Chakraborty Shreya, Subramanian Krithika, Rajesh Akkshaya, Majumder Rupanwita, Rupanagudi Khader Valli, Mensegere Abhishek, Issac Thomas Gregor, Sundarakumar Jonas, Kahali Bratati
Centre for Brain Research, Indian Institute of Science, Bangalore, India.
Interdisciplinary Mathematical Sciences (IMI), Indian Institute of Science, Bangalore, India.
Alzheimers Dement. 2025 Jul;21(7):e70429. doi: 10.1002/alz.70429.
Cardiometabolic risks affect cognition during aging, yet genetic basis for both remain understudied in Indians.
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.
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.
These findings illustrate the impact of cardiometabolic factors on cognition in a rural socioeconomically disadvantaged population, advancing efforts to address health disparities.
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.
心脏代谢风险会影响衰老过程中的认知能力，然而在印度人群中，两者的遗传基础仍未得到充分研究。
本研究构建了一个与祖先匹配的印度单倍型参考面板，用于对5111名印度农村居民进行基因型填充。对20种认知性状和10种心脏代谢性状进行单基因座、基于基因和条件全基因组关联分析，随后通过多模式功能注释对已确定的关联进行随访。此外，通过孟德尔随机化研究心脏代谢和认知表型之间的因果相互关系。
确定了1个与记忆相关的新基因座和17个与心脏代谢表型相关的新基因座（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。通过APOC3-APOA4-APOA5-ZPR1-BUD13等基因工具确定了心脏代谢性状对各种认知领域的因果作用。
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，推动了消除健康差距的努力。
我们新构建的与祖先匹配的单倍型参考面板为印度人群提供了更高的基因型填充准确性。分别确定了1个和17个与认知和心脏代谢性状相关的新的全基因组显著单基因座。确定了所有表型的几个亚基因组范围的关联。在对多个测试表型进行校正后，通过合并蛋白质截短变异（PTV），确定了2个在全基因组水平上与心脏代谢性状相关的基因。与1000基因组超级人群相比，发现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，在APOC3-APOA4-APOA5-ZPR1-BUD13等基因工具中发现了心脏代谢性状对认知的不良因果作用。
