Biology subjects

Wright, M. J.

Publications and source records attributed to Wright, M. J..

9 recordsLinked to original sources

bioRxiv2024

Reference curves for harmonizing multi-site regional diffusion MRI metrics across the lifespan

Age-related white matter (WM) microstructure maturation and decline occur throughout the human lifespan, complementing the process of gray matter development and degeneration. Here, we create normative lifespan reference curves for global and regional WM microstructure by harmonizing diffusion MRI (dMRI)-derived data from ten public datasets (N = 40,898 subjects; age: 3-95 years; 47.6% male). We tested three harmonization methods on regional diffusion tensor imaging (DTI) based fractional anisotropy (FA), a metric of WM microstructure, extracted using the ENIGMA-DTI pipeline. ComBat-GAM harmonization provided multi-study trajectories most consistent with known WM maturation peaks. Lifespan FA reference curves were validated with test-retest data and used to assess the effect of the ApoE4 risk factor for dementia in WM across the lifespan. We found significant associations between ApoE4 and FA in WM regions associated with neurodegenerative disease even in healthy individuals across the lifespan, with regional age-by-genotype interactions. Our lifespan reference curves and tools to harmonize new dMRI data to the curves are publicly available as eHarmonize (https://github.com/ahzhu/eharmonize).

neuroscience↗

bioRxiv2022

The Queensland Twin Adolescent Brain Project, a longitudinal study of adolescent brain development

We describe the Queensland Twin Adolescent Brain (QTAB) dataset and provide a detailed methodology and technical validation to facilitate data usage. The QTAB dataset comprises multimodal neuroimaging, as well as cognitive and mental health data collected in adolescent twins over two sessions (session 1: N = 422, age 9-14 years; session 2: N = 304, 10-16 years). The MRI protocol consisted of T1-weighted (MP2RAGE), T2-weighted, FLAIR, high-resolution TSE, SWI, resting-state fMRI, DWI, and ASL scans. Two fMRI tasks were added in session 2: an emotional conflict task and a passive movie-watching task. Outside of the scanner, we assessed cognitive function using standardised tests. We also obtained self-reports of symptoms for anxiety and depression, perceived stress, sleepiness, pubertal development measures, and risk and protective factors. We additionally collected several biological samples for genomic and metagenomic analysis. The QTAB project was established to promote health-related research in adolescence.

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

The reliability and heritability of cortical folds and their genetic correlations across hemispheres.

The structure of the brains cortical folds varies considerably in human populations. Specific patterns of cortical variation arise with development and aging, and cortical traits are partially influenced by genetic factors. The degree to which genetic factors affect cortical folding patterning remains unknown, yet may be estimated with large-scale in-vivo brain MRI. Using multiple MRI datasets from around the world, we estimated the reliability and heritability of sulcal morphometric characteristics including length, depth, width, and surface area, for 61 sulci per hemisphere of the human brain. Reliability was assessed across four distinct test-retest datasets. We meta-analyzed the heritability across three independent family-based cohorts (N > 3,000), and one cohort of largely unrelated individuals (N~9,000) to examine the robustness of our findings. Reliability was high (interquartile range for ICC: 0.65-0.85) for sulcal metrics. Most sulcal measures were moderately to highly heritable (heritability estimates = 0.3-0.7). These genetic influences vary regionally, with the earlier forming sulci having higher heritability estimates. The central sulcus, the subcallosal and the collateral fissure were the most highly heritable regions. For some frontal and temporal sulci, left and right genetic influences did not completely overlap, suggesting some lateralization of genetic effects on the cortex.

genetics↗

bioRxiv2019

Widespread associations between grey matter structure and the human phenome

The recent availability of large-scale neuroimaging cohorts (here the UK Biobank [UKB] and the Human Connectome Project [HCP]) facilitates deeper characterisation of the relationship between phenotypic and brain architecture variation in humans. We tested the association between 654,386 vertex-wise measures of cortical and subcortical morphology (from T1w and T2w MRI images) and behavioural, cognitive, psychiatric and lifestyle data. We found a significant association of grey-matter structure with 58 out of 167 UKB phenotypes spanning substance use, blood assay results, education or income level, diet, depression, being a twin as well as cognition domains (UKB discovery sample: N=9,888). Twenty-three of the 58 associations replicated (UKB replication sample: N=4,561; HCP, N=1,110). In addition, differences in body size (height, weight, BMI, waist and hip circumference, body fat percentage) could account for a substantial proportion of the association, providing possible insight into previous MRI case-control studies for psychiatric disorders where case status is associated with body mass index. Using the same linear mixed model, we showed that most of the associated characteristics (e.g. age, sex, body size, diabetes, being a twin, maternal smoking, body size) could be significantly predicted using all the brain measurements in out-of-sample prediction. Finally, we demonstrated other applications of our approach including a Region Of Interest (ROI) analysis that retain the vertex-wise complexity and ranking of the information contained across MRI processing options.\n\nHighlightsO_LIOur linear mixed model approach unifies association and prediction analyses for highly dimensional vertex-wise MRI data\nC_LIO_LIGrey-matter structure is associated with measures of substance use, blood assay results, education or income level, diet, depression, being a twin as well as cognition domains\nC_LIO_LIBody size (height, weight, BMI, waist and hip circumference) is an important source of covariation between the phenome and grey-matter structure\nC_LIO_LIGrey-matter scores quantify grey-matter based risk for the associated traits and allow to study phenotypes not collected\nC_LIO_LIThe most general cortical processing (\"fsaverage\" mesh with no smoothing) maximises the brain-morphometricity for all UKB phenotypes\nC_LI

