{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T20:03:00Z","timestamp":1776542580037,"version":"3.51.2"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome","doi-asserted-by":"publisher","award":["212360\/Z\/18\/Z"],"award-info":[{"award-number":["212360\/Z\/18\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["ERC-2011-StG 280559-SEPI"],"award-info":[{"award-number":["ERC-2011-StG 280559-SEPI"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u00d7\u2009depth 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 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20095\u2009\u00d7\u200910<jats:sup>\u20139<\/jats:sup>) of five rare non-coding variants with alleles conferring effects of 1.44\u20132.63 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&gt;A) (rs35004220). In the Pomak population, c.364C&gt;A (\u201cHbO-Arab\u201d, 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&gt;C) compared to other b+\u2009mutations. Overall, we uncover allelic diversity of <jats:italic>HBB<\/jats:italic> in Greek isolated populations and find an important role for additional rare variants outside of <jats:italic>HBB<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/s41598-021-04436-9","type":"journal-article","created":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T11:02:41Z","timestamp":1642762961000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Insights into the genetic architecture of haematological traits from deep phenotyping and whole-genome sequencing for two Mediterranean isolated populations"],"prefix":"10.1038","volume":"12","author":[{"given":"Karoline","family":"Kuchenbaecker","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur","family":"Gilly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Suveges","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorraine","family":"Southam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Giannakopoulou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britt","family":"Kilian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanouil","family":"Tsafantakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Karaleftheri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aliki-Eleni","family":"Farmaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepti","family":"Gurdasani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kousik","family":"Kundu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manjinder S.","family":"Sandhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Danesh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Butterworth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00eas","family":"Barroso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Dedoussis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleftheria","family":"Zeggini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"4436_CR1","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1016\/j.cell.2016.10.042","volume":"167","author":"WJ Astle","year":"2016","unstructured":"Astle, W. J. et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 167, 1415-1429.e19. https:\/\/doi.org\/10.1016\/j.cell.2016.10.042 (2016).","journal-title":"Cell"},{"key":"4436_CR2","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/s41588-018-0047-6","volume":"50","author":"M Kanai","year":"2018","unstructured":"Kanai, M. et al. Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat. Genet. 50, 390\u2013400. https:\/\/doi.org\/10.1038\/s41588-018-0047-6 (2018).","journal-title":"Nat. Genet."},{"key":"4436_CR3","doi-asserted-by":"publisher","first-page":"6944","DOI":"10.1093\/hmg\/ddu401","volume":"23","author":"MF Keller","year":"2014","unstructured":"Keller, M. F. et al. Trans-ethnic meta-analysis of white blood cell phenotypes. Hum. Mol. Genet. 