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Nat Commun. 2018 Nov 7;9(1):4674. doi: 10.1038/s41467-018-07070-8.

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits.

Author information

1
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, United Kingdom.
2
Division of Psychiatry, University College of London, London, W1T 7NF, United Kingdom.
3
UCL Genetics Institute, University College London, London, WC1E 6BT, United Kingdom.
4
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
5
Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, United Kingdom.
6
Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, D-85764, Germany.
7
Department of Health Sciences, College of Life Sciences, University of Leicester, Leicester, LE1 6TP, United Kingdom.
8
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University of Athens, Athens, 176-71, Greece.
9
Department of Mathematical Sciences, Norwegian Institute of Science and Technology, Trondheim, 7491, Norway.
10
The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, 2200, Denmark.
11
Section for Metabolic Genetics, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark.
12
Human Genetics Foundation, University of Torino, Torino, IT-10126, Italy.
13
Department of Biomedical Informatics, Harvard Medical School, Boston, 02115, MA, USA.
14
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Old Road, Headington, Oxford, OX3 7LE, United Kingdom.
15
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, United Kingdom.
16
Department of Haematology, Cambridge Biomedical Campus, University of Cambridge, Long Road, Cambridge, CB2 0PT, United Kingdom.
17
The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, University of Cambridge, Cambridge, CB1 8RN, United Kingdom.
18
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Wort's Causeway, University of Cambridge, Strangeways Research Laboratory, Cambridge, CB1 8RN, United Kingdom.
19
British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
20
Anogia Medical Centre, Anogia, 740 51, Greece.
21
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, United Kingdom. Eleftheria@sanger.ac.uk.
22
Institute of Translational Genomics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, D-85764, Germany. Eleftheria@sanger.ac.uk.

Abstract

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10-8; APOC3 and triglyceride levels, P = 1.5 × 10-26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10-8), indicating a role for this gene in lipid metabolism.

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