Biology subjects

Mather, K. A.

Publications and source records attributed to Mather, K. A..

6 recordsLinked to original sources

bioRxiv2024

Identification of Circular RNAs associated with Ageing of the Dorsolateral Prefrontal Cortex across the Adult Lifespan

BackgroundCircular RNAs (circRNAs) are emerging as crucial regulators of biological processes and have been implicated in age-related diseases. Few studies have explored age-related circRNA expression in the human brain across the adult lifespan. This study aims to identify age-related differentially expressed circRNAs in human post-mortem dorsolateral prefrontal cortex (DLPFC) samples, a region critically involved in cognition that exhibits early signs of age-related changes. MethodsTotal RNA sequencing was conducted on a discovery cohort of 67 postmortem DLPFC samples, from individuals with no neurological disease diagnosis at the time of death (35-103 years). CircRNAs were identified using CIRCexplorer2, with 11,907 circRNAs available for analyses. Linear regression was used to analyse the relationships between circRNA expression and age at death. Replication of the results was performed in an independent neurologically healthy dataset from the CommonMind Consortium (n=321, age at death: 35-91 years). Co-expression network analysis was performed to identify modules of highly co-expressed circRNAs associated with age. Potential microRNA and RNA-binding protein target sites were predicted. ResultsIn the discovery dataset, 37 circRNAs were age-associated (FDR <0.05). Seven out of the 37 were successfully replicated. The host genes of replicated age-associated circRNAs are implicated in synapse regulation. Co-expression analysis revealed two circRNA modules significantly correlated with age. We identified 484 microRNA and 99 RNA-binding protein target sites on the replicated circRNAs. ConclusionSeven age-associated circRNAs were identified as important candidates for involvement in post-transcriptional regulatory networks in the DLPFC. Future studies should aim to elucidate their functional roles in brain ageing.

genetics↗

bioRxiv2022

Brain structural covariances in the ageing brain in the UK Biobank

Brain structural covariances or pairwise correlations describe how morphologic properties of brain regions are related to one another across individuals. Although it is reported that brain structural covariance changes during brain development, it is not clear how structural covariance relates to the ageing process. Here we investigated the human brain structural covariances of cortical thickness and subcortical volumes in the ageing brain and their associations with age, cognition, and longevity polygenic risk score (longevity-PRS) by using cross-sectional data from the UK Biobank (N = 42075, aged 45-83 years, M/F=19752 /22323). The sample of participants was divided into 84 non-overlapping groups based on their age. The older the age group, the greater the variability in the whole brain structural covariance. However, there was a differential rate of age-related increase of variance between males and females. The variance of females started lower than those of males and then increased with age with a greater gradient than that of males. There was a consistent and significant enrichment of pairwise correlations within the occipital lobe in ageing process. The cortical thickness and subcortical covariances in older groups were significantly different from those in the youngest group. Sixty-two of the total 528 pairs of cortical thickness correlations and 10 of the total 21 pairs of subcortical volume correlations were significantly associated with age after Bonferroni correction. Specifically, with an increasing age, most decreased cortical thickness correlations were found between the regions within the frontal lobe as well as between the frontal lobe regions and regions in other lobes, while pairwise correlations within occipital lobe regions were all strengthening. Most of these correlations were also associated with global cognition and weakly associated with longevity-PRS. These findings revealed that the structural covariance was not stable during ageing. Given the thinning of the cortex and the volumetric reduction of subcortical structures seen in the ageing process, an increased pairwise correlation between the brain regions in the older brain suggested a strengthened coordinated decline between the brain regions involved. However, some of the brain regions demonstrated a differentiated rate of decline which was shown as the inversed or reduced pairwise correlations between these regions.

neuroscience↗

bioRxiv2020

Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins

The critical role of blood lipids in a broad range of health and disease states is well recognised, while an understanding of the complex genetic regulation of lipid homeostasis is emerging. Traditional blood lipids (LDL-C, HDL-C and triglycerides) are known to be substantially regulated by genetic variation. Less well explored is the interplay of genetics and environment within the broader blood lipidome. Here we use the twin model to examine heritability of the plasma lipidome among healthy older aged twins and explore gene expression and epigenetic (DNA methylation) associations of these lipids. Heritability of 209 plasma lipids quantified by liquid chromatography coupled mass spectrometry (LC-MS) was assessed in 75 monozygotic and 55 dizygotic twin pairs enrolled in the Older Australian Twins Study (OATS), aged 69-93 years. Only 27/209 lipids (13.3%) were significantly heritable under the classical ACE twin model (h2 = 0.28-0.59). Ceramides (Cer) and triglycerides (TG) were most heritable, while sphingomyelins (SM) and most phospholipids, especially lysophospholipids, were not significantly heritable. Lipid levels correlated with 3731 transcripts. Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, which were not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for a proportion of variability in some non-heritable lipids, especially lysophosphatidylcholine (LPC). We found a complex interplay of genetic and environmental influences on the ageing plasma lipidome, with most of the variation controlled by unique environmental influences.

genetics↗

bioRxiv2019

Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities

We conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.

neuroscience↗

bioRxiv2017

Ninety-nine independent genetic loci influencing general cognitive function include genes associated with brain health and structure (N = 280,360)

General cognitive function is a prominent human trait associated with many important life outcomes1,2, including longevity3. The substantial heritability of general cognitive function is known to be polygenic, but it has had little explication in terms of the contributing genetic variants4,5,6. Here, we combined cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N=280,360; age range = 16 to 102). We found 9,714 genome-wide significant SNPs (P<5 x 10-8) in 99 independent loci. Most showed clear evidence of functional importance. Among many novel genes associated with general cognitive function were SGCZ, ATXN1, MAPT, AUTS2, and P2RY6. Within the novel genetic loci were variants associated with neurodegenerative disorders, neurodevelopmental disorders, physical and psychiatric illnesses, brain structure, and BMI. Gene-based analyses found 536 genes significantly associated with general cognitive function; many were highly expressed in the brain, and associated with neurogenesis and dendrite gene sets. Genetic association results predicted up to 4% of general cognitive function variance in independent samples. There was significant genetic overlap between general cognitive function and information processing speed, as well as many health variables including longevity.

genetics↗

bioRxiv2017

An epigenome-wide association study of educational attainment (n = 10,767)

The epigenome has been shown to be influenced by biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption, and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here, we provide evidence on the associations between epigenetic modifications--in our case, CpG methylation--and educational attainment (EA), a biologically distal environmental factor that is arguably among of the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals. While we find that 9 CpG probes are significantly associated with EA, only two remain associated when we restrict the sample to never-smokers. These two are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, their effect sizes on EA are far smaller than the known associations between CpG probes and biologically proximal environmental factors. Two analyses that combine the effects of many probes--polygenic methylation score and epigenetic-clock analyses--both suggest small associations with EA. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

genetics↗