05927nas a2201285 4500008004100000022001400041245009300055210006900148260001600217300001000233490000800243520230500251653001102556653003202567653003102599653001902630653002402649653001102673653004002684653003802724653003402762653001702796653001502813653001102828653001602839653003002855653002702885653003602912653001202948653001802960653001402978653002502992100002003017700001603037700002003053700002203073700002403095700001703119700002103136700002703157700001903184700002203203700002003225700002103245700002203266700002303288700002203311700002403333700001903357700001503376700002603391700002203417700001803439700002003457700002103477700001703498700002203515700002003537700002103557700001903578700001903597700002303616700001603639700001803655700002003673700002103693700002203714700002503736700002203761700001803783700002003801700001803821700001803839700002303857700002803880700001803908700002403926700002103950700002003971700001903991700001604010700002104026700001704047700001704064700002204081700002004103700002704123700002004150700001904170700002004189700002304209700002004232700002204252700001904274700002304293700002004316700002804336700001904364700002704383700001904410700002404429700002204453700002804475700002004503700001804523700001904541700002104560700002404581856003604605 2010 eng d a1474-547X00aCommon genetic determinants of vitamin D insufficiency: a genome-wide association study.0 aCommon genetic determinants of vitamin D insufficiency a genomew c2010 Jul 17 a180-80 v3763 a
BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.
METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.
FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.
INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.
FUNDING: Full funding sources listed at end of paper (see Acknowledgments).
10aCanada10aChromosomes, Human, Pair 1110aChromosomes, Human, Pair 410aCohort Studies10aDietary Supplements10aEurope10aEuropean Continental Ancestry Group10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHeterozygote10aHomozygote10aHumans10aImmunoassay10aInternational Cooperation10aLinkage Disequilibrium10aPolymorphism, Single Nucleotide10aSeasons10aUnited States10aVitamin D10aVitamin D Deficiency1 aWang, Thomas, J1 aZhang, Feng1 aRichards, Brent1 aKestenbaum, Bryan1 avan Meurs, Joyce, B1 aBerry, Diane1 aKiel, Douglas, P1 aStreeten, Elizabeth, A1 aOhlsson, Claes1 aKoller, Daniel, L1 aPeltonen, Leena1 aCooper, Jason, D1 aO'Reilly, Paul, F1 aHouston, Denise, K1 aGlazer, Nicole, L1 aVandenput, Liesbeth1 aPeacock, Munro1 aShi, Julia1 aRivadeneira, Fernando1 aMcCarthy, Mark, I1 aAnneli, Pouta1 ade Boer, Ian, H1 aMangino, Massimo1 aKato, Bernet1 aSmyth, Deborah, J1 aBooth, Sarah, L1 aJacques, Paul, F1 aBurke, Greg, L1 aGoodarzi, Mark1 aCheung, Ching-Lung1 aWolf, Myles1 aRice, Kenneth1 aGoltzman, David1 aHidiroglou, Nick1 aLadouceur, Martin1 aWareham, Nicholas, J1 aHocking, Lynne, J1 aHart, Deborah1 aArden, Nigel, K1 aCooper, Cyrus1 aMalik, Suneil1 aFraser, William, D1 aHartikainen, Anna-Liisa1 aZhai, Guangju1 aMacdonald, Helen, M1 aForouhi, Nita, G1 aLoos, Ruth, J F1 aReid, David, M1 aHakim, Alan1 aDennison, Elaine1 aLiu, Yongmei1 aPower, Chris1 aStevens, Helen, E1 aJaana, Laitinen1 aVasan, Ramachandran, S1 aSoranzo, Nicole1 aBojunga, Jörg1 aPsaty, Bruce, M1 aLorentzon, Mattias1 aForoud, Tatiana1 aHarris, Tamara, B1 aHofman, Albert1 aJansson, John-Olov1 aCauley, Jane, A1 aUitterlinden, André, G1 aGibson, Quince1 aJarvelin, Marjo-Riitta1 aKarasik, David1 aSiscovick, David, S1 aEcons, Michael, J1 aKritchevsky, Stephen, B1 aFlorez, Jose, C1 aTodd, John, A1 aDupuis, Josée1 aHyppönen, Elina1 aSpector, Timothy, D uhttps://chs-nhlbi.org/node/120405033nas a2201381 4500008004100000022001400041245013800055210006900193260001600262300000800278490000600286520112300292100001501415700002201430700002001452700001901472700002001491700001901511700002001530700001901550700001701569700001701586700002201603700001901625700001701644700002501661700002701686700002301713700002201736700001201758700001801770700002201788700002501810700001901835700001401854700001701868700002201885700002001907700002101927700002801948700002201976700001801998700002702016700002802043700003102071700001802102700002502120700002002145700002702165700001802192700001702210700002002227700001902247700002402266700002302290700002302313700001502336700002302351700002802374700001702402700002002419700002002439700001902459700002202478700002002500700002002520700001802540700002202558700002202580700002002602700002002622700002002642700002202662700002102684700003002705700002402735700002702759700002002786700002002806700002102826700002202847700001502869700002302884700002002907700002502927700002802952700002602980700001703006700001603023700002003039700002403059700002503083700002103108700002303129700001903152700001903171700002203190700002803212700002003240700002303260700001903283700002003302700001903322700001903341700002503360700002403385700002103409700002503430700001803455700002503473700001703498700002103515700002003536700002103556700001703577700002103594856003603615 2018 eng d a2041-172300aGenome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.0 aGenomewide association study in 79366 Europeanancestry individua c2018 Jan 17 a2600 v93 aVitamin 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 at rs8018720 in SEC23A, and P = 1.9×10 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.
