title: Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.
abstract: Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Luca A
authors.initials: LA
authors.lastname: Lotta
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Pawan
authors.initials: P
authors.lastname: Gulati
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Felix R
authors.initials: FR
authors.lastname: Day
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Halit
authors.initials: H
authors.lastname: Ongen
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Martijn
authors.initials: M
authors.lastname: van de Bunt
authors.affiliation: Department of Pediatrics, University of California at San Diego, La Jolla, California, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Gaulton
authors.affiliation: Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Eicher
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sharp
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Emanuella
authors.initials: E
authors.lastname: De Lucia Rolfe
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Isobel D
authors.initials: ID
authors.lastname: Stewart
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Willems
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Adams
authors.affiliation: Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Nita G
authors.initials: NG
authors.lastname: Forouhi
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.affiliation: Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Frayling
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Dermitzakis
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.|Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000503:physiopathology*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008659:Metabolic Diseases / Q000503:physiopathology*; D051379:Mice; D009765:Obesity / Q000150:complications* / Q000235:genetics; D010641:Phenotype
chemical_list: D001786:Blood Glucose