23, 6944\u20136960. https:\/\/doi.org\/10.1093\/hmg\/ddu401 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"4436_CR4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002108","volume":"7","author":"AP Reiner","year":"2011","unstructured":"Reiner, A. P. et al. Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT). PLoS Genet. 7, e1002108. https:\/\/doi.org\/10.1371\/journal.pgen.1002108 (2011).","journal-title":"PLoS Genet."},{"key":"4436_CR5","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1093\/hmg\/ddx024","volume":"26","author":"D Jain","year":"2017","unstructured":"Jain, D. et al. Genome-wide association of white blood cell counts in Hispanic\/Latino Americans: the Hispanic Community Health Study\/Study of Latinos. Hum. Mol. Genet. 26, 1193\u20131204. https:\/\/doi.org\/10.1093\/hmg\/ddx024 (2017).","journal-title":"Hum. Mol. Genet."},{"key":"4436_CR6","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1038\/ng.3607","volume":"48","author":"CHARGE Consortium Hematology Working Group","year":"2016","unstructured":"CHARGE Consortium Hematology Working Group. Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. Nat. Genet. 48, 867\u2013876. https:\/\/doi.org\/10.1038\/ng.3607 (2016).","journal-title":"Nat. Genet."},{"key":"4436_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002113","volume":"7","author":"MA Nalls","year":"2011","unstructured":"Nalls, M. A. et al. Multiple loci are associated with white blood cell phenotypes. PLoS Genet. 7, e1002113. https:\/\/doi.org\/10.1371\/journal.pgen.1002113 (2011).","journal-title":"PLoS Genet."},{"key":"4436_CR8","doi-asserted-by":"publisher","first-page":"4331","DOI":"10.1182\/blood-2010-01-251348","volume":"115","author":"DJ Weatherall","year":"2010","unstructured":"Weatherall, D. J. The inherited diseases of hemoglobin are an emerging global health burden. Blood 115, 4331\u20134336. https:\/\/doi.org\/10.1182\/blood-2010-01-251348 (2010).","journal-title":"Blood"},{"key":"4436_CR9","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a011692","author":"TN Williams","year":"2012","unstructured":"Williams, T. N. & Weatherall, D. J. World Distribution, Population Genetics, and Health Burden of the Hemoglobinopathies. Cold Spring Harb. Perspect. Med. https:\/\/doi.org\/10.1101\/cshperspect.a011692 (2012).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"4436_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0950-3536(98)80069-3","volume":"11","author":"J Flint","year":"1998","unstructured":"Flint, J., Harding, R. M., Boyce, A. J. & Clegg, J. B. The population genetics of the haemoglobinopathies. Baillieres Clin. Haematol. 11, 1\u201351 (1998).","journal-title":"Baillieres Clin. Haematol."},{"key":"4436_CR11","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/S0140-6736(11)60283-3","volume":"379","author":"DR Higgs","year":"2012","unstructured":"Higgs, D. R., Engel, J. D. & Stamatoyannopoulos, G. Thalassaemia. Lancet 379, 373\u2013383. https:\/\/doi.org\/10.1016\/S0140-6736(11)60283-3 (2012).","journal-title":"Lancet"},{"key":"4436_CR12","doi-asserted-by":"publisher","first-page":"D537","DOI":"10.1093\/nar\/gkh006","volume":"32","author":"GP Patrinos","year":"2004","unstructured":"Patrinos, G. P. et al. Improvements in the HbVar database of human hemoglobin variants and thalassemia mutations for population and sequence variation studies. Nucleic Acids Res. 32, D537-541. https:\/\/doi.org\/10.1093\/nar\/gkh006 (2004).","journal-title":"Nucleic Acids Res."},{"key":"4436_CR13","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1056\/NEJMra050436","volume":"353","author":"D Rund","year":"2005","unstructured":"Rund, D. & Rachmilewitz, E. \u03b2-Thalassemia. N. Engl. J. Med. 353, 1135\u20131146. https:\/\/doi.org\/10.1056\/NEJMra050436 (2005).","journal-title":"N. Engl. J. Med."