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We previously reported a rare functional variant of\n                    <jats:italic>SHARPIN<\/jats:italic>\n                    (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of\n                    <jats:italic>SHARPIN<\/jats:italic>\n                    in Japanese population. Six highly deleterious variants of\n                    <jats:italic>SHARPIN<\/jats:italic>\n                    , comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0016, odds ratio\u2009=\u20091.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-\u03baB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.\n                  <\/jats:p>","DOI":"10.1038\/s10038-021-00987-x","type":"journal-article","created":{"date-parts":[[2021,11,4]],"date-time":"2021-11-04T22:02:54Z","timestamp":1636063374000},"page":"203-208","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A functional variant of SHARPIN confers increased risk of late-onset Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5326-4729","authenticated-orcid":false,"given":"Yuya","family":"Asanomi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daichi","family":"Shigemizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Akiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akinori","family":"Miyashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risa","family":"Mitsumori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norikazu","family":"Hara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8828-8085","authenticated-orcid":false,"given":"Takeshi","family":"Ikeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumpei","family":"Niida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouichi","family":"Ozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"987_CR1","unstructured":"Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M, et al. 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