title: Rare coding variants and X-linked loci associated with age at menarche.
abstract: More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
authors.affiliation: 1] Boston University School of Public Health, Department of Biostatistics, Boston, Massachusetts 02118, USA [2] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
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: deCODE genetics/Amgen, Inc., Reykjavik IS-101, Iceland.
authors.forename: Patrick
authors.identifier: 0000000171236123
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authors.lastname: Sulem
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ruth
authors.affiliation: 23andMe Inc., 1390 Shorebird Way, Mountain View, California 94043, USA.
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authors.initials: JY
authors.lastname: Tung
authors.affiliation: 23andMe Inc., 1390 Shorebird Way, Mountain View, California 94043, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia [2] Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA [3] Department of Genetics, Harvard Medical School, Boston, MA 02115, USA [4] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140, Cambridge, MA 02142, USA.
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
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: Cathy E
authors.initials: CE
authors.lastname: Elks
authors.affiliation: 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany [2] Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors.forename: Elisabeth
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authors.lastname: Altmaier
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authors.forename: Chunyan
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authors.affiliation: Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
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authors.affiliation: Estonian Genome Center, University of Tartu, Tartu 51010, Estonia.
authors.forename: Evelin
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authors.lastname: Mihailov
authors.affiliation: 1] Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Sardinia 09042, Italy [2] University of Sassari, Department of Biomedical Sciences, Sassari, Sassari 07100, Italy [3] Center for Statistical Genetics, Ann Arbor, University of Michigan, Michigan 48109-2029, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.affiliation: Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste 34137, Italy.
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authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215.
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authors.affiliation: Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA 98109-1024, USA.
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authors.initials: UM
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authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam 3015GE, the Netherlands.
authors.forename: Lisette
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authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN, UK.
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authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano 20132, Italy.
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authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, WA-6009, Australia.
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authors.affiliation: Program in Personalized Medicine, Division of Endocrinology, Diabetes and Nutrition-University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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authors.forename: Caterina
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authors.forename: Francesco
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authors.affiliation: Division of Epidemiology &Community Health, University of Minnesotta, Minneapolis, MN 55455, USA.
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authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
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authors.forename: Ilaria
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authors.affiliation: Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
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authors.affiliation: Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen AB25 2ZD, UK.
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authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
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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.
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authors.forename: Jian'an
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authors.forename: Frank B
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authors.forename: Andres
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authors.affiliation: School of Women's and Infants' Health, The University of Western Australia, WA-6009, Australia.
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authors.forename: Konstantin
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authors.initials: EA
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authors.forename: André G
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authors.forename: Henry
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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.
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authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
authors.forename: Anna
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authors.lastname: Murray
authors.affiliation: 1] deCODE genetics/Amgen, Inc., Reykjavik IS-101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: 1] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, MA 02118, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK [2] 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.
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mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000577:Amides; D001324:Autoantigens / Q000235:genetics*; D018797:Cell Cycle Proteins; D041321:Chromosomes, Human, X / Q000235:genetics; D018389:Codon, Nonsense; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids; D005260:Female; D005787:Gene Frequency; D050172:Genes, X-Linked / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000235:genetics; D007136:Immunoglobulins / Q000235:genetics*; D007797:Laminin / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008572:Menarche / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D019683:Penetrance; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics*; D018042:Receptors, Neurokinin-3 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C490729:ALMS1 protein, human; D000577:Amides; D001324:Autoantigens; D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; D005227:Fatty Acids; C112314:IGSF1 protein, human; D007136:Immunoglobulins; D007797:Laminin; D008565:Membrane Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D018042:Receptors, Neurokinin-3; C000601381:TACR3 protein, human; C465663:TNRC6A protein, human; C058783:laminin beta2; C526222:PRKAG1 protein, human; D055372:AMP-Activated Protein Kinases