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

Kuchenbaecker, Karoline; Gilly, Arthur; Suveges, Daniel; Southam, Lorraine; Giannakopoulou, Olga; Kilian, Britt; Tsafantakis, Emmanouil; ... Zeggini, Eleftheria; + view all (2022) Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations. Scientific Reports , 12 (1) , Article 1131. 10.1038/s41598-021-04436-9. Green open access

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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.

Type: Article
Title: Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-021-04436-9
Publisher version: https://doi.org/10.1038/s41598-021-04436-9
Language: English
Additional information: © 2022 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Biomarkers, DNA sequencing, Genetic association study, Medical genomics, Next-generation sequencing, Quantitative trait
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10142757
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