GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology

Jonas Bovijn; Leigh Jackson; Jenny Censin; Chia-Yen Chen; Triin Laisk; Samantha Laber; Teresa Ferreira; Sara L Pulit; Craig A Glastonbury; Jordan W Smoller; Jamie W Harrison; Katherine S Ruth; Robin N Beaumont; Samuel E Jones; Jessica Tyrrell; Andrew R Wood; Michael N Weedon; Reedik Mägi; Benjamin Neale; Cecilia M Lindgren; Anna Murray; Michael V Holmes

doi:10.1016/j.ajhg.2018.11.004

GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology

Am J Hum Genet. 2019 Jan 3;104(1):157-163. doi: 10.1016/j.ajhg.2018.11.004. Epub 2018 Dec 21.

Authors

Jonas Bovijn¹, Leigh Jackson², Jenny Censin³, Chia-Yen Chen⁴, Triin Laisk⁵, Samantha Laber³, Teresa Ferreira⁶, Sara L Pulit⁷, Craig A Glastonbury⁶, Jordan W Smoller⁸, Jamie W Harrison⁹, Katherine S Ruth⁹, Robin N Beaumont⁹, Samuel E Jones⁹, Jessica Tyrrell⁹, Andrew R Wood⁹, Michael N Weedon⁹, Reedik Mägi¹⁰, Benjamin Neale⁴, Cecilia M Lindgren¹¹, Anna Murray¹², Michael V Holmes¹³

Affiliations

¹ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK. Electronic address: jbovijn@well.ox.ac.uk.
² Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
³ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia; Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu, Tartu 50406, Estonia.
⁶ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK.
⁷ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
⁸ Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
¹⁰ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu 51010, Estonia.
¹¹ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
¹² Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK. Electronic address: a.murray@exeter.ac.uk.
¹³ National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital, Old Road, Oxford OX3 7LE, UK; Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Big Data Institute Building, Roosevelt Drive, University of Oxford, Oxford OX3 7LF, UK; Medical Research Council Population Health Research Unit at the University of Oxford, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Abstract

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10^-14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.

Keywords: GWAS; Mendelian randomization; SIM1; UK biobank; diabetes; erectile dysfunction; genome-wide association; impotence; mendelian randomisation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Basic Helix-Loop-Helix Transcription Factors / genetics
Chromosomes, Human, Pair 6 / genetics
Computer Simulation
Diabetes Mellitus, Type 2 / complications*
Diabetes Mellitus, Type 2 / genetics*
Erectile Dysfunction / etiology*
Erectile Dysfunction / genetics*
Europe
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Hypothalamus / pathology*
Male
Repressor Proteins / genetics

Substances

Basic Helix-Loop-Helix Transcription Factors
Repressor Proteins
SIM1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding