Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Laura J Corbin; Vanessa Y Tan; David A Hughes; Kaitlin H Wade; Dirk S Paul; Katherine E Tansey; Frances Butcher; Frank Dudbridge; Joanna M Howson; Momodou W Jallow; Catherine John; Nathalie Kingston; Cecilia M Lindgren; Michael O'Donavan; Stephen O'Rahilly; Michael J Owen; Colin N A Palmer; Ewan R Pearson; Robert A Scott; David A van Heel; John Whittaker; Tim Frayling; Martin D Tobin; Louise V Wain; George Davey Smith; David M Evans; Fredrik Karpe; Mark I McCarthy; John Danesh; Paul W Franks; Nicholas J Timpson

doi:10.1038/s41467-018-03109-y

Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference

Nat Commun. 2018 Feb 19;9(1):711. doi: 10.1038/s41467-018-03109-y.

Authors

Laura J Corbin^{1

2}, Vanessa Y Tan^{1

2}, David A Hughes^{1

2}, Kaitlin H Wade^{1

2}, Dirk S Paul^{3

4}, Katherine E Tansey⁵, Frances Butcher⁶, Frank Dudbridge⁷, Joanna M Howson³, Momodou W Jallow^{8

9}, Catherine John⁷, Nathalie Kingston¹⁰, Cecilia M Lindgren^{11

12

13

14}, Michael O'Donavan¹⁵, Stephen O'Rahilly¹⁶, Michael J Owen¹⁵, Colin N A Palmer¹⁷, Ewan R Pearson¹⁷, Robert A Scott¹⁸, David A van Heel¹⁹, John Whittaker^{8

20}, Tim Frayling²¹, Martin D Tobin^{7

22}, Louise V Wain^{7

22}, George Davey Smith^{1

2}, David M Evans^{1

2

23}, Fredrik Karpe^{24

25}, Mark I McCarthy^{12

24

25}, John Danesh^{3

4

26

27}, Paul W Franks^{24

28

29

30}, Nicholas J Timpson^{31

32}

Affiliations

¹ MRC Integrative Epidemiology Unit at University of Bristol, Bristol, BS8 2BN, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.
³ MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁴ British Heart Foundation (BHF) Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
⁵ Core Bioinformatics and Statistics Team, College of Biomedical & Life Sciences, Cardiff University, Cardiff, CF10 3XQ, UK.
⁶ Oxford School of Public Health, University of Oxford, Oxford, OX3 7LF, UK.
⁷ Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
⁸ Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
⁹ MRC Unit The Gambia (MRCG), Atlantic Boulevard, Fajara, P.O. Box 273, Banjul, Gambia.
¹⁰ National Institute for Health Research (NIHR) BioResource for Translational Research in Common and Rare Diseases & NIHR BioResource Centre Cambridge, University of Cambridge, Cambridge, CB2 0QQ, UK.
¹¹ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7FZ, UK.
¹² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
¹³ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
¹⁴ NIHR Oxford Biomedical Research Centre, OUH Hospital, Oxford, OX4 2PG, UK.
¹⁵ MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK.
¹⁶ Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, UK.
¹⁷ Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.
¹⁸ Quantitative Sciences, GlaxoSmithKline, Stevenage, SG1 2NY, UK.
¹⁹ Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
²⁰ Statistical Genetics, Projects, Clinical Platforms, and Sciences (PCPS), GlaxoSmithKline, Research Triangle Park, NC, 27709, USA.
²¹ Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, EX1 2LU, UK.
²² NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, UK.
²³ The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, 4072, Australia.
²⁴ Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK.
²⁵ NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, OX3 7LE, UK.
²⁶ Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1HH, UK.
²⁷ NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB2 0SR, UK.
²⁸ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, SE-205 02, Sweden.
²⁹ Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University, Umeå, 907 37, Sweden.
³⁰ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
³¹ MRC Integrative Epidemiology Unit at University of Bristol, Bristol, BS8 2BN, UK. n.j.timpson@bristol.ac.uk.
³² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK. n.j.timpson@bristol.ac.uk.

Abstract

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Causality
Genetic Variation
Genome-Wide Association Study* / methods
Genome-Wide Association Study* / statistics & numerical data
Genome-Wide Association Study* / trends
Genotype*
Humans
Molecular Epidemiology
Phenotype*
Risk Factors
United Kingdom

Abstract

Publication types

MeSH terms

Grants and funding