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Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.
Manousaki, Despoina; Dudding, Tom; Haworth, Simon; Hsu, Yi-Hsiang; Liu, Ching-Ti; Medina-Gómez, Carolina; Voortman, Trudy; van der Velde, Nathalie; Melhus, Håkan; Robinson-Cohen, Cassianne; Cousminer, Diana L; Nethander, Maria; Vandenput, Liesbeth; Noordam, Raymond; Forgetta, Vincenzo; Greenwood, Celia M T; Biggs, Mary L; Psaty, Bruce M; Rotter, Jerome I; Zemel, Babette S; Mitchell, Jonathan A; Taylor, Bruce; Lorentzon, Mattias; Karlsson, Magnus; Jaddoe, Vincent V W; Tiemeier, Henning; Campos-Obando, Natalia; Franco, Oscar H; Utterlinden, Andre G; Broer, Linda; van Schoor, Natasja M; Ham, Annelies C; Ikram, M Arfan; Karasik, David; de Mutsert, Renée; Rosendaal, Frits R; den Heijer, Martin; Wang, Thomas J; Lind, Lars; Orwoll, Eric S; Mook-Kanamori, Dennis O; Michaëlsson, Karl; Kestenbaum, Bryan; Ohlsson, Claes; Mellström, Dan; de Groot, Lisette C P G M; Grant, Struan F A; Kiel, Douglas P; Zillikens, M Carola; Rivadeneira, Fernando.
Afiliação
  • Manousaki D; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
  • Dudding T; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
  • Haworth S; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
  • Hsu YH; Institute for Aging Research, Hebrew SeniorLife, Boston, MA 02131, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Boston, MA 02142, USA.
  • Liu CT; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
  • Medina-Gómez C; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Generation R Study Group, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Voortman T; Generation R Study Group, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • van der Velde N; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Section of Geriatrics, Department of Internal Medicine, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands.
  • Melhus H; Department of Medical Sciences, Uppsala University, Uppsala 751 85, Sweden.
  • Robinson-Cohen C; Kidney Research Institute, Division of Nephrology, University of Washington, Seattle, WA 98195, USA.
  • Cousminer DL; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Nethander M; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden; Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41390, Sweden.
  • Vandenput L; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
  • Noordam R; Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • Forgetta V; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
  • Greenwood CMT; Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC H3A
  • Biggs ML; Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA 98101, USA.
  • Psaty BM; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98101, USA; Kaiser Permanente Washington Health Research Unit, Seattle, WA 98101, USA.
  • Rotter JI; Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  • Zemel BS; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Mitchell JA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Taylor B; Menzies Institute for Medical Research University of Tasmania, Locked Bag 23, Hobart, Tasmania 7000, Australia.
  • Lorentzon M; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden; Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 43180 Mölndal, Swe
  • Karlsson M; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, 22241 Malmö, Sweden; Department of Orthopaedics, Skåne University Hospital, 22241 Malmö, Sweden.
  • Jaddoe VVW; Generation R Study Group, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Tiemeier H; Generation R Study Group, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Campos-Obando N; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Franco OH; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Utterlinden AG; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Generation R Study Group, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Broer L; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • van Schoor NM; Department of Epidemiology and Biostatistics and EMGO Institute of Health and Care Research, VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
  • Ham AC; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Ikram MA; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Karasik D; Institute for Aging Research, Hebrew SeniorLife, Boston, MA 02131, USA.
  • de Mutsert R; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • Rosendaal FR; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • den Heijer M; Department of Endocrinology, VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
  • Wang TJ; Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Lind L; Department of Medical Sciences, Uppsala University, Uppsala 751 85, Sweden.
  • Orwoll ES; Bone and Mineral Unit, Oregon Health & Science University, Portland, OR 97239, USA; Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
  • Mook-Kanamori DO; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • Michaëlsson K; Department of Surgical Sciences, Uppsala University, 75105 Uppsala, Sweden.
  • Kestenbaum B; Kidney Research Institute, Division of Nephrology, University of Washington, Seattle, WA 98195, USA.
  • Ohlsson C; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
  • Mellström D; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden; Geriatric Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 43180 Mölndal, Swe
  • de Groot LCPGM; Division of Human Nutrition, Wageningen University, Wageningen 6708 WE, the Netherlands.
  • Grant SFA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Kiel DP; Institute for Aging Research, Hebrew SeniorLife, Boston, MA 02131, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Boston, MA 02142, USA; Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  • Zillikens MC; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
  • Rivadeneira F; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Generation R Study Group, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
Am J Hum Genet ; 101(2): 227-238, 2017 Aug 03.
Article em En | MEDLINE | ID: mdl-28757204
ABSTRACT
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10-88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10-12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10-5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vitamina D / Deficiência de Vitamina D / Predisposição Genética para Doença / Colestanotriol 26-Mono-Oxigenase / Família 2 do Citocromo P450 / Esclerose Múltipla Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Canadá
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vitamina D / Deficiência de Vitamina D / Predisposição Genética para Doença / Colestanotriol 26-Mono-Oxigenase / Família 2 do Citocromo P450 / Esclerose Múltipla Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Canadá