Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals

Kevin T Nead; Aihua Li; Mackenzie R Wehner; Binod Neupane; Stefan Gustafsson; Adam Butterworth; James C Engert; A Darlene Davis; Robert A Hegele; Ruby Miller; Marcel den Hoed; Kay-Tee Khaw; Tuomas O Kilpeläinen; Nick Wareham; Todd L Edwards; Göran Hallmans; Tibor V Varga; Sharon L R Kardia; Jennifer A Smith; Wei Zhao; Jessica D Faul; David Weir; Jie Mi; Bo Xi; Samuel Canizales Quinteros; Cyrus Cooper; Avan Aihie Sayer; Karen Jameson; Anders Grøntved; Myriam Fornage; Stephen Sidney; Craig L Hanis; Heather M Highland; Hans-Ulrich Häring; Martin Heni; Jessica Lasky-Su; Scott T Weiss; Glenn S Gerhard; Christopher Still; Melkaey M Melka; Zdenka Pausova; Tomáš Paus; Struan F A Grant; Hakon Hakonarson; R Arlen Price; Kai Wang; Andre Scherag; Johannes Hebebrand; Anke Hinney; BioBank Japan, AGEN-BMI, GIANT Consortium; Paul W Franks; Timothy M Frayling; Mark I McCarthy; Joel N Hirschhorn; Ruth J Loos; Erik Ingelsson; Hertzel C Gerstein; Salim Yusuf; Joseph Beyene; Sonia S Anand; David Meyre

doi:10.1093/hmg/ddv097

Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals

Hum Mol Genet. 2015 Jun 15;24(12):3582-94. doi: 10.1093/hmg/ddv097. Epub 2015 Mar 17.

Authors

Kevin T Nead¹, Aihua Li², Mackenzie R Wehner³, Binod Neupane², Stefan Gustafsson⁴, Adam Butterworth⁵, James C Engert⁶, A Darlene Davis⁷, Robert A Hegele⁸, Ruby Miller⁷, Marcel den Hoed⁹, Kay-Tee Khaw⁵, Tuomas O Kilpeläinen¹⁰, Nick Wareham¹¹, Todd L Edwards¹², Göran Hallmans¹³, Tibor V Varga¹⁴, Sharon L R Kardia¹⁵, Jennifer A Smith¹⁵, Wei Zhao¹⁵, Jessica D Faul¹⁶, David Weir¹⁶, Jie Mi¹⁷, Bo Xi¹⁸, Samuel Canizales Quinteros¹⁹, Cyrus Cooper²⁰, Avan Aihie Sayer²¹, Karen Jameson²¹, Anders Grøntved²², Myriam Fornage²³, Stephen Sidney²⁴, Craig L Hanis²⁵, Heather M Highland²⁵, Hans-Ulrich Häring²⁶, Martin Heni²⁶, Jessica Lasky-Su²⁷, Scott T Weiss²⁷, Glenn S Gerhard²⁸, Christopher Still²⁹, Melkaey M Melka³⁰, Zdenka Pausova³⁰, Tomáš Paus³¹, Struan F A Grant³², Hakon Hakonarson³², R Arlen Price³³, Kai Wang³⁴, Andre Scherag³⁵, Johannes Hebebrand³⁶, Anke Hinney³⁶; BioBank Japan, AGEN-BMI, GIANT Consortium; Paul W Franks³⁷, Timothy M Frayling³⁸, Mark I McCarthy³⁹, Joel N Hirschhorn⁴⁰, Ruth J Loos⁴¹, Erik Ingelsson⁴, Hertzel C Gerstein⁴², Salim Yusuf⁴², Joseph Beyene², Sonia S Anand⁴², David Meyre⁴³

Affiliations

¹ Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
² Department of Clinical Epidemiology and Biostatistics.
³ Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁵ Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
⁶ Population Health Research Institute, McMaster University, and Hamilton Health Sciences, Hamilton General Hospital, Hamilton, ON, Canada L8L 2X.
⁷ Department of Medicine.
⁸ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8, Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala SE 751 05, Sweden.
⁹ The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9, Six Nations Health Services, Ohsweken, Canada N0A 1M0.
¹⁰ The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, ON, Canada N6A 5K8.
¹¹ The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9.
¹² Department of Medicine, University of Western Ontario, London, ON, Canada N6A 3K7.
¹³ MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
¹⁴ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹⁵ The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen 2100, Denmark.
¹⁶ Center for Human Genetics Research, Vanderbilt Epidemiology Center, Department of Medicine, Vanderbilt University, Nashville, TN 37235, USA.
¹⁷ Department of Public Health and Clinical Medicine, Umeå University, Umeå 901 87, Sweden.
¹⁸ Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö 205 02, Sweden.
¹⁹ Department of Epidemiology, University of Michigan, Ann Arbor, MI 48109, USA.
²⁰ Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA, Department of Epidemiology, Capital Institute of Pediatrics, Beijing 100020, China, Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan 250100, China.
²¹ Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA.
²² Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, Universidad Nacional Autónoma de México, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.
²³ MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
²⁴ National Institute for Health Research Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, UK.
²⁵ National Institute for Health Research Biomedical Research Unit, University of Oxford, Oxford OX3 7LE, UK.
²⁶ Department of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense DK-5230, Denmark, University of Texas Health Science Center at Houston Institute of Molecular Medicine and Division of Epidemiology Human Genetics and Environmental Sciences, School of Public Health, Houston, TX 77030, USA.
²⁷ Division of Research, Kaiser Permanente of Northern California, Oakland, CA 94612, USA, The Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
²⁸ Internal Medicine IV (Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry), University Hospital of Tuebingen, Tübingen 72076, Germany.
²⁹ German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
³⁰ The Department of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³¹ Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
³² Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine, Department of Pathology and Laboratory Medicine, Pennsylvania State University, Hershey, PA 17033, USA, Geisinger Obesity Institute, Danville, PA 17822, USA.
³³ The Hospital for Sick Children, Department of Physiology, University of Toronto, Toronto, ON, Canada M5G 1X.
³⁴ MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK, Rotman Research Institute, University of Toronto, Toronto, Canada M6A 2E1.
³⁵ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³⁶ Department of Pediatrics and.
³⁷ Department of Medicine, University of Western Ontario, London, ON, Canada N6A 3K7, MRC Epidemiology Unit, University of Cambridge, Cambridge, UK, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
³⁸ Zilkha Neurogenetic Institute, Department of Psychiatry and Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90089, USA.
³⁹ Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena 07740, Germany.
⁴⁰ Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen 45141, Germany, Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA, Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX2 4TH, UK.
⁴¹ The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 9DU, UK.
⁴² Department of Clinical Epidemiology and Biostatistics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA 02115, USA.
⁴³ Department of Clinical Epidemiology and Biostatistics, Divisions of Genetics and Endocrinology, Children's Hospital, Boston, MA 02115, USA, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA, meyred@mcmaster.ca.

Abstract

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Systematic Review

MeSH terms

Alleles
Body Mass Index*
Genetic Predisposition to Disease*
Genetic Variation*
Humans
Obesity / diagnosis
Obesity / epidemiology*
Obesity / genetics*
Odds Ratio
Polymorphism, Single Nucleotide
Proprotein Convertase 1 / genetics*

Substances

PCSK1 protein, human
Proprotein Convertase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding