Genome-Wide Association Study of the Frailty Index - Atkins et al. 2021

Genome-wide summary statistics from the GWAS analysis of the Frailty Index in participants of European descent aged 60+ from UK Biobank and TwinGene. If used please cite paper Atkins et al. 2021 "A Genome-Wide Association Study of the Frailty Index Highlights Brain Pathways in Healthy Aging" Included are two files: 1. meta-analysis results, 2. individual SNP associations in UK Biobank and TwinGene README file included with each summary stats file. All base pair coordinates are GRCh37 Abstract Frailty is a common geriatric syndrome, strongly associated with disability, mortality and hospitalisation. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n=164,610, aged 60-70 years) and Swedish TwinGene participants (n=10,616, aged 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene respectively. 14 loci were associated with the FI (p<5*10-8). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p<0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain. Preprint available https://doi.org/10.1101/19007559

本数据集包含来自英国生物银行（UK Biobank）与瑞典双生子登记库（TwinGene）中60岁及以上欧洲血统参与者的衰弱指数（Frailty Index, FI）全基因组关联分析（Genome-Wide Association Study, GWAS）汇总统计数据。若使用本数据集，请引用Atkins等（2021）发表的题为"A Genome-Wide Association Study of the Frailty Index Highlights Brain Pathways in Healthy Aging"的论文。本数据集包含两个文件：1. 荟萃分析结果文件；2. 英国生物银行与瑞典双生子登记库中的单个单核苷酸多态性（Single Nucleotide Polymorphism, SNP）关联数据文件。每个汇总统计文件均附带自述文件（README file）。所有碱基对坐标均采用GRCh37版本。

摘要 衰弱是一种常见的老年综合征，与残疾、死亡及住院风险显著相关。临床通常基于个体生命进程中积累的多项健康缺陷，使用衰弱指数（FI）对衰弱状态进行量化评估。衰弱指数的潜在发病机制具有多因素复杂性，目前尚未完全阐明，但已有研究提示其存在遗传基础，遗传力估计值介于30%至45%之间。阐明衰弱指数的遗传决定因素与生物学机制，或可为延缓甚至预防衰弱发生提供新思路。

本研究对欧洲血统的英国生物银行参与者（n=164610，年龄60~70岁）与瑞典双生子登记库参与者（n=10616，年龄41~87岁）的衰弱指数开展全基因组关联研究荟萃分析。英国生物银行与瑞典双生子登记库的衰弱指数分别基于49项和44项自我报告的症状、残疾及确诊疾病条目计算得到。最终鉴定出14个与衰弱指数显著关联的基因座（p<5×10^-8）。诸多与衰弱指数相关的基因座已被证实与体重指数、心血管疾病、吸烟行为、人类白细胞抗原（Human Leukocyte Antigen, HLA）蛋白、抑郁及神经质等性状存在关联，但其中1个基因座为全新发现。本研究估计的衰弱指数单核苷酸多态性遗传力为11%（0.11，标准误SE=0.005）。富集分析结果显示，在额叶皮层与海马体中表达的基因呈现显著下调趋势（校正后p<0.05）。此外，本研究采用孟德尔随机化（Mendelian randomization）方法鉴定了可能影响衰弱风险的可干预性状与暴露因素，结果显示较高的教育程度遗传风险评分与较低的衰弱程度相关。衰弱风险受诸多遗传因素影响，包括已知的疾病风险因素与心理健康状况，其中大脑通路尤为关键。本研究预印本可通过https://doi.org/10.1101/19007559获取。