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Title: Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author
item JIANG, XIA - Harvard School Of Public Health
item O'REILLY, PAUL - King'S College
item ASCHARD, HUGUES - Harvard School Of Public Health
item HSU, YI - Beth Israel Deaconess Medical Center
item RICHARDS, J - Jewish General Hospital
item DUPUIS, JOSEE - Boston University School Of Public Health
item INGELSSON, ERIK - Stanford University School Of Medicine
item KARASIK, DAVID - Hebrew Senior Life
item PILZ, STEFAN - Medical University Of Graz
item BERRY, DIANE - University College London
item KESTENBAUM, BRYAN - University Of Washington
item ZHENG, JUSHENG - University Of Cambridge
item LUAN, JIANAN - University Of Cambridge
item SOFIANOPOULOU, ELENI - University Of Cambridge
item STREETEN, ELIZABETH - University Of Maryland School Of Medicine
item ALBANES, DEMETRIUS - National Cancer Institute (NCI, NIH)
item LUTSEY, PAMELA - University Of Minnesota
item YAO, LU - University Of Minnesota
item TANG, WEIHONG - University Of Minnesota
item ECONS, MICHAEL - Indiana University
item WALLASCHOFSKI, HENRI - University Of Greifswald
item VOLZKE, HENRY - University Of Greifswald
item ZHOU, ANG - University Of South Australia
item POWER, CHRIS - University College London
item MCCARTHY, MARK - University Of Oxford
item MICHOS, ERIN - Johns Hopkins University School Of Medicine
item BOERWINKLE, ERIC - University Of Texas Health Science Center
item WEINSTEIN, STEPHANIE - National Cancer Institute (NCI, NIH)
item FREEDMAN, NEAL - National Cancer Institute (NCI, NIH)
item HUANG, WEN - National Cancer Institute (NCI, NIH)
item VAN SCHOOR, NATASJA - Vu University Medical Center
item VAN DER VELDE, NATHALIE - Erasmus Medical Center
item DE GROOT, LISETTE - Wageningen University
item ENNEMAN, ANKE - Erasmus Medical Center
item CUPPLES, L - Boston University School Of Public Health
item BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item VASAN, RAMACHANDRAN - Framingham Heart Study
item LIU, CHING - Boston University School Of Public Health
item ZHOU, YANHUA - Boston University School Of Public Health
item RIPATTI, SAMULI - University Of Helsinki
item OHLSSON, CLAES - University Of Gothenburg
item VANDEPUT, LIESBETH - University Of Gothenburg
item LORENTZON, MATTIAS - University Of Gothenburg
item ERIKSSON, JOHAN - University Of Helsinki
item SHEA, M - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item HOUSTON, DENISE - Wake Forest School Of Medicine
item KRITSHEVSKY, STEPHEN - Wake Forest School Of Medicine
item LIU, YONGMEI - Wake Forest School Of Medicine
item LOHMAN, KURT - Wake Forest School Of Medicine
item FERUCCI, LUIGI - National Institute On Aging (NIA, NIH)
item PEACOCK, MUNRO - Indiana University
item GIEGER, CHRISTIAN - German Research Center For Environmental Health
item BEEKMAN, MARIAN - Leiden University Medical Center
item SLAGBOOM, ELINE - Leiden University Medical Center
item DEELEN, JORIS - Leiden University Medical Center
item VAN HEEMST, DIANA - Leiden University Medical Center
item KLEBER, MARCUS - University Of Heidelberg
item MARZ, WINFRIED - University Of Heidelberg
item DE BOER, IAN - University Of Washington
item WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC)
item ROTTER, JEROME - Harbor-Ucla Medical Center
item RICH, STEPHEN - University Of Virginia
item ROBINSON-COHEN, CASSIANNE - Vanderbilt University Medical Center
item DEN HEIJER, MARTIN - Erasmus Medical Center
item JARVELIN, MARJO - Imperial College
item CAVADINO, ALANA - University College London
item JOSHI, PETER - University Of Edinburgh
item WILSON, JAMES - University Of Edinburgh
item HAYWARD, CAROLINE - University Of Edinburgh
item LIND, LARS - Uppsala University
item MICHAELSSON, KARL - Uppsala University
item TROMPET, STELLA - Leiden University Medical Center
item ZILLIKENS, M - Erasmus Medical Center
item UITTERLINDEN, ANDRE - Erasmus Medical Center
item RIVADENEIRA, FERNANDO - Erasmus Medical Center
item BROER, LINDA - Erasmus Medical Center
item ZGAGA, LINA - University Of Dublin
item CAMPBELL, HARRY - University Of Edinburgh
item THEODORATOU, EVROPI - University Of Edinburgh
item FARRINGTON, SUSAN - University Of Edinburgh
item TIMOFEEVA, MARIA - University Of Edinburgh
item DUNLOP, MALCOM - University Of Edinburgh
item VALDES, ANA - University Of Nottingham
item TIKKANEN, EMMI - University Of Helsinki
item LEHTIMAKI, TERHO - University Of Tampere
item LYYTIKAINEN, LEO - University Of Tampere
item KAHONEN, MIKA - Tampere University Hospital
item RAITAKARI, OLLI - University Of Turku
item WANG, THOMAS - Vanderbilt University Medical Center
item HYPPONEN, ELENA - University College London
item KRAFT, PETER - Harvard School Of Public Health
item KIEL, DOUGLAS - Hebrew Senior Life