},{"key":"4436_CR14","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1093\/bfgp\/elu022","volume":"13","author":"K Hatzikotoulas","year":"2014","unstructured":"Hatzikotoulas, K., Gilly, A. & Zeggini, E. Using population isolates in genetic association studies. Brief Funct. Genomics. 13, 371\u2013377. https:\/\/doi.org\/10.1093\/bfgp\/elu022 (2014).","journal-title":"Brief Funct. Genomics."},{"key":"4436_CR15","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1017\/S1368980016003207","volume":"20","author":"A-E Farmaki","year":"2017","unstructured":"Farmaki, A.-E. et al. The mountainous Cretan dietary patterns and their relationship with cardiovascular risk factors: the Hellenic Isolated Cohorts MANOLIS study. Public Health Nutr. 20, 1063\u20131074. https:\/\/doi.org\/10.1017\/S1368980016003207 (2017).","journal-title":"Public Health Nutr."},{"key":"4436_CR16","doi-asserted-by":"publisher","first-page":"5345","DOI":"10.1038\/ncomms6345","volume":"5","author":"K Panoutsopoulou","year":"2014","unstructured":"Panoutsopoulou, K. et al. Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants. Nat. Commun. 5, 5345. https:\/\/doi.org\/10.1038\/ncomms6345 (2014).","journal-title":"Nat. Commun."},{"key":"4436_CR17","doi-asserted-by":"publisher","first-page":"15606","DOI":"10.1038\/ncomms15606","volume":"8","author":"L Southam","year":"2017","unstructured":"Southam, L. et al. Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits. Nat. Commun. 8, 15606. https:\/\/doi.org\/10.1038\/ncomms15606 (2017).","journal-title":"Nat. Commun."},{"key":"4436_CR18","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1093\/nar\/29.1.308","volume":"29","author":"ST Sherry","year":"2001","unstructured":"Sherry, S. T. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29, 308\u2013311. https:\/\/doi.org\/10.1093\/nar\/29.1.308 (2001).","journal-title":"Nucleic Acids Res."},{"key":"4436_CR19","first-page":"255","volume":"90","author":"V Papadopoulos","year":"2005","unstructured":"Papadopoulos, V. et al. HbO-Arab mutation originated in the Pomak population of Greek Thrace. Haematologica 90, 255\u2013257 (2005).","journal-title":"Haematologica"},{"key":"4436_CR20","unstructured":"Papadopoulos V, Vassiliadou D, Xanthopoulidis G, Petridis D, Agorasti A, Loukopoulos D. The implications of haemoglobin O-Arab mutation. Haema. 2003;6."},{"key":"4436_CR21","doi-asserted-by":"publisher","unstructured":"Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, Stitziel NO, Stirrups KE, Masca NGD, Erdmann J, Ferrario PG, et al. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. N Engl J Med. 2016;374: 1134\u20131144. https:\/\/doi.org\/10.1056\/NEJMoa1507652","DOI":"10.1056\/NEJMoa1507652"},{"key":"4436_CR22","doi-asserted-by":"publisher","first-page":"144","DOI":"10.17305\/bjbms.2014.3.43","volume":"14","author":"A Sa\u0142acka","year":"2014","unstructured":"Sa\u0142acka, A. et al. Possible association of ABCB1:c.3435T>C polymorphism with high-density-lipoprotein-cholesterol response to statin treatment-a pilot study. Bosn. J. Basic Med. Sci. 14, 144\u2013149. https:\/\/doi.org\/10.17305\/bjbms.2014.3.43 (2014).","journal-title":"Bosn. J. Basic Med. Sci."},{"key":"4436_CR23","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1089\/gtmb.2014.0065","volume":"18","author":"Q Wang","year":"2014","unstructured":"Wang, Q. et al. ABCB1 C3435T polymorphism and the risk of ischemic heart disease: a meta-analysis. Genet. Test Mol. Biomark. 18, 636\u2013645. https:\/\/doi.org\/10.1089\/gtmb.2014.0065 (2014).","journal-title":"Genet. Test Mol. Biomark."},{"key":"4436_CR24","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1186\/s12944-018-0926-y","volume":"17","author":"S Antwi-Baffour","year":"2018","unstructured":"Antwi-Baffour, S., Kyeremeh, R., Boateng, S. O., Annison, L. & Seidu, M. A. Haematological parameters and lipid profile abnormalities among patients with Type-2 diabetes mellitus in Ghana. Lipids Health Dis. 17, 283. https:\/\/doi.org\/10.1186\/s12944-018-0926-y (2018).","journal-title":"Lipids Health Dis."