title: Genome-wide association study using family-based cohorts identifies the WLS and CCDC170/ESR1 loci as associated with bone mineral density.
abstract: BACKGROUND
  Osteoporosis is a common and debilitating bone disease that is characterised by a low bone mineral density (BMD), a highly heritable trait. Genome-wide association studies (GWAS) have proven to be very successful in identifying common genetic variants associated with BMD adjusted for age, gender and weight, however a large portion of the genetic variance for this trait remains unexplained. There is evidence to suggest significant genetic correlation between body size traits and BMD. It has also recently been suggested that unintended bias can be introduced as a result of adjusting a phenotype for a correlated trait. We performed a GWAS meta-analysis in two populations (total n = 6,696) using BMD data adjusted for only age and gender, in an attempt to identify genetic variants associated with BMD including those that may have potential pleiotropic effects on BMD and body size traits.
  
  
  RESULTS
  We observed a single variant, rs2566752, associated with spine BMD at the genome-wide significance level in the meta-analysis (P = 3.36 × 10(-09)). Logistic regression analysis also revealed an association between rs2566752 and fracture rate in one of our study cohorts (P = 0.017, n = 5,654). This is an intronic variant located in the wntless Wnt ligand secretion mediator (WLS) gene (1p31.3), a known BMD locus which encodes an integral component of the Wnt ligand secretion pathway. Bioinformatics analyses of variants in moderate LD with rs2566752 produced strong evidence for a regulatory role for the variants rs72670452, rs17130567 and rs1430738. Expression quantitative trait locus (eQTL) analysis suggested that the variants rs12568456 and rs17130567 are associated with expression of the WLS gene in whole blood, cerebellum and temporal cortex brain tissue (P = 0.034-1.19 × 10(-23)). Gene-wide association testing using the VErsatile Gene-based Association Study 2 (VEGAS2) software revealed associations between the coiled-coil domain containing 170 (CCDC170) gene, located adjacent to the oestrogen receptor 1 (ESR1) gene, and BMD at the spine, femoral neck and total hip sites (P = 1.0 × 10(-06), 2.0 × 10(-06) and 2.0 × 10(-06) respectively).
  
  
  CONCLUSIONS
  Genetic variation at the WLS and CCDC170/ESR1 loci were found to be significantly associated with BMD adjusted for only age and gender at the genome-wide level in this meta-analysis.
authors.affiliation: Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia. Benjamin.Mullin@uwa.edu.au.|School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia. Benjamin.Mullin@uwa.edu.au.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Mullin
authors.affiliation: Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia. John.Walsh@health.wa.gov.au.|School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia. John.Walsh@health.wa.gov.au.
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.affiliation: Institute of Aging Research, School of Medicine, Hangzhou Normal University, and the Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China. hfzheng@hznu.edu.cn.
authors.forename: Hou-Feng
authors.initials: HF
authors.lastname: Zheng
authors.affiliation: Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia. Suzanne.Brown@health.wa.gov.au.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Brown
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. Gabriela.L.Surdulescu@kcl.ac.uk.
authors.forename: Gabriela L
authors.initials: GL
authors.lastname: Surdulescu
authors.affiliation: MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Charles.Curtis@kcl.ac.uk.|NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Charles.Curtis@kcl.ac.uk.
authors.forename: Charles
authors.initials: C
authors.lastname: Curtis
authors.affiliation: MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Gerome.Breen@kcl.ac.uk.|NIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Gerome.Breen@kcl.ac.uk.
authors.forename: Gerome
authors.initials: G
authors.lastname: Breen
authors.affiliation: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. Frank.Dudbridge@lshtm.ac.uk.
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. Brent.Richards@mcgill.ca.|Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Jewish General Hospital, Lady Davis Institute, McGill University, Montreal, Canada. Brent.Richards@mcgill.ca.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. Tim.Spector@kcl.ac.uk.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia. Scott.Wilson@uwa.edu.au.|School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia. Scott.Wilson@uwa.edu.au.|Department of Twin Research & Genetic Epidemiology, King's College London, London, UK. Scott.Wilson@uwa.edu.au.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005272:Femur Neck / Q000473:pathology; D050723:Fractures, Bone / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D013131:Spine / Q000473:pathology; D055815:Young Adult
chemical_list: C000599973:CCDC170 protein, human; D002352:Carrier Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C549111:WLS protein, human