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These advantages make family-based association tests (FBATs) that use siblings as well as parents especially suited for the analysis of late-onset diseases such as Alzheimer\u2019s Disease (AD). However, the application of FBATs to assess sex-specific effects can require additional filtering steps, as sensitivity to sequencing errors is amplified in this type of analysis. Here, we illustrate the implementation of robust analysis approaches and additional filtering steps that can minimize the chances of false positive-findings due to sex-specific sequencing errors. We apply this approach to two family-based AD datasets and identify four novel loci (<jats:italic>GRID1<\/jats:italic>,<jats:italic>RIOK3<\/jats:italic>,<jats:italic>MCPH1<\/jats:italic>,<jats:italic>ZBTB7C<\/jats:italic>) showing sex-specific association with AD risk. Following stringent quality control filtering, the strongest candidate is<jats:italic>ZBTB7C (P<\/jats:italic><jats:sub>inter<\/jats:sub>\u2009=\u20091.83\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>), in which the minor allele of rs1944572 confers increased risk for AD in females and protection in males.<jats:italic>ZBTB7C<\/jats:italic>encodes the Zinc Finger and BTB Domain Containing 7C, a transcriptional repressor of membrane metalloproteases (MMP). Members of this MMP family were implicated in AD neuropathology.<\/jats:p>","DOI":"10.1038\/s41598-020-61883-6","type":"journal-article","created":{"date-parts":[[2020,3,19]],"date-time":"2020-03-19T11:04:07Z","timestamp":1584615847000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Identification of Novel Alzheimer\u2019s Disease Loci Using Sex-Specific Family-Based Association Analysis of Whole-Genome Sequence Data"],"prefix":"10.1038","volume":"10","author":[{"given":"Dmitry","family":"Prokopenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Hecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-5885","authenticated-orcid":false,"given":"Rory","family":"Kirchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad A.","family":"Chapman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Mullin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8621-3271","authenticated-orcid":false,"given":"Winston","family":"Hide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Bertram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Laird","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn L.","family":"DeMeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7032-1454","authenticated-orcid":false,"given":"Rudolph E.","family":"Tanzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,19]]},"reference":[{"key":"61883_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.jalz.2018.06.3063","volume":"15","author":"KA Matthews","year":"2019","unstructured":"Matthews, K. 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