Moonil Kang, Ting Fang Alvin Ang, Sherral A. Devine, Richard Sherva, Shubhabrata Mukherjee, Emily H. Trittschuh, Phoebe Scollard, Michael Lee, Seo-Eun Choi, Brandon Klinedinst, Connie Nakano, Logan C. Dumitrescu, Timothy J. Hohman, Michael L. Cuccaro, Andrew J. Saykin, Walter A. Kukull, David A. Bennett, Li-San Wang, Richard P. Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Paul K. Crane, Rhoda Au, Kathryn L. Lunetta, Jesse Mez, Lindsay A. Farrer
{"title":"纵向血压和协调认知表现测量的全基因组多效性分析","authors":"Moonil Kang, Ting Fang Alvin Ang, Sherral A. Devine, Richard Sherva, Shubhabrata Mukherjee, Emily H. Trittschuh, Phoebe Scollard, Michael Lee, Seo-Eun Choi, Brandon Klinedinst, Connie Nakano, Logan C. Dumitrescu, Timothy J. Hohman, Michael L. Cuccaro, Andrew J. Saykin, Walter A. Kukull, David A. Bennett, Li-San Wang, Richard P. Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Paul K. Crane, Rhoda Au, Kathryn L. Lunetta, Jesse Mez, Lindsay A. Farrer","doi":"10.1002/alz.70681","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Identifying pleiotropy for blood pressure (BP) and cognitive performance measures may indicate mechanistic links between hypertension and Alzheimer's disease (AD).</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>We performed a pleiotropy genome-wide association study (GWAS) for paired measures of systolic, diastolic, pulse, and mean arterial pressure with memory, executive function, and language scores using 116,075 exam data from 25,726 participants in clinic-based and prospective cohorts. Significant findings were evaluated by Bayesian colocalization and differential gene expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Genome-wide significant pleiotropy for BP and cognitive performance with <i>JPH2</i>, <i>GATA3</i>, <i>PAX2</i>, <i>LOC105371656</i>, and <i>SUFU</i> in the total sample; <i>RTN4</i>, <i>ULK2</i>, <i>SORBS2</i>, and <i>LOC100128993</i> in prospective cohorts; and <i>ADAMTS3</i> and <i>LINC02946</i> in clinic-based cohorts. Six pleiotropic loci influence cognition directly, and six genes were differentially expressed between pathologically confirmed AD cases with and without antemortem cognitive impairment.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our results provide insight into mechanisms underlying hypertension and AD.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Genome-wide significant pleiotropy in blood pressure (BP) and cognitive performance measures were identified with 11 novel loci: <i>JPH2</i>, <i>GATA3</i>, <i>PAX2</i>, <i>LOC105371656</i>, <i>SUFU</i> in the total sample; <i>RTN4</i>, <i>ULK2</i>, <i>SORBS2</i>, <i>LOC100128993</i> in prospective cohorts; and <i>ADAMTS3</i>, <i>LINC02946</i> in clinic-based cohorts.</li>\n \n <li><i>SUFU</i>, <i>RTN4</i>, <i>SORBS2</i>, <i>ADAMTS3</i>, and <i>GATA3</i> affected cognition directly rather than through BP.</li>\n \n <li><i>ACTR1A</i>, <i>HIF1AN</i>, <i>ADAMTS3</i>, <i>RTN4</i>, <i>SORBS2</i>, and <i>SUFU</i> at pleiotropic loci were differentially expressed among controls and pathologically confirmed AD cases with and without clinical symptoms.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 9","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70681","citationCount":"0","resultStr":"{\"title\":\"Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures\",\"authors\":\"Moonil Kang, Ting Fang Alvin Ang, Sherral A. Devine, Richard Sherva, Shubhabrata Mukherjee, Emily H. Trittschuh, Phoebe Scollard, Michael Lee, Seo-Eun Choi, Brandon Klinedinst, Connie Nakano, Logan C. Dumitrescu, Timothy J. Hohman, Michael L. Cuccaro, Andrew J. Saykin, Walter A. Kukull, David A. Bennett, Li-San Wang, Richard P. Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Paul K. Crane, Rhoda Au, Kathryn L. Lunetta, Jesse Mez, Lindsay A. Farrer\",\"doi\":\"10.1002/alz.70681\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>Identifying pleiotropy for blood pressure (BP) and cognitive performance measures may indicate mechanistic links between hypertension and Alzheimer's disease (AD).</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>We performed a pleiotropy genome-wide association study (GWAS) for paired measures of systolic, diastolic, pulse, and mean arterial pressure with memory, executive function, and language scores using 116,075 exam data from 25,726 participants in clinic-based and prospective cohorts. Significant findings were evaluated by Bayesian colocalization and differential gene expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>Genome-wide significant pleiotropy for BP and cognitive performance with <i>JPH2</i>, <i>GATA3</i>, <i>PAX2</i>, <i>LOC105371656</i>, and <i>SUFU</i> in the total sample; <i>RTN4</i>, <i>ULK2</i>, <i>SORBS2</i>, and <i>LOC100128993</i> in prospective cohorts; and <i>ADAMTS3</i> and <i>LINC02946</i> in clinic-based cohorts. 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Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures
INTRODUCTION
Identifying pleiotropy for blood pressure (BP) and cognitive performance measures may indicate mechanistic links between hypertension and Alzheimer's disease (AD).
METHODS
We performed a pleiotropy genome-wide association study (GWAS) for paired measures of systolic, diastolic, pulse, and mean arterial pressure with memory, executive function, and language scores using 116,075 exam data from 25,726 participants in clinic-based and prospective cohorts. Significant findings were evaluated by Bayesian colocalization and differential gene expression in brain tissue from pathologically confirmed AD cases with and without clinical symptoms.
RESULTS
Genome-wide significant pleiotropy for BP and cognitive performance with JPH2, GATA3, PAX2, LOC105371656, and SUFU in the total sample; RTN4, ULK2, SORBS2, and LOC100128993 in prospective cohorts; and ADAMTS3 and LINC02946 in clinic-based cohorts. Six pleiotropic loci influence cognition directly, and six genes were differentially expressed between pathologically confirmed AD cases with and without antemortem cognitive impairment.
DISCUSSION
Our results provide insight into mechanisms underlying hypertension and AD.
Highlights
Genome-wide significant pleiotropy in blood pressure (BP) and cognitive performance measures were identified with 11 novel loci: JPH2, GATA3, PAX2, LOC105371656, SUFU in the total sample; RTN4, ULK2, SORBS2, LOC100128993 in prospective cohorts; and ADAMTS3, LINC02946 in clinic-based cohorts.
SUFU, RTN4, SORBS2, ADAMTS3, and GATA3 affected cognition directly rather than through BP.
ACTR1A, HIF1AN, ADAMTS3, RTN4, SORBS2, and SUFU at pleiotropic loci were differentially expressed among controls and pathologically confirmed AD cases with and without clinical symptoms.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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