},{"key":"4436_CR25","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.ajhg.2015.06.007","volume":"97","author":"G Kichaev","year":"2015","unstructured":"Kichaev, G. & Pasaniuc, B. Leveraging functional-annotation data in trans-ethnic fine-mapping studies. Am. J. Hum. Genet. 97, 260\u2013271. https:\/\/doi.org\/10.1016\/j.ajhg.2015.06.007 (2015).","journal-title":"Am. J. Hum. Genet."},{"key":"4436_CR26","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1038\/s41588-019-0494-8","volume":"51","author":"I Jung","year":"2019","unstructured":"Jung, I. et al. A compendium of promoter-centered long-range chromatin interactions in the human genome. Nat. Genet. 51, 1442\u20131449. https:\/\/doi.org\/10.1038\/s41588-019-0494-8 (2019).","journal-title":"Nat. Genet."},{"key":"4436_CR27","doi-asserted-by":"publisher","first-page":"19836","DOI":"10.1073\/pnas.0906268106","volume":"106","author":"BM Steele","year":"2009","unstructured":"Steele, B. M. et al. Canonical Wnt signaling negatively regulates platelet function. Proc. Natl. Acad. Sci. USA 106, 19836\u201319841. https:\/\/doi.org\/10.1073\/pnas.0906268106 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"4436_CR28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-3768.2011.4451.x","author":"A Gardin","year":"2011","unstructured":"Gardin, A. & White, J. The sanger mouse genetics programme: High throughput characterisation of knockout mice. Acta Ophthalmol. (Copenh.). https:\/\/doi.org\/10.1111\/j.1755-3768.2011.4451.x (2011).","journal-title":"Acta Ophthalmol. (Copenh.)."},{"key":"4436_CR29","doi-asserted-by":"publisher","unstructured":"The UK10K Consortium. The UK10K project identifies rare variants in health and disease. Nature. 2015;526: 82\u201390. https:\/\/doi.org\/10.1038\/nature14962","DOI":"10.1038\/nature14962"},{"key":"4436_CR30","doi-asserted-by":"publisher","first-page":"4330","DOI":"10.1038\/s41467-019-12026-7","volume":"10","author":"K Kuchenbaecker","year":"2019","unstructured":"Kuchenbaecker, K. et al. The transferability of lipid loci across African, Asian and European cohorts. Nat. Commun. 10, 4330. https:\/\/doi.org\/10.1038\/s41467-019-12026-7 (2019).","journal-title":"Nat. Commun."},{"key":"4436_CR31","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.bcmd.2007.11.003","volume":"40","author":"M Boussiou","year":"2008","unstructured":"Boussiou, M. et al. The molecular heterogeneity of beta-thalassemia in Greece. Blood Cells Mol. Dis. 40, 317\u2013319. https:\/\/doi.org\/10.1016\/j.bcmd.2007.11.003 (2008).","journal-title":"Blood Cells Mol. Dis."},{"key":"4436_CR32","first-page":"46","volume":"40","author":"D Vassiliadou","year":"1998","unstructured":"Vassiliadou, D., Papadopoulos, V., Konstantinidou, C. & Arnaoutoglou, M. HbOThrace trait, HbOThrace hemoglobinopathy and HbOThrace\/Hb beta zero hemoglobinopathy: a retrospective study of 118 cases. Folia. Med. (Plovdiv). 40, 46\u201350 (1998).","journal-title":"Folia. Med. (Plovdiv)."},{"key":"4436_CR33","doi-asserted-by":"publisher","first-page":"501","DOI":"10.3109\/03630268108991827","volume":"5","author":"SK Ballas","year":"1981","unstructured":"Ballas, S. K., Embi, K., Goshar, D. & Burka, E. R. Binding of beta S, beta C and beta O Arab globins to the erythrocyte membrane. Hemoglobin 5, 501\u2013505 (1981).","journal-title":"Hemoglobin"},{"key":"4436_CR34","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1038\/jhh.2013.102","volume":"28","author":"AI Triantafyllou","year":"2014","unstructured":"Triantafyllou, A. I. et al. Impact of \u03b2-thalassemia trait carrier state on cardiovascular risk factors and metabolic profile in patients with newly diagnosed hypertension. J. Hum. Hypertens. 