Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Despoina Manousaki; Tom Dudding; Simon Haworth; Yi-Hsiang Hsu; Ching-Ti Liu; Carolina Medina-Gómez; Trudy Voortman; Nathalie van der Velde; Håkan Melhus; Cassianne Robinson-Cohen; Diana L Cousminer; Maria Nethander; Liesbeth Vandenput; Raymond Noordam; Vincenzo Forgetta; Celia M T Greenwood; Mary L Biggs; Bruce M Psaty; Jerome I Rotter; Babette S Zemel; Jonathan A Mitchell; Bruce Taylor; Mattias Lorentzon; Magnus Karlsson; Vincent V W Jaddoe; Henning Tiemeier; Natalia Campos-Obando; Oscar H Franco; Andre G Utterlinden; Linda Broer; Natasja M van Schoor; Annelies C Ham; M Arfan Ikram; David Karasik; Renée de Mutsert; Frits R Rosendaal; Martin den Heijer; Thomas J Wang; Lars Lind; Eric S Orwoll; Dennis O Mook-Kanamori; Karl Michaëlsson; Bryan Kestenbaum; Claes Ohlsson; Dan Mellström; Lisette C P G M de Groot; Struan F A Grant; Douglas P Kiel; M Carola Zillikens; Fernando Rivadeneira; Stephen Sawcer; Nicholas J Timpson; J Brent Richards

doi:10.1016/j.ajhg.2017.06.014

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Am J Hum Genet. 2017 Aug 3;101(2):227-238. doi: 10.1016/j.ajhg.2017.06.014. Epub 2017 Jul 27.

Authors

Despoina Manousaki¹, Tom Dudding², Simon Haworth², Yi-Hsiang Hsu³, Ching-Ti Liu⁴, Carolina Medina-Gómez⁵, Trudy Voortman⁶, Nathalie van der Velde⁷, Håkan Melhus⁸, Cassianne Robinson-Cohen⁹, Diana L Cousminer¹⁰, Maria Nethander¹¹, Liesbeth Vandenput¹², Raymond Noordam¹³, Vincenzo Forgetta¹, Celia M T Greenwood¹⁴, Mary L Biggs¹⁵, Bruce M Psaty¹⁶, Jerome I Rotter¹⁷, Babette S Zemel¹⁸, Jonathan A Mitchell¹⁸, Bruce Taylor¹⁹, Mattias Lorentzon²⁰, Magnus Karlsson²¹, Vincent V W Jaddoe⁶, Henning Tiemeier²², Natalia Campos-Obando²³, Oscar H Franco²⁴, Andre G Utterlinden⁵, Linda Broer²³, Natasja M van Schoor²⁵, Annelies C Ham²³, M Arfan Ikram²⁶, David Karasik²⁷, Renée de Mutsert²⁸, Frits R Rosendaal²⁸, Martin den Heijer²⁹, Thomas J Wang³⁰, Lars Lind⁸, Eric S Orwoll³¹, Dennis O Mook-Kanamori³², Karl Michaëlsson³³, Bryan Kestenbaum⁹, Claes Ohlsson¹², Dan Mellström³⁴, Lisette C P G M de Groot³⁵, Struan F A Grant³⁶, Douglas P Kiel³⁷, M Carola Zillikens²³, Fernando Rivadeneira⁵, Stephen Sawcer³⁸, Nicholas J Timpson², J Brent Richards³⁹

Affiliations

¹ 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.
² Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
³ 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.
⁴ Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
⁵ 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.
⁶ Generation R Study Group, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
⁷ 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.
⁸ Department of Medical Sciences, Uppsala University, Uppsala 751 85, Sweden.
⁹ Kidney Research Institute, Division of Nephrology, University of Washington, Seattle, WA 98195, USA.
¹⁰ 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.
¹¹ 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.
¹² Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden.
¹³ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
¹⁴ 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 1A2, Canada; Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada.
¹⁵ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA 98101, USA.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ Menzies Institute for Medical Research University of Tasmania, Locked Bag 23, Hobart, Tasmania 7000, Australia.
²⁰ 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, Sweden; Geriatric Medicine, Sahlgrenska University Hospital, 43180 Mölndal, Sweden.
²¹ Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, 22241 Malmö, Sweden; Department of Orthopaedics, Skåne University Hospital, 22241 Malmö, Sweden.
²² 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.
²³ Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
²⁴ Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.
²⁵ Department of Epidemiology and Biostatistics and EMGO Institute of Health and Care Research, VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
²⁶ 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.
²⁷ Institute for Aging Research, Hebrew SeniorLife, Boston, MA 02131, USA.
²⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
²⁹ Department of Endocrinology, VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
³⁰ Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
³¹ Bone and Mineral Unit, Oregon Health & Science University, Portland, OR 97239, USA; Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
³² 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.
³³ Department of Surgical Sciences, Uppsala University, 75105 Uppsala, Sweden.
³⁴ 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, Sweden.
³⁵ Division of Human Nutrition, Wageningen University, Wageningen 6708 WE, the Netherlands.
³⁶ 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.
³⁷ 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.
³⁸ Department of Clinical Neurosciences, University of Cambridge, Box 165, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.
³⁹ 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 Twin Research and Genetic Epidemiology, King's College London, London WC2R 2LS, UK; Department of Medicine, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address: [email protected].

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.

Keywords: GWAS; low-frequency genetic variants; multiple sclerosis; vitamin D.

Publication types

Meta-Analysis

MeSH terms

Cholestanetriol 26-Monooxygenase / genetics*
Cytochrome P450 Family 2 / genetics*
Gene Frequency
Genetic Predisposition to Disease / genetics*
Genome, Human / genetics
Genome-Wide Association Study
Humans
Multiple Sclerosis / etiology
Multiple Sclerosis / genetics*
Polymorphism, Single Nucleotide
Risk Factors
Vitamin D / analogs & derivatives*
Vitamin D / blood
Vitamin D Deficiency / diagnosis*
Vitamin D Deficiency / genetics*

Substances

Vitamin D
25-hydroxyvitamin D
Cytochrome P450 Family 2
CYP2R1 protein, human
Cholestanetriol 26-Monooxygenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding