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Simulation studies have shown that the regional heritability mapping (RHM) method, which makes use of multiple adjacent SNPs jointly to estimate the genetic effect of a given region of the genome, generally has higher detection power than single-SNP GWAS. However, thus far its use has been mostly limited to agricultural settings, and its potential for the discovery of new genes in human diseases is yet to be fully exploited. In this study, by applying the RHM method to primary biliary cholangitis (PBC) in the Japanese population, we identified three novel loci (<jats:italic>STAT4, ULK4<\/jats:italic>, and <jats:italic>KCNH5<\/jats:italic>) at the genome-wide significance level, two of which (<jats:italic>ULK4<\/jats:italic> and <jats:italic>KCNH5<\/jats:italic>) have not been found associated with PBC in any population previously. Notably, these genes could not be detected by using conventional single-SNP GWAS, highlighting the potential of the RHM method for the detection of new susceptibility loci in human diseases. These findings thereby provide strong empirical evidence that RHM is an effective and practical complementary approach to GWAS in this context. Also, liver tissue mRNA microarray analysis revealed higher gene expression levels in <jats:italic>ULK4<\/jats:italic> in PBC patients (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). Lastly, we estimated the common SNP heritability of PBC in the Japanese population (0.210\u2009\u00b1\u20090.026).<\/jats:p>","DOI":"10.1038\/s41431-021-00854-5","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T01:02:58Z","timestamp":1617930178000},"page":"1282-1291","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Regional heritability mapping identifies several novel loci (STAT4, ULK4, and KCNH5) for primary biliary cholangitis in the Japanese population"],"prefix":"10.1038","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6215-7044","authenticated-orcid":false,"given":"Olivier","family":"Gervais","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3194-0735","authenticated-orcid":false,"given":"Kazuko","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0666-1224","authenticated-orcid":false,"given":"Yosuke","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6713-7875","authenticated-orcid":false,"given":"Yuki","family":"Hitomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6839-4673","authenticated-orcid":false,"given":"Yoshihiro","family":"Aiba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayumi","family":"Ueta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minoru","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushi","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4292-8785","authenticated-orcid":false,"given":"Masao","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,9]]},"reference":[{"key":"854_CR1","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.ajhg.2011.02.002","volume":"88","author":"SH Lee","year":"2011","unstructured":"Lee SH, Wray NR, Goddard ME, Visscher PM. 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Available from: http:\/\/www.lifescience.mext.go.jp\/files\/pdf\/n1115_01.pdf (in Japanese)."}],"container-title":["European Journal of Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00854-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00854-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00854-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T02:03:04Z","timestamp":1629856984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41431-021-00854-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,9]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["854"],"URL":"https:\/\/doi.org\/10.1038\/s41431-021-00854-5","relation":{},"ISSN":["1018-4813","1476-5438"],"issn-type":[{"value":"1018-4813","type":"print"},{"value":"1476-5438","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,9]]},"assertion":[{"value":"19 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This project has been conducted in accordance with the Japanese National Ethical Guidelines for Human Genome\/Gene Analysis [], and reviewed and approved by the ethics committees of the University of Tokyo and of all other participating institutions.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All of the participants gave their written consent prior to study enrollment.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}