Genome-wide study links cardiometabolic factors to cognition via APOA4-APOA5-ZPR1-BUD13 and other loci in rural Indians

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-15 DOI:10.1002/alz.70429

Shreya Chakraborty, Krithika Subramanian, Akkshaya Rajesh, Rupanwita Majumder, Khader Valli Rupanagudi, Abhishek Mensegere, TLSA study team, Thomas Gregor Issac, SANSCOG study team, Jonas Sundarakumar, Bratati Kahali

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引用次数: 0

Abstract

INTRODUCTION

Cardiometabolic risks affect cognition during aging, yet genetic basis for both remain understudied in Indians.

METHODS

This study constructs an ancestry-matched Indian haplotype reference panel for genotype imputation of 5111 rural Indians. Single-locus, gene-based, conditional genome-wide association analyses are performed on 20 cognitive and 10 cardiometabolic traits, with subsequent follow-up of identified associations through multimodal functional annotation. Furthermore, causal interrelationships between cardiometabolic and cognitive phenotypes by Mendelian randomization are investigated.

RESULTS

One novel memory-associated and 17 novel cardiometabolic phenotypes-associated (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], total cholesterol [TC], TG:HDL, and visceral adiposity index [VAI]) genome-wide significant loci, and multiple genes are identified. AMIGO1 (delayed-recall) and ZPR1-APOA5 (metabolic syndrome) exhibit distinct haplotype structure compared to other populations. Causal roles of cardiometabolic traits on various cognitive domains are identified via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13 among others.

DISCUSSION

These findings illustrate the impact of cardiometabolic factors on cognition in a rural socioeconomically disadvantaged population, advancing efforts to address health disparities.

Highlights

Our newly constructed ancestry-matched haplotype reference panel gives better genotype imputation accuracy for the Indian population.
One and 17 novel genome-wide significant single-loci were identified to be associated with cognitive and cardiometabolic traits, respectively. Several subgenome-wide hits for all phenotypes were identified.
Collapsing protein truncating variants (PTVs), there were two genes identified to be associated with cardiometabolic traits at a genome-wide level of significance, correcting for multiple phenotypes tested.
Haplotypic differences were identified compared to 1000 Genomes superpopulations for genes influencing delayed recall and metabolic syndrome.
Adverse causal roles of cardiometabolic traits on cognition were uncovered via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13, among others, through Mendelian randomization.

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全基因组研究通过印度农村APOA4-APOA5-ZPR1-BUD13和其他基因座将心脏代谢因素与认知联系起来

心脏代谢风险会影响衰老过程中的认知能力，但在印度人身上，这两者的遗传基础仍未得到充分研究。方法构建5111例农村印第安人的遗传匹配单倍型参考面板。对20个认知特征和10个心脏代谢特征进行了单位点、基于基因的条件全基因组关联分析，随后通过多模态功能注释对确定的关联进行了随访。此外，通过孟德尔随机化研究了心脏代谢和认知表型之间的因果关系。结果发现了1个新的记忆相关基因位点和17个新的心脏代谢表型相关基因位点（高密度脂蛋白胆固醇[HDL- c]、低密度脂蛋白胆固醇[LDL-C]、甘油三酯[TG]、总胆固醇[TC]、TG:HDL和内脏脂肪指数[VAI]），以及多个基因。与其他人群相比，AMIGO1（延迟回忆）和ZPR1-APOA5（代谢综合征）表现出独特的单倍型结构。在apo3 - apoa4 - apoa5 - zpr1 - bud13等基因中，心脏代谢性状在各种认知领域的因果作用被确定。这些发现说明了心脏代谢因素对农村社会经济弱势人群认知的影响，促进了解决健康差异的努力。我们新构建的祖先匹配单倍型参考面板为印度人群提供了更好的基因型插入准确性。分别鉴定出1个和17个新的全基因组显著单位点与认知和心脏代谢性状相关。确定了所有表型的几个亚基因组全命中。在蛋白质截断变异（PTVs）中，有两个基因在全基因组水平上被鉴定为与心脏代谢性状相关，纠正了多种表型。与1000个基因组超级群体相比，确定了影响延迟回忆和代谢综合征的基因的单倍型差异。通过孟德尔随机化，通过遗传工具揭示了APOC3-APOA4-APOA5-ZPR1-BUD13等心脏代谢性状对认知的不利因果作用。

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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.