Abstract
Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sexdifferential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
| Original language | English |
|---|---|
| Article number | 111 |
| Pages (from-to) | 1-20 |
| Number of pages | 20 |
| Journal | Wellcome Open Research |
| Volume | 5 |
| DOIs | |
| Publication status | E-pub ahead of print - 24 May 2021 |
Keywords
- expression
- genome-wide interaction study
- HHIP
- lung function
- sex
ASJC Scopus subject areas
- Medicine (miscellaneous)
- General Biochemistry,Genetics and Molecular Biology
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In: Wellcome Open Research, Vol. 5, 111, 24.05.2021, p. 1-20.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Variants associated with HHIP expression have sexdifferential effects on lung function
AU - Fawcett, Katherine A.
AU - Obeidat, Ma'en
AU - Melbourne, Carl
AU - Shrine, Nick
AU - Guyatt, Anna L.
AU - John, Catherine
AU - Luan, Jian'an
AU - Richmond, Anne
AU - Moksnes, Marta R.
AU - Granell, Raquel
AU - Weiss, Stefan
AU - Imboden, Medea
AU - May-Wilson, Sebastian
AU - Hysi, Pirro
AU - Boutin, Thibaud S.
AU - Portas, Laura
AU - Flexeder, Claudia
AU - Harris, Sarah E.
AU - Wang, Carol A.
AU - Lyytikäinen, Leo Pekka
AU - Palviainen, Teemu
AU - Foong, Rachel E.
AU - Keidel, Dirk
AU - Minelli, Cosetta
AU - Langenberg, Claudia
AU - Bossé, Yohan
AU - Berge, Maarten Van den
AU - Sin, Don D.
AU - Hao, Ke
AU - Campbell, Archie
AU - Porteous, David
AU - Padmanabhan, Sandosh
AU - Smith, Blair H.
AU - Evans, David M.
AU - Ring, Sue
AU - Langhammer, Arnulf
AU - Hveem, Kristian
AU - Willer, Cristen
AU - Ewert, Ralf
AU - Stubbe, Beate
AU - Pirastu, Nicola
AU - Klaric, Lucija
AU - Joshi, Peter K.
AU - Patasova, Karina
AU - Massimo, Mangino
AU - Polasek, Ozren
AU - Starr, John M.
AU - Karrasch, Stefan
AU - Strauch, Konstantin
AU - Meitinger, Thomas
AU - Rudan, Igor
AU - Rantanen, Taina
AU - Pietiläinen, Kirsi
AU - Kähönen, Mika
AU - Raitakari, Olli T.
AU - Hall, Graham L.
AU - Sly, Peter D.
AU - Pennell, Craig E.
AU - Kaprio, Jaakko
AU - Lehtimäki, Terho
AU - Vitart, Veronique
AU - Deary, Ian J.
AU - Jarvis, Debbie
AU - Wilson, James F.
AU - Spector, Tim
AU - Probst-Hensch, Nicole
AU - Wareham, Nicholas J.
AU - Völzke, Henry
AU - Henderson, John
AU - Strachan, David P.
AU - Brumpton, Ben M.
AU - Hayward, Caroline
AU - Hall, Ian P.
AU - Tobin, Martin D.
AU - Wain, Louise V.
