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

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. ZemelJonathan 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

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

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.

Original language	English (US)
Pages (from-to)	227-238
Number of pages	12
Journal	American Journal of Human Genetics
Volume	101
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2017.06.014
State	Published - Aug 3 2017
Externally published	Yes

Keywords

GWAS
low-frequency genetic variants
multiple sclerosis
vitamin D

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2017.06.014

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Manousaki, D., Dudding, T., Haworth, S., Hsu, Y. H., Liu, C. T., Medina-Gómez, C., Voortman, T., van der Velde, N., Melhus, H., Robinson-Cohen, C., Cousminer, D. L., Nethander, M., Vandenput, L., Noordam, R., Forgetta, V., Greenwood, C. M. T., Biggs, M. L., Psaty, B. M., Rotter, J. I., ... Richards, J. B. (2017). Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis. American Journal of Human Genetics, 101(2), 227-238. https://doi.org/10.1016/j.ajhg.2017.06.014

Manousaki, D, Dudding, T, Haworth, S, Hsu, YH, Liu, CT, Medina-Gómez, C, Voortman, T, van der Velde, N, Melhus, H, Robinson-Cohen, C, Cousminer, DL, Nethander, M, Vandenput, L, Noordam, R, Forgetta, V, Greenwood, CMT, Biggs, ML, Psaty, BM, Rotter, JI, Zemel, BS, Mitchell, JA, Taylor, B, Lorentzon, M, Karlsson, M, Jaddoe, VVW, Tiemeier, H, Campos-Obando, N, Franco, OH, Utterlinden, AG, Broer, L, van Schoor, NM, Ham, AC, Ikram, MA, Karasik, D, de Mutsert, R, Rosendaal, FR, den Heijer, M, Wang, TJ, Lind, L, Orwoll, ES, Mook-Kanamori, DO, Michaëlsson, K, Kestenbaum, B, Ohlsson, C, Mellström, D, de Groot, LCPGM, Grant, SFA, Kiel, DP, Zillikens, MC, Rivadeneira, F, Sawcer, S, Timpson, NJ & Richards, JB 2017, 'Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis', American Journal of Human Genetics, vol. 101, no. 2, pp. 227-238. https://doi.org/10.1016/j.ajhg.2017.06.014

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

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",

author = "Despoina Manousaki and Tom Dudding and Simon Haworth and Hsu, {Yi Hsiang} and Liu, {Ching Ti} and Carolina Medina-G{\'o}mez and Trudy Voortman and {van der Velde}, Nathalie and H{\aa}kan Melhus and Cassianne Robinson-Cohen and Cousminer, {Diana L.} and Maria Nethander and Liesbeth Vandenput and Raymond Noordam and Vincenzo Forgetta 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 Bruce Taylor and Mattias Lorentzon and Magnus Karlsson and Jaddoe, {Vincent V.W.} and Henning Tiemeier and Natalia Campos-Obando and Franco, {Oscar H.} and Utterlinden, {Andre G.} and Linda Broer and {van Schoor}, {Natasja M.} and Ham, {Annelies C.} and Ikram, {M. Arfan} and David Karasik and {de Mutsert}, Ren{\'e}e and Rosendaal, {Frits R.} and {den Heijer}, Martin and Wang, {Thomas J.} and Lars Lind and Orwoll, {Eric S.} and Mook-Kanamori, {Dennis O.} and Karl Micha{\"e}lsson and Bryan Kestenbaum and Claes Ohlsson and Dan Mellstr{\"o}m and {de Groot}, {Lisette C.P.G.M.} and Grant, {Struan F.A.} and Kiel, {Douglas P.} and Zillikens, {M. Carola} and Fernando Rivadeneira and Stephen Sawcer and Timpson, {Nicholas J.} and Richards, {J. Brent}",

note = "Publisher Copyright: {\textcopyright} 2017 American Society of Human Genetics",

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month = aug,

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doi = "10.1016/j.ajhg.2017.06.014",

language = "English (US)",

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T1 - Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

AU - Manousaki, Despoina

AU - Dudding, Tom

AU - Haworth, Simon

AU - Hsu, Yi Hsiang

AU - Liu, Ching Ti

AU - Medina-Gómez, Carolina

AU - Voortman, Trudy

AU - van der Velde, Nathalie

AU - Melhus, Håkan

AU - Robinson-Cohen, Cassianne

AU - Cousminer, Diana L.

AU - Nethander, Maria

AU - Vandenput, Liesbeth

AU - Noordam, Raymond

AU - Forgetta, Vincenzo

AU - Greenwood, Celia M.T.

AU - Biggs, Mary L.

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Zemel, Babette S.

AU - Mitchell, Jonathan A.

AU - Taylor, Bruce

AU - Lorentzon, Mattias

AU - Karlsson, Magnus

AU - Jaddoe, Vincent V.W.

AU - Tiemeier, Henning

AU - Campos-Obando, Natalia

AU - Franco, Oscar H.

AU - Utterlinden, Andre G.

AU - Broer, Linda

AU - van Schoor, Natasja M.

AU - Ham, Annelies C.

AU - Ikram, M. Arfan

AU - Karasik, David

AU - de Mutsert, Renée

AU - Rosendaal, Frits R.

AU - den Heijer, Martin

AU - Wang, Thomas J.

AU - Lind, Lars

AU - Orwoll, Eric S.

AU - Mook-Kanamori, Dennis O.

AU - Michaëlsson, Karl

AU - Kestenbaum, Bryan

AU - Ohlsson, Claes

AU - Mellström, Dan

AU - de Groot, Lisette C.P.G.M.

AU - Grant, Struan F.A.

AU - Kiel, Douglas P.

AU - Zillikens, M. Carola

AU - Rivadeneira, Fernando

AU - Sawcer, Stephen

AU - Timpson, Nicholas J.

AU - Richards, J. Brent

PY - 2017/8/3

Y1 - 2017/8/3

N2 - 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.

AB - 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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KW - low-frequency genetic variants

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KW - vitamin D

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

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