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

Summary, in English

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.

• Författare: 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 W. V. 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 J. Sawcer; Nicholas J. Timpson; J Brent Richards
• Avdelning/ar: Ortopedi - klinisk och molekylär osteoporosforskning; EpiHealth: Epidemiology for Health
• Publiceringsår: 2017-08-03
• Språk: Engelska
• Sidor: 227-238
• Publikation/Tidskrift/Serie: American Journal of Human Genetics
• Volym: 101
• Issue: 2
• Länkar: http://dx.doi.org/10.1016/j.ajhg.2017.06.014
• Dokumenttyp: Artikel i tidskrift
• Förlag: Cell Press
• Ämne: Medical Genetics; Neurology
• Nyckelord: GWAS; low-frequency genetic variants; multiple sclerosis; vitamin D
• Status: Published
• Forskningsgrupp: Orthopedics - Clinical and Molecular Osteoporosis Research
• ISBN/ISSN/Övrigt: ISSN: 0002-9297