28, 328\u2013332. https:\/\/doi.org\/10.1038\/jhh.2013.102 (2014).","journal-title":"J. Hum. Hypertens."},{"key":"4436_CR35","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1016\/S0140-6736(63)92478-4","volume":"1","author":"P Fessas","year":"1963","unstructured":"Fessas, P., Stamatoyannopoulos, G. & Keys, A. Serum-cholesterol and thalassemia trait. Lancet Lond Engl. 1, 1182\u20131183 (1963).","journal-title":"Lancet Lond Engl."},{"key":"4436_CR36","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/0021-9150(89)90182-2","volume":"75","author":"M Maioli","year":"1989","unstructured":"Maioli, M. et al. Plasma lipids in beta-thalassemia minor. Atherosclerosis 75, 245\u2013248 (1989).","journal-title":"Atherosclerosis"},{"key":"4436_CR37","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1111\/j.1365-2796.1991.tb00416.x","volume":"230","author":"M Gallerani","year":"1991","unstructured":"Gallerani, M. et al. Thalassaemia trait and myocardial infarction: low infarction incidence in male subjects confirmed. J. Intern. Med. 230, 109\u2013111 (1991).","journal-title":"J. Intern. Med."},{"key":"4436_CR38","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1159\/000205887","volume":"78","author":"JP Crowley","year":"1987","unstructured":"Crowley, J. P., Sheth, S., Capone, R. J. & Schilling, R. F. A paucity of thalassemia trait in Italian men with myocardial infarction. Acta Haematol. 78, 249\u2013251. https:\/\/doi.org\/10.1159\/000205887 (1987).","journal-title":"Acta Haematol."},{"key":"4436_CR39","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/ajh.2830490112","volume":"49","author":"CH Wang","year":"1995","unstructured":"Wang, C. H. & Schilling, R. F. Myocardial infarction and thalassemia trait: an example of heterozygote advantage. Am. J. Hematol. 49, 73\u201375 (1995).","journal-title":"Am. J. Hematol."},{"key":"4436_CR40","first-page":"199","volume":"26","author":"T Tassiopoulos","year":"1995","unstructured":"Tassiopoulos, T., Stamatelos, G., Zakopoulos, N., Fessas, P. & Eliopoulos, G. D. Low incidence of acute myocardial infarction in beta-thalassaemia trait carriers. Haematologia (Budap). 26, 199\u2013203 (1995).","journal-title":"Haematologia (Budap)."},{"key":"4436_CR41","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/S0306-9877(02)00264-5","volume":"59","author":"MR Namazi","year":"2002","unstructured":"Namazi, M. R. Minor thalassemia as a protective factor against cerebrovascular accidents. Med. Hypotheses. 59, 361\u2013362 (2002).","journal-title":"Med. Hypotheses."},{"key":"4436_CR42","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1038\/ng.3977","volume":"49","author":"DJ Liu","year":"2017","unstructured":"Liu, D. J. et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 49, 1758. https:\/\/doi.org\/10.1038\/ng.3977 (2017).","journal-title":"Nat. Genet."},{"key":"4436_CR43","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1017\/S0016672300014634","volume":"23","author":"JM Smith","year":"1974","unstructured":"Smith, J. M. & Haigh, J. The hitch-hiking effect of a favourable gene. Genet. Res. 23, 23\u201335 (1974).","journal-title":"Genet. Res."},{"key":"4436_CR44","unstructured":"R Core Team. R: A language and environment for statistical computing. 2021. Available: https:\/\/www.R-project.org\/"},{"key":"4436_CR45","doi-asserted-by":"publisher","first-page":"4674","DOI":"10.1038\/s41467-018-07070-8","volume":"9","author":"A Gilly","year":"2018","unstructured":"Gilly, A. et al. Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits. Nat. Commun. 9, 4674. https:\/\/doi.org\/10.1038\/s41467-018-07070-8 (2018).","journal-title":"Nat. Commun."},{"key":"4436_CR46","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1038\/ng.2310","volume":"44","author":"X Zhou","year":"2012","unstructured":"Zhou, X. & Stephens, M. Genome-wide efficient mixed-model analysis for association studies. Nat. Genet. 