N1 - Funding Information: the work of the authors and will serve as guarantors for the contents of this paper. CROATIA-Korcula/Split/Vis: MRC, University Unit Programme Grant (MC_PC_U127592696), European Union, EUROSPAN project (contract no. LSHG-CT-2006-018947), Croatian Ministry of Science (216-1080315-0302) (I.R.) ECRHS: This work was supported by a contract from the European Commission (018996), Fondo de Investigación Sanitaria (91/0016-060-05/E, 92/0319, 93/0393, 97/0035-01, 99/0034-01 and 99/0034-02), Hospital General de Albacete, Hospital General Ramón Jiménez, Consejería de Sanidad del Principado de Asturias, CIRIT (1997SGR 00079, 1999SGR 00241), and Servicio Andaluz de Salud, SEPAR, Public Health Service (R01 HL62633-01), RCESP (C03/09), Red RESPIRA (C03/011), Basque Health Department, Swiss National Science Foundation, Swiss Federal Office for Education and Science, Swiss National Accident Insurance Fund (SUVA), GSF-National Research Centre for Environment and Health, Deutsche Forschungsgemeinschaft (DFG) (FR 1526/1-1, MA 711/4-1), Programme Hospitalier de Recherche Clinique-DRC de Grenoble 2000 no. 2610, Ministry of Health, Direction de la Recherche Clinique, Ministere de l’Emploi et de la Solidarite, Direction Generale de la Sante, CHU de Grenoble, Comite des Maladies Respiratoires de l’Isere. UCB-Pharma (France), Aventis (France), Glaxo France. Estonian Science Foundation, and Asthma UK (formerly known as National Asthma Campaign UK). EPIC-Norfolk: Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048) Cancer Research UK (C864/A14136). FTC: Academy of Finland (308248, 312073) (J.K.), Sigrid Juselius Foundation (J.K.), Academy of Finland (213506 ) (T.R.), Academy of Finland (272376, 314383, 266286) (K.P.), Finnish Medical Foundation (K.P.), Novo Nordisk Foundation (K.P.), Finnish Diabetes Research Foundation (K.P.), State Research Funds (K.P.), University of Helsinki (K.P.) Generation Scotland: MRC, University Unit Programme Grant (MC_PC_U127592696), Wellcome Trust Strategic Award (104036), Chief Scientist Office (CZD/16/6), Scottish Funding Council (HR03006). HUNT: Stiftelsen Kristian Gerhard Jebsen (K.H.), The Liaison Committee for education, research and innovation in Central Norway (K.H., B.M.B.), NIH (HL135824, HL109946, HL127564) (C.W.): The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. B.M.B. received a research grant from the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. KORA: MC-Health, LMUinnovativ: The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. LBC1936: Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F019394/1), Age UK (The Disconnected Mind Project) (DCM and DCM PHASE 2), Cross Council Lifelong Health and Wellbeing Initiative (MR/K026992/1). ORCADES/VIKING: Chief Scientist Office (CZB/4/276, CZB/4/710) (J.F.W.), MRC (MC_UU_00007/10) (J.F.W.), MRC (MR/N013166/1) (S.M.), EU FP6 (LSHG-CT-2006-018947) (J.F.W.), Royal Society (URF to J.F.W.). The work of LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). The Raine Study: National Health and Medical Research Council of Australia (NHMRC) (572613, 403981, 003209), Canadian Institutes of Health Research (CIHR) (MOP-82893), Raine Medical Research Foundation. SAPALDIA: Swiss National Science Foundation (33CS30-148470/1&2, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPDP3_129021/1, PMPDP3_141671/1) (SAPALDIA1 to SAPALIDA5), Canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich, Federal Offices of Environment, of Public Health, and of Roads and Transport, Cantonal lung leages of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais, Graubünden and Zurich, Horizon 2020 (633212) (ALEC Project), European Commission (308610, 018996) (GABRIEL Project), Freie Akademische Gesellschaft (N.P.), UBS Wealth Foundation (N.P.), Wellcome Trust (084703) (GABRIEL Project), Talecris Biotherapeutics GmbH (N.P.), Abbott Diagnostics (N.P.) SHIP/SHIP_Trend/SHIP_Trend_B2: German Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), German Research Foundation (GR 1912/5-1) YFS: Academy of Finland (286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi)), Social Insurance Institution of Finland, Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals, Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation for Cardiovascular Research, Finnish Cultural Foundation, The Sigrid Juselius Foundation, Tampere Tuberculosis Foundation, Emil Aaltonen Foundation, Yrjö Jahnsson Foundation, Signe and Ane Gyllenberg Foundation, Diabetes Research Foundation of Finnish Diabetes Association, EU Horizon 2020 (755320 for TAXINOMISIS), European Research Council (742927 for MULTIEPIGEN), Tampere University Hospital Supporting Foundation. Funding Information: Visualization, Writing – Original Draft Preparation, Writing – Review & Editing; Obeidat M: Formal Analysis, Investigation, Resources, Visualization, Writing – Review & Editing; Melbourne C: Conceptualization, Methodology, Software, Writing – Original Draft Preparation, Writing – Review & Editing; Shrine N: Conceptualization, Data Curation, Methodology, Resources, Software, Writing – Original Draft Preparation, Writing – Review & Editing; Guyatt AL: Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing; John C: Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing; Luan J: Formal Analysis, Investigation, Writing – Review & Editing; Richmond A: Formal Analysis, Investigation, Writing – Review & Editing; Moksnes MR : Formal Analysis, Investigation, Writing – Review & Editing; Granell R: Formal Analysis, Investigation, Resources, Writing – Review & Editing; Weiss S: Formal Analysis, Investigation, Resources, Writing – Review & Editing; Imboden M: Conceptualization, Formal Analysis, Investigation, Resources, Writing – Review & Editing; May-Wilson S: Formal Analysis, Investigation, Writing – Review & Editing; Hysi P: Conceptualization, Resources, Writing – Review & Editing; Boutin TS: Formal Analysis, Investigation, Writing – Review & Editing; Portas L: Formal Analysis, Investigation, Writing – Review & Editing; Flexeder C: Formal Analysis, Investigation, Writing – Review & Editing; Harris SE: Formal Analysis, Investigation, Resources, Writing – Review & Editing; Wang CA: Formal Analysis, Investigation, Resources, Writing – Review & Editing; Lyytikäinen LP: Formal Analysis, Investigation, Resources, Writing – Review & Editing; Palviainen T: Formal Analysis, Investigation, Writing – Review & Editing; Foong RE: Formal Analysis, Investigation, Resources, Writing – Review & Editing; Keidel D: Formal Analysis, Investigation, Resources, Writing – Review & Editing; Minelli C: Resources, Writing – Review & Editing; Langenberg C: Conceptualization, Resources, Writing – Review & Editing; Bossé Y: Resources, Writing – Review & Editing; Van den Berge M: Formal Analysis, Investigation, Writing – Review & Editing; Sin DD: Conceptualization, Writing – Review & Editing; Hao K: Conceptualization, Writing – Review & Editing; Campbell A: Resources, Writing – Review & Editing; Porteous D: Resources, Writing – Review & Editing; Padmanabhan S: Resources, Writing – Review & Editing; Smith BH: Resources, Writing – Review & Editing; Evans DM: Resources, Writing – Review & Editing; Ring S: Resources, Writing – Review & Editing; Langhammer A: Resources, Writing – Review & Editing; Hveem K: Resources, Writing – Review & Editing; Willer C: Resources, Writing – Review & Editing; Ewert R: Conceptualization, Resources, Writing – Review & Editing; Stubbe B: Conceptualization, Resources, Writing – Review & Editing; Pirastu N: Formal Analysis, Investigation, Writing – Review & Editing; Klaric L: Resources, Writing – Review & Editing; Joshi PK: Resources, Writing – Review & Editing; Patasova K: Formal Analysis, Investigation, Writing – Review & Editing; Massimo M: Resources, Writing – Review & Editing; Polasek O: Conceptualization, Resources, Writing – Review & Editing; Starr JM: Conceptualization, Resources, Writing – Review & Editing; Karrasch S: Conceptualization, Resources, Writing – Review & Editing; Strauch K: Resources, Writing – Review & Editing; Meitinger T: Resources, Writing – Review & Editing; Rudan I: Conceptualization, Resources, Writing – Review & Editing; Rantanen T: Resources, Writing – Review & Editing; Pietiläinen K: Conceptualization, Resources, Writing – Review & Editing; Kähönen M: Conceptualization, Resources, Writing – Review & Editing; Raitakari OT: Conceptualization, Resources, Writing – Review & Editing; Hall GL: Conceptualization, Resources, Writing – Review & Editing; Sly PD: Conceptualization, Resources, Writing – Review & Editing; Pennell CE: Conceptualization, Resources, Writing – Review & Editing; Kaprio J: Conceptualization, Resources, Writing – Review & Editing; Lehtimäki T: Conceptualization, Resources, Writing – Review & Editing; Vitart V: Resources, Writing – Review & Editing; Deary IJ: Conceptualization, Resources, Writing – Review & Editing; Jarvis D: Resources, Writing – Review & Editing; Wilson JF: Conceptualization, Resources, Writing – Review & Editing; Spector T: Resources, Writing – Review & Editing; Probst-Hensch N: Conceptualization, Formal Analysis, Investigation, Resources, Writing – Review & Editing; Wareham NJ: Conceptualization, Formal Analysis, Investigation, Resources, Writing – Review & Editing; Völzke H: Conceptualization, Resources, Writing – Review & Editing; Henderson J: Resources, Writing – Review & Editing; Strachan DP: Conceptualization, Formal Analysis, Investigation, Resources, Writing – Review & Editing; Brumpton BM: Conceptualization, Formal Analysis, Investigation, Resources, Writing – Review & Editing; Hayward C: Conceptualization, Resources, Writing – Review & Editing; Hall IP: Conceptualization, Data Curation, Funding Acquisition, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing; Tobin