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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 and Robinson-Cohen, Cassianne, et al. (2017) In American Journal of Human Genetics 101(2). p.227-238
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... (More)

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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published
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keywords
GWAS, low-frequency genetic variants, multiple sclerosis, vitamin D
in
American Journal of Human Genetics
volume
101
issue
2
pages
12 pages
publisher
Cell Press
external identifiers
  • scopus:85026218390
  • wos:000406854800007
ISSN
0002-9297
DOI
10.1016/j.ajhg.2017.06.014
language
English
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yes
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1c614c70-4ef0-4f03-86d1-5da5a25aabea
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2017-08-24 09:12:48
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2018-01-07 12:16:02
@article{1c614c70-4ef0-4f03-86d1-5da5a25aabea,
  abstract     = {<p>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&gt;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<sup>−88</sup>). 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<sup>−12</sup>). 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<sup>−5</sup>) 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.</p>},
  author       = {Manousaki, Despoina and Dudding, Tom and Haworth, Simon and Hsu, Yi-Hsiang and Liu, Ching-Ti and Medina-Gómez, Carolina and Voortman, Trudy and van der Velde, Nathalie and Melhus, Håkan and Robinson-Cohen, Cassianne and Cousminer, Diana L and Nethander, Maria and Vandenput, Liesbeth and Noordam, Raymond and Forgetta, Vincenzo and Greenwood, Celia M T and Biggs, Mary L. and Psaty, Bruce M. and Rotter, Jerome I. and Zemel, Babette S. and Mitchell, Jonathan A. and Taylor, Bruce and Lorentzon, Mattias and Karlsson, Magnus and Jaddoe, Vincent W. V. and Tiemeier, Henning and Campos-Obando, Natalia and Franco, Oscar H. and Utterlinden, Andre G. and Broer, Linda and van Schoor, Natasja M. and Ham, Annelies C and Ikram, M Arfan and Karasik, David and De Mutsert, Renée and Rosendaal, Frits R and den Heijer, Martin and Wang, Thomas J and Lind, Lars and Orwoll, Eric S and Mook-Kanamori, Dennis O. and Michaëlsson, Karl and Kestenbaum, Bryan and Ohlsson, Claes and Mellström, Dan and de Groot, Lisette C P G M and Grant, Struan F A and Kiel, Douglas P and Zillikens, M. Carola and Rivadeneira, Fernando and Sawcer, Stephen J. and Timpson, Nicholas J. and Richards, J Brent},
  issn         = {0002-9297},
  keyword      = {GWAS,low-frequency genetic variants,multiple sclerosis,vitamin D},
  language     = {eng},
  month        = {08},
  number       = {2},
  pages        = {227--238},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2017.06.014},
  volume       = {101},
  year         = {2017},
}