Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations.
dc.contributor.author | Kuchenbaecker, K | |
dc.contributor.author | Gilly, A | |
dc.contributor.author | Suveges, D | |
dc.contributor.author | Southam, L | |
dc.contributor.author | Giannakopoulou, O | |
dc.contributor.author | Kilian, B | |
dc.contributor.author | Tsafantakis, E | |
dc.contributor.author | Karaleftheri, M | |
dc.contributor.author | Farmaki, A-E | |
dc.contributor.author | Gurdasani, D | |
dc.contributor.author | Kundu, K | |
dc.contributor.author | Sandhu, MS | |
dc.contributor.author | Danesh, J | |
dc.contributor.author | Butterworth, A | |
dc.contributor.author | Barroso, I | |
dc.contributor.author | Dedoussis, G | |
dc.contributor.author | Zeggini, E | |
dc.date.accessioned | 2022-01-28T09:08:44Z | |
dc.date.issued | 2022-01-21 | |
dc.date.updated | 2022-01-27T16:10:52Z | |
dc.description.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. | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.description.sponsorship | European Research Council | en_GB |
dc.format.extent | 1131- | |
dc.identifier.citation | Vol. 12, article 1131 | en_GB |
dc.identifier.doi | https://doi.org/10.1038/s41598-021-04436-9 | |
dc.identifier.grantnumber | WT098051 | en_GB |
dc.identifier.grantnumber | ERC-2011-StG 280559-SEPI | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/128627 | |
dc.identifier | ORCID: 0000-0001-5800-4520 (Barroso, Inês) | |
dc.language.iso | en | en_GB |
dc.publisher | Nature Research | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/35064169 | en_GB |
dc.relation.url | https://www.ebi.ac.uk/ega/home | en_GB |
dc.rights | © The Author(s) 2022. Open Access Tis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. | en_GB |
dc.subject | Biomarkers | en_GB |
dc.subject | DNA sequencing | en_GB |
dc.subject | Genetic association study | en_GB |
dc.subject | Medical genomics | en_GB |
dc.subject | Next-generation sequencing | en_GB |
dc.subject | Quantitative trait | en_GB |
dc.title | Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2022-01-28T09:08:44Z | |
dc.identifier.issn | 2045-2322 | |
exeter.article-number | 1131 | |
exeter.place-of-publication | England | |
dc.description | This is the final version. Available from Nature Research via the DOI in this record. | en_GB |
dc.description | The data generated and/or analysed during the current study (i.e. the HELIC genotype and WGS datasets) are available on the the European Genome-phenome Archive (https://www.ebi.ac.uk/ega/home): EGAD00010000518; EGAD00010000522; EGAD00010000610; EGAD00001001636, EGAD00001001637. | en_GB |
dc.identifier.eissn | 2045-2322 | |
dc.identifier.journal | Scientific Reports | en_GB |
dc.relation.ispartof | Sci Rep, 12(1) | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2021-12-06 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2022-01-21 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2022-01-28T09:01:53Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2022-01-28T09:08:50Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2022-01-21 |
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the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.