{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:26:34Z","timestamp":1789986394178,"version":"4.0.1"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2018,12,21]],"date-time":"2018-12-21T00:00:00Z","timestamp":1545350400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["098051"],"award-info":[{"award-number":["098051"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","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\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT091310"],"award-info":[{"award-number":["WT091310"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Very low-depth sequencing has been proposed as a cost-effective approach to capture low-frequency and rare variation in complex trait association studies. However, a full characterization of the genotype quality and association power for very low-depth sequencing designs is still lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We perform cohort-wide whole-genome sequencing (WGS) at low depth in 1239 individuals (990 at 1\u00d7 depth and 249 at 4\u00d7 depth) from an isolated population, and establish a robust pipeline for calling and imputing very low-depth WGS genotypes from standard bioinformatics tools. Using genotyping chip, whole-exome sequencing (75\u00d7 depth) and high-depth (22\u00d7) WGS data in the same samples, we examine in detail the sensitivity of this approach, and show that imputed 1\u00d7 WGS recapitulates 95.2% of variants found by imputed GWAS with an average minor allele concordance of 97% for common and low-frequency variants. In our study, 1\u00d7 further allowed the discovery of 140\u00a0844 true low-frequency variants with 73% genotype concordance when compared to high-depth WGS data. Finally, using association results for 57 quantitative traits, we show that very low-depth WGS is an efficient alternative to imputed GWAS chip designs, allowing the discovery of up to twice as many true association signals than the classical imputed GWAS design.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The HELIC genotype and WGS datasets have been deposited to the European Genome-phenome Archive (https:\/\/www.ebi.ac.uk\/ega\/home): EGAD00010000518; EGAD00010000522; EGAD00010000610; EGAD00001001636, EGAD00001001637. The peakplotter software is available at https:\/\/github.com\/wtsi-team144\/peakplotter, the transformPhenotype app can be downloaded at https:\/\/github.com\/wtsi-team144\/transformPhenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty1032","type":"journal-article","created":{"date-parts":[[2018,12,17]],"date-time":"2018-12-17T21:45:11Z","timestamp":1545083111000},"page":"2555-2561","source":"Crossref","is-referenced-by-count":90,"title":["Very low-depth whole-genome sequencing in complex trait association studies"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-4358","authenticated-orcid":false,"given":"Arthur","family":"Gilly","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"},{"name":"Institute of Translational Genomics, Helmholtz Zentrum M\u00fcnchen \u2013 German Research Center for Environmental Health, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Southam","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"},{"name":"Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Suveges","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karoline","family":"Kuchenbaecker","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio E M","family":"Melloni","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Hatzikotoulas","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"},{"name":"Institute of Translational Genomics, Helmholtz Zentrum M\u00fcnchen \u2013 German Research Center for Environmental Health, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliki-Eleni","family":"Farmaki","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Ritchie","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"},{"name":"European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Schwartzentruber","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Danecek","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt","family":"Kilian","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8738-0920","authenticated-orcid":false,"given":"Martin O","family":"Pollard","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanouil","family":"Tsafantakis","sequence":"additional","affiliation":[{"name":"Anogia Medical Centre, Anogia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Dedoussis","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Zeggini","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK"},{"name":"Institute of Translational Genomics, Helmholtz Zentrum M\u00fcnchen \u2013 German Research Center for Environmental Health, Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,12,21]]},"reference":[{"key":"2023062713060643700_bty1032-B1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","year":"2015","journal-title":"Nature"},{"key":"2023062713060643700_bty1032-B2","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.1111\/mec.12105","article-title":"Population genomics based on low coverage sequencing: how low should we go?","volume":"22","author":"Alex Buerkle","year":"2013","journal-title":"Mol. Ecol"},{"key":"2023062713060643700_bty1032-B3","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1093\/bioinformatics\/btw576","article-title":"AKT: ancestry and kinship toolkit","volume":"33","author":"Arthur","year":"2017","journal-title":"Bioinformatics"},{"key":"2023062713060643700_bty1032-B4","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.cell.2016.10.042","article-title":"The allelic landscape of human blood cell trait variation and links to common complex disease","volume":"167","author":"Astle","year":"2016","journal-title":"Cell"},{"key":"2023062713060643700_bty1032-B5","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/ng.3968","article-title":"Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology","volume":"49","author":"Brody","year":"2017","journal-title":"Nat. Genet"},{"key":"2023062713060643700_bty1032-B6","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ajhg.2015.11.020","article-title":"Genotype Imputation with Millions of Reference Samples","volume":"98","author":"Browning","year":"2016","journal-title":"Am. J. Hum. Genet"},{"key":"2023062713060643700_bty1032-B7","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1086\/521987","article-title":"Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering","volume":"81","author":"Browning","year":"2007","journal-title":"Am. J. Hum. Genet"},{"key":"2023062713060643700_bty1032-B8","article-title":"Genome-wide