{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:39:56Z","timestamp":1772159996027,"version":"3.50.1"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T00:00:00Z","timestamp":1580860800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Human Genetics"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Previous studies have implicated common and rare genetic variants as risk factors for late\u2010onset Alzheimer's disease (LOAD). Here, weighted burden analysis was applied to over 10,000 exome\u2010sequenced subjects from the Alzheimer's Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for\n                    <jats:italic>TREM2<\/jats:italic>\n                    ,\n                    <jats:italic>ABCA7<\/jats:italic>\n                    , and\n                    <jats:italic>SORL1<\/jats:italic>\n                    . Additional support was provided for\n                    <jats:italic>PSEN1<\/jats:italic>\n                    (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a00.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in\n                    <jats:italic>PIK3R1<\/jats:italic>\n                    ,\n                    <jats:italic>WNT7A<\/jats:italic>\n                    ,\n                    <jats:italic>C1R<\/jats:italic>\n                    , and\n                    <jats:italic>EXOC5<\/jats:italic>\n                    might increase risk and that variants in\n                    <jats:italic>TIAF1<\/jats:italic>\n                    and\/or\n                    <jats:italic>NDRG2<\/jats:italic>\n                    might have a protective effect. Overall, there was strong evidence (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a05\u00a0\u00d7\u00a010\n                    <jats:sup>\u22126<\/jats:sup>\n                    ) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Because\n                    <jats:italic>PIK3R1<\/jats:italic>\n                    variants are expected to impair PI3K\/Akt\/GSK\u20103\u03b2 signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models, suggesting that this pathway is protective against Alzheimer's disease.\n                  <\/jats:p>","DOI":"10.1111\/ahg.12375","type":"journal-article","created":{"date-parts":[[2020,2,5]],"date-time":"2020-02-05T04:25:27Z","timestamp":1580876727000},"page":"291-302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Weighted burden analysis of exome\u2010sequenced late\u2010onset Alzheimer's cases and controls provides further evidence for a role for\n                    <i>PSEN1<\/i>\n                    and suggests involvement of the PI3K\/Akt\/GSK\u20103\u03b2 and WNT signalling 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