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/15/2017
Publication Date: 1/17/2018
Citation: Jiang, X., O'Reilly, P.F., Aschard, H., Hsu, Y.H., Richards, J.B., Dupuis, J., Ingelsson, E., Karasik, D., Pilz, S., Berry, D., Kestenbaum, B., Zheng, J., Luan, J., Sofianopoulou, E., Streeten, E.A., Albanes, D., Lutsey, P.L., Yao, L., Tang, W., Econs, M.J., Wallaschofski, H., Volzke, H., Zhou, A., Power, C., McCarthy, M.I., Michos, E.D., Boerwinkle, E., Weinstein, S.J., Freedman, N.D., Huang, W.Y., Van Schoor, N.M., van der Velde, N., de Groot, L.C., Enneman, A., Cupples, L.A., Booth, S.L., Vasan, R.S., Liu, C.T., Zhou, Y., Ripatti, S., Ohlsson, C., Vandeput, L., Lorentzon, M., Eriksson, J.G., Shea, M.K., Houston, D.K., Kritshevsky, S.B., Liu, Y., Lohman, K.K., Ferucci, L., Peacock, M., Gieger, C., Beekman, M., Slagboom, E., Deelen, J., van Heemst, D., Kleber, M.E., Marz, W., de Boer, I.H., Wood, A.C., Rotter, J.I., Rich, S.S., Robinson-Cohen, C., den Heijer, M., Jarvelin, M.R., Cavadino, A., Joshi, P.K., Wilson, J.F., Hayward, C., Lind, L., Michaelsson, K., Trompet, S., Zillikens, M.C., Uitterlinden, A.G., Rivadeneira, F., Broer, L., Zgaga, L., Campbell, H., Theodoratou, E., Farrington, S.M., Timofeeva, M., Dunlop, M.G., Valdes, A.M., Tikkanen, E., Lehtimaki, T., Lyytikainen, L.P., Kahonen, M., Raitakari, O.T., Wang, T.J., Hypponen, E., Kraft, P., Kiel, D.P. 2018. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature Communications. 9:260. http://dx.doi.org/10.1038/s41467-017-02662-2.

Interpretive Summary: Vitamin D deficiency has been linked to many health conditions, including obesity and its outcomes cardiovascular disease and cancer. Levels of Vitamin D in the blood are influenced by many factors including sun exposure, age, dietary intake of certain foods such as fortified dairy products and oily fish, supplements, and genetic factors, but the genetic reasons why some individuals have higher (better) levels of blood Vitamin D than others are poorly understood. To address this problem, we analyzed genetic variation across the whole genome to look for locations where genetic differences associate with differences in Vitamin D levels. We confirmed three known genetic loci, validated one suspected genetic locus, and identified two new genetic loci associated with Vitamin D levels. This work is of importance to other scientists who can use this information to identify the biological pathways explaining why some people have higher Vitamin D in their blood than others. Eventually, this subsequent information may help us design new interventions or therapeutic options for raising Vitamin D in the blood, which should be of interest to those at risk of obesity and cardiovascular disease, as well as their care providers.

Technical Abstract: Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P=4.7×10-9 at rs8018720 in SEC23A, and P=1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.