Investigating the shared genetic architecture of osteoarthritis and frailty: a genome-wide cross-trait analysis.

Am J Nucl Med Mol Imaging 2024;14(5):316-326 www.ajnmmi.us /ISSN:2160-8407/ajnmmi0159718 Original Article Investigating the shared genetic architecture of osteoarthritis and frailty: a genome-wide cross-trait analysis Honghui Guo1*, Yanjing Chen2*, Xinlu Zhang1, Hong Xiang1, Xin Xiang1, Xingdou Chen1, Wenjie Fu1, Yunhua Wang1, Xiaowei Ma1 Department of Nuclear Medicine, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, PR China; 2Department of Radiology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha 410011, Hunan, PR China. *Equal contributors. 1 Received August 10, 2024; Accepted September 1, 2024; Epub October 15, 2024; Published October 30, 2024 Abstract: Observational studies suggest a link between osteoarthritis (OA) and frailty, but the shared genetic architecture and causal relationships remain unclear. We analyzed X-ray and 18F-FDG PET/CT images in frail and non-frail individuals and conducted genetic correlation analyses using Linkage Disequilibrium Score Regression (LDSC) based on recent Genome-Wide Association Studies (GWAS) for OA and frailty. We identified pleiotropic single-nucleotide polymorphisms (SNPs) through Cross-Phenotype Association (CPASSOC) and Colocalization (COLOC) analyses and investigated genetic overlaps using Multi-marker Analysis of GenoMic Annotation (MAGMA). Transcriptome-wide association studies (TWAS) were conducted to analyze pleiotropic gene expression, and Mendelian Randomization (MR) was used to assess causal relationships between OA and frailty. Frail individuals showed more severe OA on X-ray (67% vs. 31%, P ≤ 0.01) and higher SUVmax on 18F-FDG PET/CT (4.1 vs. 3.6, P < 0.05) compared to non-frail individuals. Genetic correlation between frailty and OA was significant (rg = 0.532, P = 4.230E-88). Cross-trait analyses identified 42 genomic loci and 138 genes shared between the conditions. COLOC analysis revealed 2 pleiotropic loci, while TWAS identified 27 significant shared genetic expressions in whole blood and musculoskeletal tissue. Bidirectional MR indicated that OA increases the risk of frailty (IVW: beta: 0.13, P = 1.52E-08) and vice versa (IVW: beta: 0.73, P = 1.66E-04). Frail individuals exhibit more severe imaging features of OA. The shared genetic basis between OA and frailty suggests an intrinsic link, providing new insights into the relationship between these conditions. Keywords: X-ray, 18F-FDG PET/CT, genome-wide cross-trait analysis, osteoarthritis, frailty Introduction Osteoarthritis (OA) is a chronic disease characterized by degenerative changes in joint cartilage, affecting approximately 350 million people worldwide [1]. In the United States, about 23% of adults are diagnosed with osteoarthritis, and the incidence increases significantly with age. Frailty is a multisystem functional decline syndrome characterized by increased vulnerability to stressors [2] and the prevalence of frailty is about 10-15% in people aged 60 and above [3]. As a degenerative disease, OA can lead to a reduced ability to adapt to external stressors, resulting in adverse outcomes such as organ damage and an increased risk of death [4, 5]. In the United States, the treatment and care of OA alone generates a financial expenditure of $27 billion [6]. Early prevention and treatment of OA, as well as identifying patients at high risk of severe pain, are very important. Epidemiological studies indicated that symptomatic OA and other chronic pain are associated with an increased risk of frailty. This connection is likely due to common mechanisms including chronic inflammation, neuroinflammation, and endocrine dysregulation [7]. On the other hand, the condition arises from the chronic pain, inflammation, and restricted activity associated with OA, which in turn contribute to a reduction in physical function and a heightened risk of frailty [8]. Despite numerous studies supporting the association between OA and frailty, some results remain inconsistent. In a crosssectional study, Song et al. found a significant association between knee OA and frailty [9] and frailty were related to the severity of pain of OA [10]. A UK Biobank analysis indicated that those with OA had significantly higher relative risk ratios for pre-frailty and frailty compared to those without OA [11]. However, some studies have found no link between musculoskeletal pain and frailty [12]. The comorbidity rate of OA and frailty is higher in older populations, while this association may be less significant in younger groups. What is more, research in older Chileans found that frailty was significantly more prevalent among women with OA than men [13]. Lifestyle factors like sedentary behavior can also been shown to increase the risk of physical frailty [14]. Overall, the results of observational studies are prone to confounding factors, and the true association between the two still requires further exploration. With the rapid progress of GWAS, the relationship between genetic background and traits has gradually been revealed. Previous studies using MR have found that frailty increases the risk of developing mental disorders [15, 16]. But whether the related genetic variations affect the occurrence and development of OA remains unknown. https://doi.org/10.62347/BLXC1352 Genetic architecture between OA and frailty such as comorbidities, physical function, disability, depression, and cognition. It is calculated by summing the existing health deficits and dividing the result by 32. Therefore, the FI is a continuous variable ranging from 0 to 1, with higher values indicating a greater degree of frailty [19]. We conducted frailty index assessments and collected corresponding imaging data for 31 frail and 34 non-frail patients with osteoarthritis at the Second Xiangya Hospital of Central South University. Figure 1. Overview of research of shared genetic architecture between OA and frailty. Given the importance of early diagnosis of OA, it is crucial to identify potential modifiable risk factors. The frail population, due to its prevalence and association with various health outcomes, is increasingly being recognized as a potential target. What is more, imaging plays a crucial role in the diagnosis and management of OA. X-ray is the most commonly used technique, capable of showing joint space narrowing, osteophyte formation, subchondral bone sclerosis, and cystic changes, which provide important support for early diagnosis, disease progression assessment, and treatment decision-making [17]. Additionally, 18F-FDG positron emission tomography/computed tomography (PET/CT) imaging was widely used, which offers high image resolution and/or functional characterization at the early disease stage [18]. Therefore, in this study we mainly used post-GWAS analysis methods to investigate their genetic structure, including: (1) we conducted a clinical cross-sectional study to analyze X-ray and 1 (...truncated)