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      Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes

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          Abstract

          Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7 879 351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance ( P<5 × 10 −8), with minor allele frequencies of 1.3–23.9%. Novel signals included variants for progesterone ( P=7.68 × 10 −12), oestradiol ( P=1.63 × 10 −8) and FAI ( P=1.50 × 10 −8). A genetic variant near the FSHB gene was identified which influenced both FSH ( P=1.74 × 10 −8) and LH ( P=3.94 × 10 −9) levels. A separate locus on chromosome 7 was associated with both DHEAS ( P=1.82 × 10 −14) and progesterone ( P=6.09 × 10 −14). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

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          Most cited references 30

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          Ensembl 2012

          The Ensembl project (http://www.ensembl.org) provides genome resources for chordate genomes with a particular focus on human genome data as well as data for key model organisms such as mouse, rat and zebrafish. Five additional species were added in the last year including gibbon (Nomascus leucogenys) and Tasmanian devil (Sarcophilus harrisii) bringing the total number of supported species to 61 as of Ensembl release 64 (September 2011). Of these, 55 species appear on the main Ensembl website and six species are provided on the Ensembl preview site (Pre!Ensembl; http://pre.ensembl.org) with preliminary support. The past year has also seen improvements across the project.
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            The UCSC Genome Browser database: extensions and updates 2013

            The University of California Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of organisms. The Browser is an integrated tool set for visualizing, comparing, analysing and sharing both publicly available and user-generated genomic datasets. As of September 2012, genomic sequence and a basic set of annotation ‘tracks’ are provided for 63 organisms, including 26 mammals, 13 non-mammal vertebrates, 3 invertebrate deuterostomes, 13 insects, 6 worms, yeast and sea hare. In the past year 19 new genome assemblies have been added, and we anticipate releasing another 28 in early 2013. Further, a large number of annotation tracks have been either added, updated by contributors or remapped to the latest human reference genome. Among these are an updated UCSC Genes track for human and mouse assemblies. We have also introduced several features to improve usability, including new navigation menus. This article provides an update to the UCSC Genome Browser database, which has been previously featured in the Database issue of this journal.
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              The UK Adult Twin Registry (TwinsUK Resource).

              TwinsUK is a nation-wide registry of volunteer twins in the United Kingdom, with about 12,000 registered twins (83% female, equal number of monozygotic and dizygotic twins, predominantly middle-aged and older). Over the last 20 years, questionnaire and blood/urine/tissue samples have been collected on over 7,000 subjects, as well as three comprehensive phenotyping assessments in the clinical facilities of the Department of Twin Research and Genetic Epidemiology, King's College London. The primary focus of study has been the genetic basis of healthy aging process and complex diseases, including cardiovascular, metabolic, musculoskeletal, and ophthalmologic disorders. Alongside the detailed clinical, biochemical, behavioral, and socio-economic characterization of the study population, the major strength of TwinsUK is availability of several 'omics' technologies for the participants. These include genome-wide scans of single nucleotide variants, next-generation sequencing, exome sequencing, epigenetic markers (MeDIP sequencing), gene expression arrays and RNA sequencing, telomere length measures, metabolomic profiles, and gut flora microbiomics. The scientific community now can freely access parts of the phenotype data from the 'TwinsUK', and interested researchers are encouraged to contact us via our Web site (www.twinsuk.ac.uk) for future collaborations.
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                Author and article information

                Journal
                Eur J Hum Genet
                Eur. J. Hum. Genet
                European Journal of Human Genetics
                Nature Publishing Group
                1018-4813
                1476-5438
                February 2016
                27 May 2015
                1 February 2016
                : 24
                : 2
                : 284-290
                Affiliations
                [1 ]Genetics of Complex Traits, University of Exeter Medical School, University of Exeter , Exeter, UK
                [2 ]Endocrinology and Diabetes, Sir Charles Gairdner Hospital , Nedlands, Australia
                [3 ]Pathwest Laboratory Medicine WA , Nedlands, Australia
                [4 ]School of Medicine and Pharmacology, University of Western Australia , Nedlands, Australia
                [5 ]Department of Epidemiology Research, Statens Serum Institut , Copenhagen, Denmark
                [6 ]Department of Twin Research and Genetic Epidemiology, King's College London , London, UK
                [7 ]Department of Medicine, Human Genetics, McGill University , Montreal, Canada
                [8 ]Lady Davis Institute, McGill University , Montreal, Canada
                [9 ]MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Hills Road , Cambridge, UK
                Author notes
                [* ]Senior Investigator Scientist MRC Epidemiology Unit, Institute of Metabolic Science, Box 285 , Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK. Tel: +44 0 1223 769135; Fax: +44 0 1223 330316; E-mail: john.perry@ 123456mrc-epid.cam.ac.uk
                [10]

                These authors contributed equally to this work.

                Article
                ejhg2015102
                10.1038/ejhg.2015.102
                4564946
                26014426
                Copyright © 2016 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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                Genetics

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