title: Shared genetic aetiology of puberty timing between sexes and with health-related outcomes.
abstract: Understanding of the genetic regulation of puberty timing has come largely from studies of rare disorders and population-based studies in women. Here, we report the largest genomic analysis for puberty timing in 55,871 men, based on recalled age at voice breaking. Analysis across all genomic variants reveals strong genetic correlation (0.74, P=2.7 × 10(-70)) between male and female puberty timing. However, some loci show sex-divergent effects, including directionally opposite effects between sexes at the SIM1/MCHR2 locus (Pheterogeneity=1.6 × 10(-12)). We find five novel loci for puberty timing (P<5 × 10(-8)), in addition to nine signals in men that were previously reported in women. Newly implicated genes include two retinoic acid-related receptors, RORB and RXRA, and two genes reportedly disrupted in rare disorders of puberty, LEPR and KAL1. Finally, we identify genetic correlations that indicate shared aetiologies in both sexes between puberty timing and body mass index, fasting insulin levels, lipid levels, type 2 diabetes and cardiovascular disease.
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Felix R
authors.initials: FR
authors.lastname: Day
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Bulik-Sullivan
authors.affiliation: 23andMe Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.|Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Hilary K
authors.initials: HK
authors.lastname: Finucane
authors.affiliation: NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA.|Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: 23andMe Inc., 899 W. Evelyn Avenue, Mountain View, California 94041, USA.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Tung
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.|Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Ken K
authors.initials: KK
authors.lastname: Ong
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: John R B
authors.initials: JRB
authors.lastname: Perry
mesh_terms: D000293:Adolescent; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001827:Body Height / Q000235:genetics; D015992:Body Mass Index; D015519:Bone Density / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics*; D002648:Child; D008076:Cholesterol, HDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000097:blood; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2 / Q000235:genetics; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D011627:Puberty / Q000235:genetics*; D011859:Radiography; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics; D011979:Receptors, Pituitary Hormone / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000235:genetics; D012737:Sex Factors; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008076:Cholesterol, HDL; D016326:Extracellular Matrix Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D043562:Receptors, G-Protein-Coupled; D054411:Receptors, Leptin; D011979:Receptors, Pituitary Hormone; D012097:Repressor Proteins; D047490:Retinoid X Receptor alpha; D014280:Triglycerides; C076266:ANOS1 protein, human; C515448:LEPR protein, human; C431280:MCHR2 protein, human; C539740:RORB protein, human; C491094:SIM1 protein, human