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

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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 The American Journal of Human Genetics Volume 101, Issue 2, Pages 227-238 (August 2017) DOI: 10.1016/j.ajhg.2017.06.014 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Schematic of the Discovery Single-Variant Meta-analysis The American Journal of Human Genetics 2017 101, 227-238DOI: (10.1016/j.ajhg.2017.06.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Discovery Single-Variant Meta-analysis (A) Quantile-quantile plot for the single SNV meta-analysis. (B) Manhattan plot of the meta-analysis depicts variants with MAF > 0.5% across the 22 autosomes against the −log10 p value from the meta-analysis of 19 cohorts, which included 42,274 individuals. The American Journal of Human Genetics 2017 101, 227-238DOI: (10.1016/j.ajhg.2017.06.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Forest Plot by Cohort for rs117913124 and Forest Plot for rs117913124 and the Previously Described Common 25OHD-Related Variants from Discovery Meta-analysis (A) Forest plot of estimates from all 19 studies for the low-frequency CYP2R1 variant rs117913124. (B) Forest plot of the effect of the four common SUNLIGHT variants and the CYP2R1 low-frequency variant rs117913124 on log-transformed 25OHD levels. Squares represent beta values in the 19 studies, and bars around the squares represent 95% confidence intervals (CIs). The American Journal of Human Genetics 2017 101, 227-238DOI: (10.1016/j.ajhg.2017.06.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 Association Signals from 11p.15.2 (A) UCSC Genome Browser snapshot including the top low-frequency SNVs (see Table 2) and the lead common variant rs10741657 in CYP2R1. The position of rs117913124 is highlighted in light blue. (B) Regional disequilibrium plot showing rs117913124 (purple dot), its perfect proxy rs11670203 (red dot), and the other genome-wide-significant SNVs in the same locus (blue and green dots). The plot depicts SNVs within 1 Mb of a locus’s lead SNV (x axis) and their associated meta-analysis p value (−log10) (see Table S10 for more details). SNVs are color coded according to r2 with the lead SNV (labeled; r2 was calculated from the UK10K WGS dataset). The recombination rate (blue line), position of genes and their exons, and direction of transcription are also displayed (below plot). (C) Linkage-disequilibrium plot indicating the r2 values between the SNVs of Table 2 (top low-frequency variants) and between these low-frequency SNVs and the lead common variant (rs107416570) at the same CYP2R1 locus (r2 calculated from the 1000 Genomes dataset). The American Journal of Human Genetics 2017 101, 227-238DOI: (10.1016/j.ajhg.2017.06.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 5 Effect of rs117913124 on Vitamin D Insufficiency Forest plot of the effect of the low-frequency CYP2R1 variant rs117913124 on vitamin D insufficiency in four studies. Squares represent odds ratios for vitamin D insufficiency in the four studies, and bars represent 95% CIs. The American Journal of Human Genetics 2017 101, 227-238DOI: (10.1016/j.ajhg.2017.06.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 6 Association Signals from Chromosomes 12 and 14 Forest plots with (A) estimates for the chromosome 12 common variant rs3819817 and (B) estimates for the chromosome 14 common variant rs2277458 from all 19 studies of the meta-analysis where both variants were present. Squares represent beta values in the 19 studies, and bars around the squares represent 95% CIs. The American Journal of Human Genetics 2017 101, 227-238DOI: (10.1016/j.ajhg.2017.06.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 7 Schematic of the Vitamin D Metabolic Pathway UVB, ultraviolet B rays. The American Journal of Human Genetics 2017 101, 227-238DOI: (10.1016/j.ajhg.2017.06.014) Copyright © 2017 American Society of Human Genetics Terms and Conditions