Biology subjects

Geraghty, B.

Publications and source records attributed to Geraghty, B..

4 recordsLinked to original sources

bioRxiv2025

Metabolomics Ex/GWAS in the Amish reveals novel insights into cardiometabolic disease pathways

We conducted an exome and genome-wide association study (Ex/GWAS) of 1,015 metabolites in serum samples from 5,981 Amish adults. We identified 149 functional or likely functional genetic variants, based on CADD scores significantly associated (P < 5.8 x 10-8) with 519 metabolite levels, 69 of which were >10-fold enriched in the Amish versus Europeans in gnomAD. We discovered novel associations involving a PCK2 splice-donor variant (rs138881435) and metabolites important for energy metabolism and mitochondrial function. In UK Biobank participants, this variant was associated with increased longitudinal relaxation time (T1) values on liver MRI suggesting increased inflammation and fibrosis. Furthermore, we found novel associations involving ENPEP stop-gain variant (rs33966350) and peptide and amino acid metabolite levels, implicating ENPEPs roles in blood pressure regulation. Additional known and novel genetic variant-metabolite associations were identified including genes involved in Amish-enriched Mendelian diseases and cardiometabolic traits, providing insights into underlying mechanisms of these disorders.

genomics↗

bioRxiv2023

Joint testing of rare variant burden scores using non-negative least squares

Gene-based burden tests are a popular and powerful approach for analysis of exome-wide association studies. These approaches combine sets of variants within a gene into a single burden score that is then tested for association. Typically, a range of burden scores are calculated and tested across a range of annotation classes and frequency bins. Correlation between these tests can complicate the multiple testing correction and hamper interpretation of the results. We introduce a new method called the Sparse Burden Association Test (SBAT) that tests the joint set of burden scores under the assumption that causal burden scores act in the same effect direction. The method simultaneously assesses the significance of the model fit and selects the set of burden scores that best explain the association at the same time. Using simulated data, we show that the method is well calibrated and highlight some scenarios where the test outperforms existing gene-based tests. We apply the method to 73 quantitative traits from the UK Biobank which further illustrates the power of the method. This test is implemented in the REGENIE software.

genetics↗

bioRxiv2021

Biomechanics of aging and osteoarthritic human knee ligaments

BackgroundLigaments work to stabilize the human knee joint and prevent excessive movement. Whilst ligaments are known to decline in structure and function with aging, there has been no systematic effort to study changes in gross mechanical properties in the four major human knee ligaments due to osteoarthritis (OA). This study aims to collate material properties for the anterior (ACL) and posterior (PCL) cruciate ligaments, medial (MCL) and lateral (LCL) collateral ligaments. Our cadaveric samples come from a diverse demographic from which the effects of aging and OA on bone and cartilage material properties have already been quantified. Therefore, by combining our previous bone and cartilage data with the new ligament data from this study we are facilitating subject-specific whole-joint modelling studies. MethodsThe demographics of the collected cadaveric knee joints were diverse with age range between 31 to 88 years old, and OA International Cartilage Repair Society grade 0 to 4. Twelve cadaveric human knee joints were dissected, and bone-ligament-bone specimens were extracted for mechanical loading to failure. Ligament material properties were determined from the load-extension curves, namely: linear and ultimate (failure) stress and strain, secant modulus, tangent modulus, and stiffness. ResultsThere were significant negative correlations between age and ACL linear force (p=0.01), stress (p=0.03) and extension (p=0.05), ACL failure force (p=0.02), stress (p=0.02) and extension (p=0.02), PCL secant (p=0.02) and tangent (p=0.02) modulus, and LCL stiffness (p=0.05). Significant negative correlations were also found between OA grades and ACL linear force (p=0.05), stress (p=0.02), extension (p=0.01) and strain (p=0.03), and LCL failure stress (p=0.05). However, changes in age or OA grade did not show a statistically significant correlation with the MCL tensile parameters. Trends showed that almost all the tensile parameters of the ACL and PCLs decreased with increasing age and progression of OA. Due to small sample size, the combined effect of age and presence of OA could not be statistically derived. ConclusionsThis research is the first to correlate changes in tensile properties of the four major human knee ligaments to aging and OA. The current ligament study when combined with our previous findings on bone and cartilage for the same twelve knee cadavers, supports conceptualization of OA as a whole-joint disease that impairs the integrity of many peri-articular tissues within the knee. The subject-specific data pool consisting of the material properties of the four major knee ligaments, subchondral and trabecular bones and articular cartilage will aid reconstruction and graft replacements and advance knee joint finite element models, whilst knowledge of aged or diseased mechanics may direct future therapeutic interventions.

bioengineering↗

bioRxiv2020

Viscoelastic characteristics of the canine cranial cruciate ligament complex at slow strain rates

Ligaments including the cruciate ligaments support and transfer loads between bones applied to the knee joint organ. The functions of these ligaments can get compromised due to changes to their viscoelastic material properties. Currently there are discrepancies in the literature on the viscoelastic characteristics of knee ligaments which are thought to be due to tissue variability and different testing protocols. The aim of this study was to characterise the viscoelastic properties of healthy cranial cruciate ligaments (CCLs), from the canine knee (stifle) joint, with a focus on the toe region of the stress-strain properties where any alterations in the extracellular matrix which would affect viscoelastic properties would be seen. Six paired CCLs, from skeletally mature and disease-free Staffordshire bull terrier stifle joints were retrieved as a femur-CCL-tibia complex and mechanically tested under uniaxial cyclic loading up to 10 N at three strain rates, namely 0.1, 1 and 10 %/min, to assess the viscoelastic property of strain rate dependency. The effect of strain history was also investigated by subjecting contralateral CCLs to an ascending (0.1, 1 and 10 %/min) or descending (10, 1 and 0.1 %/min) strain rate protocol. The differences between strain rates were not statistically significant. However, hysteresis and recovery of ligament lengths showed some dependency on strain rate. Only hysteresis was affected by the test protocol and lower strain rates resulted in higher hysteresis and lower recovery. These findings could be explained by the slow process of uncrimping of collagen fibres and the contribution of proteoglycans in the ligament extracellular matrix to intra-fibrillar gliding, which results in more tissue elongations and higher energy dissipation. This study further expands our understanding of canine CCL behaviour, providing data for material models of femur-CCL-tibia complexes, and demonstrating the challenges for engineering complex biomaterials such as knee joint ligaments.

bioengineering↗