{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:14Z","timestamp":1786976834222,"version":"build-2736575974"},"reference-count":28,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,12,21]],"date-time":"2011-12-21T00:00:00Z","timestamp":1324425600000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We performed whole exome sequencing to further understand the heightened prevalence of MS in these families.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Forty\u2010three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, &gt;58,000 variants were identified in each individual. A rare variant in the\n                      <jats:italic>CYP27B1<\/jats:italic>\n                      gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D\u2010dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent\u2010affected child trios (\n                      <jats:italic>p<\/jats:italic>\n                      = 1 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ). Further genotyping in &gt;12,500 individuals showed that other rare loss of function\n                      <jats:italic>CYP27B1<\/jats:italic>\n                      variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3\u20139.4;\n                      <jats:italic>p<\/jats:italic>\n                      = 5 \u00d7 10\n                      <jats:sup>\u22127<\/jats:sup>\n                      ). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35\u00d7 (\n                      <jats:italic>p<\/jats:italic>\n                      = 3 \u00d7 10\n                      <jats:sup>\u22129<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation:<\/jats:title>\n                    <jats:p>\n                      A causative role for\n                      <jats:italic>CYP27B1<\/jats:italic>\n                      in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present.\n                      <jats:italic>CYP27B1<\/jats:italic>\n                      encodes the vitamin D\u2010activating 1\u2010alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated. ANN NEUROL 2011;70:881\u2013886\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.22678","type":"journal-article","created":{"date-parts":[[2011,11,25]],"date-time":"2011-11-25T12:09:42Z","timestamp":1322222982000},"page":"881-886","source":"Crossref","is-referenced-by-count":203,"title":["Rare variants in the\n                    <i>CYP27B1<\/i>\n                    gene are associated with multiple sclerosis"],"prefix":"10.1002","volume":"70","author":[{"given":"Sreeram V.","family":"Ramagopalan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Dyment","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Zameel","family":"Cader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie M.","family":"Morrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Disanto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia M.","family":"Morahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio J.","family":"Berlanga\u2010Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Handel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele C.","family":"De Luca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Dessa","family":"Sadovnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Lepage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Montpetit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George C.","family":"Ebers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,12,21]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70042-5"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181a92c25"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-007-0194-6"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1647"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa073493"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.733"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2779"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.499"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0317167100034041"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-3-r25"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03412.x"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/88.2.441"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-2664"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10251"},{"key":"e_1_2_7_19_2","first-page":"506","article-title":"Transmission test for linkage disequilibrium: the insulin gene region and insulin\u2010dependent diabetes mellitus (IDDM)","volume":"52","author":"Spielman RS","year":"1993","journal-title":"Am J Hum Genet"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1086\/301714"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1086\/302156"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.6.809"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2278"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107920.110"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.23.2832"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.38301.686030.63"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra070553"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.87.6.2424"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1340"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.22678","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.22678","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T22:48:28Z","timestamp":1697496508000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.22678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["10.1002\/ana.22678"],"URL":"https:\/\/doi.org\/10.1002\/ana.22678","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.13437018.14811145","asserted-by":"object"}]},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12]]}}}