44, 821\u2013824. https:\/\/doi.org\/10.1038\/ng.2310 (2012).","journal-title":"Nat. Genet."},{"key":"4436_CR47","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell, S. et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559\u2013575. https:\/\/doi.org\/10.1086\/519795 (2007).","journal-title":"Am. J. Hum. Genet."},{"key":"4436_CR48","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1002\/gepi.20504","volume":"34","author":"MS Udler","year":"2010","unstructured":"Udler, M. S., Tyrer, J. & Easton, D. F. Evaluating the power to discriminate between highly correlated SNPs in genetic association studies. Genet. Epidemiol. 34, 463\u2013468. https:\/\/doi.org\/10.1002\/gepi.20504 (2010).","journal-title":"Genet. Epidemiol."},{"key":"4436_CR49","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","volume":"8","author":"K Watanabe","year":"2017","unstructured":"Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826. https:\/\/doi.org\/10.1038\/s41467-017-01261-5 (2017).","journal-title":"Nat. Commun."},{"key":"4436_CR50","doi-asserted-by":"publisher","first-page":"D710","DOI":"10.1093\/nar\/gkv1157","volume":"44","author":"A Yates","year":"2016","unstructured":"Yates, A. et al. Ensembl 2016. Nucleic Acids Res. 44, D710-716. https:\/\/doi.org\/10.1093\/nar\/gkv1157 (2016).","journal-title":"Nucleic Acids Res."},{"key":"4436_CR51","doi-asserted-by":"publisher","first-page":"D930","DOI":"10.1093\/nar\/gkr917","volume":"40","author":"LD Ward","year":"2012","unstructured":"Ward, L. D. & Kellis, M. HaploReg: A resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930-934. https:\/\/doi.org\/10.1093\/nar\/gkr917 (2012).","journal-title":"Nucleic Acids Res."},{"key":"4436_CR52","doi-asserted-by":"publisher","first-page":"D1056","DOI":"10.1093\/nar\/gky1133","volume":"47","author":"D Carvalho-Silva","year":"2019","unstructured":"Carvalho-Silva, D. et al. Open Targets Platform: New developments and updates two years on. Nucleic Acids Res. 47, D1056\u2013D1065. https:\/\/doi.org\/10.1093\/nar\/gky1133 (2019).","journal-title":"Nucleic Acids Res."},{"key":"4436_CR53","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","volume":"46","author":"MJ Landrum","year":"2018","unstructured":"Landrum, M. J. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 46, D1062\u2013D1067. https:\/\/doi.org\/10.1093\/nar\/gkx1153 (2018).","journal-title":"Nucleic Acids Res."},{"key":"4436_CR54","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/j.ajhg.2012.06.007","volume":"91","author":"S Lee","year":"2012","unstructured":"Lee, S. et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am. J. Hum. Genet. 91, 224\u2013237. https:\/\/doi.org\/10.1016\/j.ajhg.2012.06.007 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"4436_CR55","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/gepi.21775","volume":"38","author":"D Jiang","year":"2014","unstructured":"Jiang, D. & McPeek, M. S. Robust rare variant association testing for quantitative traits in samples with related individuals. Genet Epidemiol. 38, 10\u201320. https:\/\/doi.org\/10.1002\/gepi.21775 (2014).","journal-title":"Genet Epidemiol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04436-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04436-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04436-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T21:24:52Z","timestamp":1669325092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-04436-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,21]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["4436"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-04436-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,21]]},"assertion":[{"value":"11 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1131"}}