1 aJiang, Xia1 aO'Reilly, Paul, F1 aAschard, Hugues1 aHsu, Yi-Hsiang1 aRichards, Brent1 aDupuis, Josée1 aIngelsson, Erik1 aKarasik, David1 aPilz, Stefan1 aBerry, Diane1 aKestenbaum, Bryan1 aZheng, Jusheng1 aLuan, Jianan1 aSofianopoulou, Eleni1 aStreeten, Elizabeth, A1 aAlbanes, Demetrius1 aLutsey, Pamela, L1 aYao, Lu1 aTang, Weihong1 aEcons, Michael, J1 aWallaschofski, Henri1 aVölzke, Henry1 aZhou, Ang1 aPower, Chris1 aMcCarthy, Mark, I1 aMichos, Erin, D1 aBoerwinkle, Eric1 aWeinstein, Stephanie, J1 aFreedman, Neal, D1 aHuang, Wen-Yi1 avan Schoor, Natasja, M1 avan der Velde, Nathalie1 ade Groot, Lisette, C P G M1 aEnneman, Anke1 aCupples, Adrienne, L1 aBooth, Sarah, L1 aVasan, Ramachandran, S1 aLiu, Ching-Ti1 aZhou, Yanhua1 aRipatti, Samuli1 aOhlsson, Claes1 aVandenput, Liesbeth1 aLorentzon, Mattias1 aEriksson, Johan, G1 aShea, Kyla1 aHouston, Denise, K1 aKritchevsky, Stephen, B1 aLiu, Yongmei1 aLohman, Kurt, K1 aFerrucci, Luigi1 aPeacock, Munro1 aGieger, Christian1 aBeekman, Marian1 aSlagboom, Eline1 aDeelen, Joris1 avan Heemst, Diana1 aKleber, Marcus, E1 aMärz, Winfried1 ade Boer, Ian, H1 aWood, Alexis, C1 aRotter, Jerome, I1 aRich, Stephen, S1 aRobinson-Cohen, Cassianne1 aHeijer, Martin, den1 aJarvelin, Marjo-Riitta1 aCavadino, Alana1 aJoshi, Peter, K1 aWilson, James, F1 aHayward, Caroline1 aLind, Lars1 aMichaëlsson, Karl1 aTrompet, Stella1 aZillikens, Carola, M1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aBroer, Linda1 aZgaga, Lina1 aCampbell, Harry1 aTheodoratou, Evropi1 aFarrington, Susan, M1 aTimofeeva, Maria1 aDunlop, Malcolm, G1 aValdes, Ana, M1 aTikkanen, Emmi1 aLehtimäki, Terho1 aLyytikäinen, Leo-Pekka1 aKähönen, Mika1 aRaitakari, Olli, T1 aMikkilä, Vera1 aIkram, Arfan, M1 aSattar, Naveed1 aJukema, Wouter1 aWareham, Nicholas, J1 aLangenberg, Claudia1 aForouhi, Nita, G1 aGundersen, Thomas, E1 aKhaw, Kay-Tee1 aButterworth, Adam, S1 aDanesh, John1 aSpector, Timothy1 aWang, Thomas, J1 aHyppönen, Elina1 aKraft, Peter1 aKiel, Douglas, P uhttps://chs-nhlbi.org/node/766703699nas a2200673 4500008004100000022001400041245018700055210006900242260001600311300000900327520167400336100001402010700002002024700002102044700002402065700002402089700001602113700002302129700001402152700002002166700002202186700002002208700002002228700002802248700002202276700002402298700002202322700001902344700001602363700002302379700002102402700002802423700002302451700002402474700002202498700002102520700002602541700002102567700002002588700002202608700002102630700002202651700002002673700002302693700002202716700002002738700002502758700001702783700001902800700002002819700001902839700002502858700001902883700002102902700002002923700002102943700002502964856003602989 2018 eng d a1475-266200aMeta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.0 aMetaanalysis across Cohorts for Heart and Aging Research in Geno c2018 Sep 12 a1-123 aThe role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
1 aXu, Jiayi1 aBartz, Traci, M1 aChittoor, Geetha1 aEiriksdottir, Gudny1 aManichaikul, Ani, W1 aSun, Fangui1 aTerzikhan, Natalie1 aZhou, Xia1 aBooth, Sarah, L1 aBrusselle, Guy, G1 ade Boer, Ian, H1 aFornage, Myriam1 aFrazier-Wood, Alexis, C1 aGraff, Mariaelisa1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHofman, Albert1 aHou, Ruixue1 aHouston, Denise, K1 aJacobs, David, R1 aKritchevsky, Stephen, B1 aLatourelle, Jeanne1 aLemaitre, Rozenn, N1 aLutsey, Pamela, L1 aO'Connor, George1 aOelsner, Elizabeth, C1 aPankow, James, S1 aPsaty, Bruce, M1 aRohde, Rebecca, R1 aRich, Stephen, S1 aRotter, Jerome, I1 aSmith, Lewis, J1 aStricker, Bruno, H1 aVoruganti, Saroja1 aWang, Thomas, J1 aZillikens, Carola, M1 aBarr, Graham1 aDupuis, Josée1 aGharib, Sina, A1 aLahousse, Lies1 aLondon, Stephanie, J1 aNorth, Kari, E1 aSmith, Albert, V1 aSteffen, Lyn, M1 aHancock, Dana, B1 aCassano, Patricia, A uhttps://chs-nhlbi.org/node/7775