Genome-wide pleiotropy analysis of longitudinal blood pressure and harmonized cognitive performance measures

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-09-15 DOI:10.1002/alz.70681

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

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引用次数: 0

Abstract

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.

Abstract Image

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纵向血压和协调认知表现测量的全基因组多效性分析

识别血压（BP）和认知能力测量的多效性可能提示高血压和阿尔茨海默病（AD）之间的机制联系。方法：我们进行了一项多效性全基因组关联研究（GWAS），对收缩压、舒张压、脉搏和平均动脉压与记忆、执行功能和语言评分的配对测量，使用了来自25,726名临床和前瞻性队列参与者的116,075份检查数据。通过贝叶斯共定位和脑组织中有临床症状和无临床症状的病理确诊AD病例的差异基因表达来评估重要发现。结果在全基因组范围内，JPH2、GATA3、PAX2、LOC105371656和SUFU对BP和认知表现具有显著的多效性；RTN4、ULK2、SORBS2和LOC100128993在前瞻性队列中；和ADAMTS3和LINC02946在临床队列中。6个多效性基因座直接影响认知，6个基因在有和没有死前认知障碍的AD病理确诊病例中表达差异。我们的研究结果为高血压和AD的潜在机制提供了见解。在整个样本中发现了11个新的基因座：JPH2、GATA3、PAX2、LOC105371656、SUFU，在血压（BP）和认知能力测量中存在全基因组显著多效性；RTN4、ULK2、SORBS2、LOC100128993在前瞻性队列中；和ADAMTS3， LINC02946在临床队列中。SUFU、RTN4、SORBS2、ADAMTS3和GATA3直接影响认知，而不是通过BP。ACTR1A、HIF1AN、ADAMTS3、RTN4、SORBS2和SUFU的多性位点在对照和病理证实的有和无临床症状的AD患者中表达差异。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

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.