New Results
An integrated platform to systematically identify causal variants and genes for polygenic human traits
View ORCID ProfileDamien J. Downes, View ORCID ProfileRon Schwessinger, Stephanie J. Hill, View ORCID ProfileLea Nussbaum, View ORCID ProfileCaroline Scott, View ORCID ProfileMatthew E. Gosden, Priscila P. Hirschfeld, View ORCID ProfileJelena M. Telenius, Chris Q. Eijsbouts, View ORCID ProfileSimon J. McGowan, View ORCID ProfileAntony J. Cutler, Jon Kerry, Jessica L. Davies, View ORCID ProfileCalliope A. Dendrou, View ORCID ProfileJamie R.J. Inshaw, Martin S.C. Larke, View ORCID ProfileA. Marieke Oudelaar, View ORCID ProfileYavor Bozhilov, Andrew J. King, Richard C. Brown, View ORCID ProfileMaria C. Suciu, View ORCID ProfileJames O.J. Davies, View ORCID ProfilePhilip Hublitz, Chris Fisher, Ryo Kurita, Yukio Nakamura, Gerton Lunter, View ORCID ProfileStephen Taylor, View ORCID ProfileVeronica J. Buckle, View ORCID ProfileJohn A. Todd, View ORCID ProfileDouglas R. Higgs, View ORCID ProfileJim R. Hughes
doi: https://doi.org/10.1101/813618
Damien J. Downes
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Ron Schwessinger
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Stephanie J. Hill
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Lea Nussbaum
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Caroline Scott
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Matthew E. Gosden
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Priscila P. Hirschfeld
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Jelena M. Telenius
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Chris Q. Eijsbouts
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
3Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK
4Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Simon J. McGowan
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Antony J. Cutler
4Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
5JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Jon Kerry
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Jessica L. Davies
6MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Calliope A. Dendrou
4Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
6MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Jamie R.J. Inshaw
5JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Martin S.C. Larke
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
A. Marieke Oudelaar
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Yavor Bozhilov
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Andrew J. King
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Richard C. Brown
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Maria C. Suciu
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
James O.J. Davies
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Philip Hublitz
7WIMM Genome Engineering Facility, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Chris Fisher
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Ryo Kurita
8Dept. of Research and Development, Central Blood Institute, Japanese Red Cross Society, Minato-ku, Tokyo, Japan
Yukio Nakamura
9Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Ibaraki, Japan
Gerton Lunter
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Stephen Taylor
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Veronica J. Buckle
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
John A. Todd
5JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Douglas R. Higgs
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
Jim R. Hughes
1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
2MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

ABSTRACT
Genome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is to identify disease-causing variants, the genes they affect, and the cells in which these effects occur. We have developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C and machine learning to address this challenge. Applying this approach to red blood cell traits identifies a significant proportion of known causative variants and their effector genes, which we show can be validated by direct in vivo modelling.
Footnotes
Extended version including all supplemental figures.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Posted January 15, 2020.
An integrated platform to systematically identify causal variants and genes for polygenic human traits
Damien J. Downes, Ron Schwessinger, Stephanie J. Hill, Lea Nussbaum, Caroline Scott, Matthew E. Gosden, Priscila P. Hirschfeld, Jelena M. Telenius, Chris Q. Eijsbouts, Simon J. McGowan, Antony J. Cutler, Jon Kerry, Jessica L. Davies, Calliope A. Dendrou, Jamie R.J. Inshaw, Martin S.C. Larke, A. Marieke Oudelaar, Yavor Bozhilov, Andrew J. King, Richard C. Brown, Maria C. Suciu, James O.J. Davies, Philip Hublitz, Chris Fisher, Ryo Kurita, Yukio Nakamura, Gerton Lunter, Stephen Taylor, Veronica J. Buckle, John A. Todd, Douglas R. Higgs, Jim R. Hughes
bioRxiv 813618; doi: https://doi.org/10.1101/813618
An integrated platform to systematically identify causal variants and genes for polygenic human traits
Damien J. Downes, Ron Schwessinger, Stephanie J. Hill, Lea Nussbaum, Caroline Scott, Matthew E. Gosden, Priscila P. Hirschfeld, Jelena M. Telenius, Chris Q. Eijsbouts, Simon J. McGowan, Antony J. Cutler, Jon Kerry, Jessica L. Davies, Calliope A. Dendrou, Jamie R.J. Inshaw, Martin S.C. Larke, A. Marieke Oudelaar, Yavor Bozhilov, Andrew J. King, Richard C. Brown, Maria C. Suciu, James O.J. Davies, Philip Hublitz, Chris Fisher, Ryo Kurita, Yukio Nakamura, Gerton Lunter, Stephen Taylor, Veronica J. Buckle, John A. Todd, Douglas R. Higgs, Jim R. Hughes
bioRxiv 813618; doi: https://doi.org/10.1101/813618
Subject Area
Subject Areas
- Biochemistry (13876)
- Bioengineering (10577)
- Bioinformatics (33610)
- Biophysics (17319)
- Cancer Biology (14384)
- Cell Biology (20375)
- Clinical Trials (138)
- Developmental Biology (10988)
- Ecology (16218)
- Epidemiology (2067)
- Evolutionary Biology (20524)
- Genetics (13520)
- Genomics (18814)
- Immunology (13944)
- Microbiology (32523)
- Molecular Biology (13533)
- Neuroscience (70891)
- Paleontology (533)
- Pathology (2222)
- Pharmacology and Toxicology (3779)
- Physiology (5959)
- Plant Biology (12161)
- Synthetic Biology (3403)
- Systems Biology (8242)
- Zoology (1871)