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库（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）全基因组关联研究（Genome-Wide Association Study, GWAS）汇总统计数据。若使用本数据集，请引用Atkins等人2021年发表的论文《全基因组关联研究揭示健康衰老中的脑通路》（原文标题：A Genome-Wide Association Study of the Frailty Index Highlights Brain Pathways in Healthy Aging）。

本数据集包含两类文件：1. 全基因组荟萃分析结果文件；2. 英国生物库与瑞典双生子登记库中的单个单核苷酸多态性（single nucleotide polymorphism, SNP）关联结果文件。每份汇总统计数据文件均附带README说明文档。所有碱基对坐标均采用GRCh37参考基因组版本。

**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。临床实践中通常基于个体生命过程中积累的多项健康缺损指标，通过衰弱指数（FI）对衰弱状态进行量化评估。衰弱指数的潜在发病机制呈多因素特征，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提供新的干预思路。

本研究针对欧洲血统人群的衰弱指数开展全基因组关联研究荟萃分析，研究对象包括英国生物库的164610名60至70岁参与者，以及瑞典双生子登记库的10616名41至87岁参与者。衰弱指数的计算分别基于英国生物库的49项、瑞典双生子登记库的44项自我报告的症状、残疾及确诊疾病条目。

本研究共鉴定出14个与衰弱指数显著关联的基因座（p<5×10^-8）。多个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（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。本研究估算的衰弱指数单核苷酸多态性（SNP）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，本研究通过孟德尔随机化（Mendelian randomization）分析筛选出可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。

研究结果表明，衰弱风险受多种遗传因素影响，包括已知的疾病风险因素与心理健康状态，其中脑通路的作用尤为关键。本研究预印本可通过以下链接获取：https://doi.org/10.1101/19007559