neuroscience↗

bioRxiv2019

The thalamic basis of outcome and cognitive impairment in traumatic brain injury

ObjectiveTo understand how, biologically, the acute event of traumatic brain injury gives rise to a long-term disease, we address the relationship between evolving cortical and subcortical brain damage and measures of functional outcome and cognitive functioning at six months post-injury.\n\nMethodsLongitudinal analysis of clinical and MRI data collected, in a tertiary neurointensive care setting, in a continuous sample of 157 patients surviving moderate to severe traumatic brain injury between 2000 and 2018. For each patient we collected T1- and T2-weighted MRI data, acutely and at a six-months follow-up, as well as acute measures of injury severity (Glasgow Coma Scale) and follow-up measures of functional impairment (Glasgow Outcome Scale extended), and, in a subset of patients, neuropsychological measures of attention, executive functions, and episodic memory.\n\nResultsIn the final cohort of 113 subcortical and 92 cortical datasets that survived (blind) quality control, extensive atrophy was observed over the first six months post-injury across the brain. Nonetheless, only atrophy within subcortical regions, particularly in left thalamus, were associated with functional outcome and neuropsychological measures of attention, executive functions, and episodic memory. Furthermore, when brought together in an analytical model, longitudinal brain measurements could distinguish good versus bad outcome with 90% accuracy, whereas acute brain and clinical measurements alone could only achieve 20% accuracy.\n\nInterpretationDespite great injury heterogeneity, secondary thalamic pathology is a measurable minimum common denominator mechanism directly relating biology to clinical measures of outcome and cognitive functioning, potentially linking the acute \"event\" and the long(er)-term \"disease\" of TBI.

neuroscience↗

bioRxiv2018

Bivariate genome-wide association analysis strengthens the role of bitter receptor clusters on chromosomes 7 and 12 in human bitter taste

Human perception of bitter substances is partially genetically determined. Previously we discovered a single nucleotide polymorphism (SNP) within the bitter taste receptor gene TAS2R19 on chromosome 12 that accounts for 5.8% of the variance in the perceived intensity rating of quinine, and we strengthened the classic association between TAS2R38 genotype and the bitterness of propylthiouracil (PROP). Here we performed a genome-wide association study (GWAS) using a 40% larger sample (n = 1999) together with a bivariate approach to detect previously unidentified common variants with small effects on bitter perception. We identified two signals, both with small effects (< 2%), within the bitter taste receptor clusters on chromosomes 7 and 12, which influence the perceived bitterness of denatonium benzoate and sucrose octaacetate respectively. We also provided the first independent replication for an association of caffeine bitterness on chromosome 12. Furthermore, we provided evidence for pleiotropic effects on quinine, caffeine, sucrose octaacetate and denatonium benzoate for the three SNPs on chromosome 12 and the functional importance of the SNPs for denatonium benzoate bitterness. These findings provide new insights into the genetic architecture of bitter taste and offer a useful starting point for determining the biological pathways linking perception of bitter substances.

genetics↗

bioRxiv2017

Genome-wide association analysis links multiple psychiatric liability genes to oscillatory brain activity

Oscillations in neuronal activity are widely thought to play a crucial role in information processing and cortical communication 1-8. Brain oscillations have been widely investigated as biomarkers of psychiatric disorders and variation in normal human behavior 9, 10, including intelligence 11, 12, schizophrenia 13, 14, attentional deficits 15, 16, and substance use 17, 18. Beyond the biomarker, oscillatory activity may indeed cause variation in behavior, as it has been shown that disrupting oscillatory activity by blocking GABAergic fast-spiking interneurons in the frontal cortex of mice impairs behavioral flexibility8, consistent with ...

genetics↗

bioRxiv2017

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

genetics↗