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

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

Author information

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: brent.richards@mcgill.ca.

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

PMID:
28757204
PMCID:
PMC5544392
DOI:
10.1016/j.ajhg.2017.06.014
[Indexed for MEDLINE]
Free PMC Article

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