MD: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing; Wain LV: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: The following authors report potential competing interests: L.V.W.: Louise V. Wain has received grant support from GSK. M.D.T.: Martin D. Tobin has received grant support from GSK. I.P.H.: Ian P. Hall has received support from GSK and BI. Funding Information: We gratefully acknowledge the contributions of co-authors Professor John M. Starr and Professor John Henderson, both of whom died prior to the publication of this manuscript. We thank UK Biobank and all the participants for generating this important health research resource. This study used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester. The ALSPAC study team are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The ECRHS study would like to thank the participants, field workers and researchers who have participated in the ECRHS study for their time and cooperation. The EPICNorfolk study team are grateful to all the participants who have been part of the EPIC-Norfolk project and to the many members of the study teams at the University of Cambridge who have enabled this research. Generation Scotland is grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. The HUNT study team are grateful for the contributions from He Zhang and Hyun Min Kang and would also like to acknowledge the support given to them by the Genotyping core and Jin Chen. We thank the LBC1936 participants and team members who contributed to this study. The ORCADES study would like to acknowledge the invaluable contributions of the research nurses in Shetland, the administrative team in Edinburgh and the people of Shetland. The VIKING study would like to acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. The Viking Health Study ? Shetland (VIKING) DNA extractions and genotyping were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. The Orkney Complex Disease Study (ORCADES) DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. The Raine study would like to acknowledge the continued contribution of Raine Study participants and their families, Raine Study team for cohort coordination and data collection, NHMRC for long term funding over last 30 years, The University of Western Australia, Curtin University, Women and Infants Research Foundation, Telethon Kids Institute, Edith Cowan University, Murdoch University, The University of Notre Dame Australia, and The Raine Medical Research Foundation for providing funding for Core Management of the Raine Study. The Raine study would also like to acknowledge The University of Western Australia (Division of Obstetrics and Gynaecology, King Edward Memorial Hospital and Medical School, Royal Perth Hospital), and Telethon Kids Institute for providing in-kind support for the storage and curation of biological samples, and Pawsey Supercomputing Centre with funding from Australian Government and the Government of Western Australia for providing computation resource to carry out analyses required. Funding Information: Grant information: This work was supported by the Wellcome Trust through a Wellcome Trust/BHF Fellowship awarded to A.L.G.; an Investigator Award awarded to M.D.T (202849); core support for ALSPAC (102215); a Strategic Award as support for Generation Scotland (104036); and GABRIEL project funding as support for SAPALDIA (084703). Sources of support: K.A.F. holds an Asthma UK fellowship. A.L.G. is supported by a Wellcome Trust/BHF fellowship. C.J. holds a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/P00167X/1). L.V.W. holds a GSK/British Lung Foundation Chair in Respiratory Research. M.D.T. is supported by a Wellcome Trust Investigator Award (202849). M.D.T. and L.V. Wain have been supported by the MRC (MR/N011317/1). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. I.P.H.: The research was partially supported by the NIHR Nottingham Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Study-specific sources of support: ALSPAC: The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); Lung function measurements at 24 years were specifically funded by MRC MR/M022501/1. This publication is Publisher Copyright: © 2021. Fawcett KA et al.
PY - 2021/5/24
Y1 - 2021/5/24
N2 - Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sexdifferential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
AB - Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sexdifferential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10-8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
KW - expression
KW - genome-wide interaction study
KW - HHIP
KW - lung function
KW - sex
UR - http://www.scopus.com/inward/record.url?scp=85117324479&partnerID=8YFLogxK
U2 - 10.12688/WELLCOMEOPENRES.15846.2
DO - 10.12688/WELLCOMEOPENRES.15846.2
M3 - Article
AN - SCOPUS:85117324479
SN - 2398-502X
VL - 5
SP - 1
EP - 20
JO - Wellcome Open Research
JF - Wellcome Open Research
M1 - 111
ER -