genetic data on \u223c500, 000 UK Biobank participants","author":"Bycroft","year":"2017"},{"key":"2023062713060643700_bty1032-B9","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/nature14659","article-title":"Sparse whole-genome sequencing identifies two loci for major depressive disorder","volume":"523","year":"2015","journal-title":"Nature"},{"key":"2023062713060643700_bty1032-B10","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/ng.3594","article-title":"Rapid genotype imputation from sequence without reference panels","volume":"48","author":"Davies","year":"2016","journal-title":"Nat. Genet"},{"key":"2023062713060643700_bty1032-B11","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.ajhg.2013.09.002","article-title":"Haplotype estimation using sequencing reads","volume":"93","author":"Delaneau","year":"2013","journal-title":"Am. J. Hum. Genet"},{"key":"2023062713060643700_bty1032-B12","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1101\/gr.210500.116","article-title":"A reference data set of 5.4 million phased human variants validated by genetic inheritance from sequencing a three-generation 17-member pedigree","volume":"27","author":"Eberle","year":"2017","journal-title":"Genome Res"},{"key":"2023062713060643700_bty1032-B13","doi-asserted-by":"crossref","first-page":"2360","DOI":"10.1093\/hmg\/ddw088","article-title":"Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation","volume":"25","author":"Gilly","year":"2016","journal-title":"Hum. Mol. Genet"},{"key":"2023062713060643700_bty1032-B14","doi-asserted-by":"crossref","first-page":"4674","DOI":"10.1038\/s41467-018-07070-8","article-title":"Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits","volume":"9","author":"Gilly","year":"2018","journal-title":"Nat. Commun"},{"key":"2023062713060643700_bty1032-B16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1046\/j.1365-3016.2001.00325.x","article-title":"ALSPAC\u2013the Avon Longitudinal Study of Parents and Children. I. Study methodology","volume":"15","author":"Golding","year":"2001","journal-title":"Paediatr. Perinat. Epidemiol"},{"key":"2023062713060643700_bty1032-B17","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/gepi.22109","article-title":"Strategies for phasing and imputation in a population isolate","volume":"42","author":"Herzig","year":"2018","journal-title":"Genet. Epidemiol"},{"key":"2023062713060643700_bty1032-B18","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1534\/g3.111.001198","article-title":"Genotype imputation with thousands of genomes","volume":"1","author":"Howie","year":"2011","journal-title":"G3 (Bethesda)"},{"key":"2023062713060643700_bty1032-B19","doi-asserted-by":"crossref","first-page":"e1000529.","DOI":"10.1371\/journal.pgen.1000529","article-title":"A flexible and accurate genotype imputation method for the next generation of genome-wide association studies","volume":"5","author":"Howie","year":"2009","journal-title":"PLoS Genet"},{"key":"2023062713060643700_bty1032-B20","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1101\/gr.113084.110","article-title":"SNP detection and genotyping from low-coverage sequencing data on multiple diploid samples","volume":"21","author":"Le","year":"2011","journal-title":"Genome Res"},{"key":"2023062713060643700_bty1032-B21","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023062713060643700_bty1032-B22","doi-asserted-by":"crossref","first-page":"e1004139","DOI":"10.1371\/journal.pcbi.1004139","article-title":"PRIMAL: fast and accurate pedigree-based imputation from sequence data in a founder population","volume":"11","author":"Livne","year":"2015","journal-title":"PLoS Comput. Biol"},{"key":"2023062713060643700_bty1032-B23","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/ng.3643","article-title":"A reference panel of 64, 976 haplotypes for genotype imputation","volume":"48","author":"McCarthy","year":"2016","journal-title":"Nat. Genet"},{"key":"2023062713060643700_bty1032-B24","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res"},{"key":"2023062713060643700_bty1032-B25","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1017\/thg.2012.89","article-title":"The UK Adult Twin Registry (TwinsUK Resource)","volume":"16","author":"Moayyeri","year":"2013","journal-title":"Twin Res. Hum. Genet"},{"key":"2023062713060643700_bty1032-B26","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/ng.2283","article-title":"Extremely low-coverage sequencing and imputation increases power for genome-wide association studies","volume":"44","author":"Pasaniuc","year":"2012","journal-title":"Nat. Genet"},{"key":"2023062713060643700_bty1032-B27","doi-asserted-by":"crossref","first-page":"15606","DOI":"10.1038\/ncomms15606","article-title":"Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits","volume":"8","author":"Southam","year":"2017","journal-title":"Nat. Commun"},{"key":"2023062713060643700_bty1032-B29","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.ajhg.2017.04.014","article-title":"Whole-genome sequencing coupled to imputation discovers genetic signals for anthropometric traits","volume":"100","author":"Tachmazidou","year":"2017","journal-title":"Am. J. Hum. Genet"},{"key":"2023062713060643700_bty1032-B30","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/nature14962","article-title":"The UK10K project identifies rare variants in health and disease","volume":"526","year":"2015","journal-title":"Nature"},{"key":"2023062713060643700_bty1032-B31","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/ng.2310","article-title":"Genome-wide efficient mixed-model analysis for association studies","volume":"44","author":"Zhou","year":"2012","journal-title":"Nat. Genet"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/15\/2555\/50722570\/bioinformatics_35_15_2555.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/15\/2555\/50722570\/bioinformatics_35_15_2555.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T09:06:36Z","timestamp":1687856796000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/15\/2555\/5255875"}},"subtitle":[],"editor":[{"given":"John","family":"Hancock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2018,12,21]]},"references-count":29,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2019,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/bty1032","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/169789","asserted-by":"object"}]},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,8,1]]},"published":{"date-parts":[[2018,12,21]]}}}