Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements

Fiona Allum; Åsa K Hedman; Xiaojian Shao; Warren A Cheung; Jinchu Vijay; Frédéric Guénard; Tony Kwan; Marie-Michelle Simon; Bing Ge; Cristiano Moura; Elodie Boulier; Lars Rönnblom; Sasha Bernatsky; Mark Lathrop; Mark I McCarthy; Panos Deloukas; André Tchernof; Tomi Pastinen; Marie-Claude Vohl; Elin Grundberg

doi:10.1038/s41467-019-09184-z

Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements

Nat Commun. 2019 Mar 14;10(1):1209. doi: 10.1038/s41467-019-09184-z.

Authors

Fiona Allum^{1

2}, Åsa K Hedman³, Xiaojian Shao^{1

2}, Warren A Cheung^{1

2

4}, Jinchu Vijay^{1

2}, Frédéric Guénard⁵, Tony Kwan^{1

2}, Marie-Michelle Simon^{1

2}, Bing Ge^{1

2}, Cristiano Moura⁶, Elodie Boulier^{1

2}, Lars Rönnblom⁷, Sasha Bernatsky⁶, Mark Lathrop^{1

2}, Mark I McCarthy^{8

9

10}, Panos Deloukas¹¹, André Tchernof¹², Tomi Pastinen^{1

2

4}, Marie-Claude Vohl⁵, Elin Grundberg^{13

14

15}

Affiliations

¹ Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada.
² McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada.
³ Department of Medicine Solna, Cardiovascular Medicine Unit, Karolinska Institute, Stockholm, 171 76, Sweden.
⁴ Children's Mercy Hospitals and Clinics, Kansas City, MO, 64108, USA.
⁵ Institute of Nutrition and Functional Foods (INAF), Université Laval, Québec, QC, G1V 0A6, Canada.
⁶ Department of Epidemiology, McGill University, Montréal, QC, H3A 1A2, Canada.
⁷ Department of Medical Sciences, Uppsala University, Uppsala, 751 85, Sweden.
⁸ Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Old Road, Headington, Oxford, OX3 7LJ, UK.
⁹ Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
¹⁰ Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
¹¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
¹² Québec Heart and Lung Institute, Université Laval, Québec, QC, G1V 0A6, Canada.
¹³ Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada. egrundberg@cmh.edu.
¹⁴ McGill University and Genome Quebec Innovation Centre, Montréal, QC, H3A 0G1, Canada. egrundberg@cmh.edu.
¹⁵ Children's Mercy Hospitals and Clinics, Kansas City, MO, 64108, USA. egrundberg@cmh.edu.

Abstract

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (N_total~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in ~800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

Publication types

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

MeSH terms

Adipose Tissue / metabolism
Adult
Aged
Cardiovascular Diseases / blood
Cardiovascular Diseases / genetics*
Cardiovascular Diseases / metabolism
CpG Islands / genetics*
DNA Methylation
Epigenesis, Genetic*
Epigenomics / methods
Female
Gene Expression Profiling
Genome, Human
Genome-Wide Association Study
High-Throughput Nucleotide Sequencing / methods
Humans
Lipids / blood
Male
Metabolic Diseases / blood
Metabolic Diseases / genetics*
Metabolic Diseases / metabolism
Middle Aged
Polymorphism, Single Nucleotide
Regulatory Sequences, Nucleic Acid / genetics*
Sequence Analysis, DNA / methods

Substances

Lipids

Abstract

Publication types

MeSH terms

Substances

Grants and funding