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Studies have shown that haplotype\u2010based methods may provide more power in disease mapping than methods based on single markers when, for example, multiple disease\u2010susceptibility variants occur within the same gene. A limitation of haplotype\u2010based methods is that the number of parameters increases exponentially with the number of SNPs, inducing a commensurate increase in the degrees of freedom and weakening the power to detect associations. To address this limitation, we introduce a hierarchical linkage disequilibrium model for disease mapping, based on a reparametrization of the multinomial haplotype distribution, where every parameter corresponds to the cumulant of each possible subset of a set of loci. This hierarchy present in the parameters enables us to employ flexible testing strategies over a range of parameter sets: from standard single SNP analyses through the full haplotype distribution tests, reducing degrees of freedom and increasing the power to detect associations. We show via extensive simulations that our approach maintains the type I error at nominal level and has increased power under many realistic scenarios, as compared to single SNP and standard haplotype\u2010based studies. To evaluate the performance of our proposed methodology in real data, we analyze genome\u2010wide data from the Wellcome Trust Case\u2010Control\u00a0Consortium.<\/jats:p>","DOI":"10.1002\/bimj.201800053","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T08:02:14Z","timestamp":1548748934000},"page":"747-768","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Powerful testing via hierarchical linkage disequilibrium in haplotype association studies"],"prefix":"10.1002","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8953-804X","authenticated-orcid":false,"given":"Brunilda","family":"Balliu","sequence":"first","affiliation":[{"name":"Department of Biomathematics David Geffen School of Medicine UCLA Los Angeles CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeanine J.","family":"Houwing\u2010Duistermaat","sequence":"additional","affiliation":[{"name":"School of Mathematics University of Leeds Leeds UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9108-9212","authenticated-orcid":false,"given":"Stefan","family":"B\u00f6hringer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Sciences Section Medical Statistics and Bioinformatics Leiden University Medical Center Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,1,28]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Ahlbach C. 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