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The sequences of 150,119 genomes in the UK Biobank.

ABSTRACT: Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data^1,2. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank³. This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.

SUBMITTER: Halldorsson BV

PROVIDER: S-EPMC9329122 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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The sequences of 150,119 genomes in the UK Biobank.

Halldorsson Bjarni V BV Eggertsson Hannes P HP Moore Kristjan H S KHS Hauswedell Hannes H Eiriksson Ogmundur O Ulfarsson Magnus O MO Palsson Gunnar G Hardarson Marteinn T MT Oddsson Asmundur A Jensson Brynjar O BO Kristmundsdottir Snaedis S Sigurpalsdottir Brynja D BD Stefansson Olafur A OA Beyter Doruk D Holley Guillaume G Tragante Vinicius V Gylfason Arnaldur A Olason Pall I PI Zink Florian F Asgeirsdottir Margret M Sverrisson Sverrir T ST Sigurdsson Brynjar B Gudjonsson Sigurjon A SA Sigurdsson Gunnar T GT Halldorsson Gisli H GH Sveinbjornsson Gardar G Norland Kristjan K Styrkarsdottir Unnur U Magnusdottir Droplaug N DN Snorradottir Steinunn S Kristinsson Kari K Sobech Emilia E Jonsson Helgi H Geirsson Arni J AJ Olafsson Isleifur I Jonsson Palmi P Pedersen Ole Birger OB Erikstrup Christian C Brunak Søren S Ostrowski Sisse Rye SR Thorleifsson Gudmar G Jonsson Frosti F Melsted Pall P Jonsdottir Ingileif I Rafnar Thorunn T Holm Hilma H Stefansson Hreinn H Saemundsdottir Jona J Gudbjartsson Daniel F DF Magnusson Olafur T OT Masson Gisli G Thorsteinsdottir Unnur U Helgason Agnar A Jonsson Hakon H Sulem Patrick P Stefansson Kari K

Nature 20220720 7920

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data<sup>1,2</sup>. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank<sup>3</sup>. ...[more]

PMID: 35859178

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Project description:BackgroundLimited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF.MethodsWe analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes.ResultsWe detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p < 0.05].ConclusionsWe leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.

Dataset Information

The sequences of 150,119 genomes in the UK Biobank.

Publications

The sequences of 150,119 genomes in the UK Biobank.

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