Volume
12
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Kuchenbaecker, K., Gilly, A., Suveges, D., Southam, L., Giannakopoulou, O., Kilian, B., Tsafantakis, E., et al. (2022). Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations.. Sci Rep, 12 (1) https://doi.org/10.1038/s41598-021-04436-9
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.
Keywords
Article, /631/208/514/1948, /631/208/514/2254, /631/208/205, /631/208/212/2301, /631/208/480, /692/53, article
Sponsorship
European Research Council (ERC-2011-StG 280559-SEPI).
Funder references
Wellcome (212360/Z/18/Z)
European Research Council (ERC-2011-StG 280559-SEPI)
Identifiers
s41598-021-04436-9, 4436
External DOI: https://doi.org/10.1038/s41598-021-04436-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333223
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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