ORCID Profile
0000-0002-4816-785X
Current Organisations
CSIRO
,
Institute of Biological Psychiatry
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Publisher: University of Queensland Library
Date: 2023
DOI: 10.14264/C3439CA
Publisher: Cold Spring Harbor Laboratory
Date: 08-10-2020
DOI: 10.1101/2020.10.08.331561
Abstract: Zebrafish scales are mineralised plates that can regenerate involving de novo bone formation. This presents an opportunity to uncover genes and pathways relevant to human musculoskeletal disease relevant to impaired bone formation. To investigate this hypothesis, we defined transcriptomic profiles of ontogenetic and regenerating scales, and identified 604 differentially expressed genes (DEGs) that were enriched for extracellular matrix, ossification, and cell adhesion pathways. Next, we showed that human orthologues of DEGs were 2.8 times more likely to cause human monogenic skeletal diseases (P ×10 −11 ), and they showed enrichment for human orthologues associated with polygenetic disease traits including stature, bone density and osteoarthritis (P .005). Finally, zebrafish mutants of two human orthologues that were robustly associated with height and osteoarthritis ( COL11A2 ) or bone density only ( SPP1 ) developed skeletal abnormalities consistent with our genetic association studies. Col11a2 Y228X/Y228X mutants showed endoskeletal features consistent with abnormal growth and osteoarthritis, whereas spp1 P160X/P160X mutants had elevated bone density (P .05). In summary, we show that transcriptomic studies of regenerating zebrafish scales have potential to identify new genes and pathways relevant to human skeletal disease.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Cold Spring Harbor Laboratory
Date: 14-03-2022
DOI: 10.1101/2022.03.13.22272317
Abstract: The multifactorial nature of chronic pain with its numerous comorbidities presents a formidable challenge in disentangling their aetiology. Here, we performed genome-wide association studies of eight regional chronic pain types using UK Biobank data (N=4,037–79,089 cases N=239,125 controls), followed by bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine (respectively) their genetic correlations and genetic causal proportion (GCP) parameters with 1,492 other complex traits. We report evidence of a shared genetic signature across common chronic pain types as their genetic correlations and GCP parameter directions were broadly consistent across a wide array of biopsychosocial traits. Across 5,942 significant genetic correlations, 570 trait pairs could be explained by a causal association (|GCP| 0.6 5% false discovery rate), including 82 traits affected by pain while 488 contributed to an increased risk of chronic pain such as certain somatic pathologies (e.g., musculoskeletal), psychiatric traits (e.g., depression), socioeconomic factors (e.g., occupation) and medical comorbidities (e.g., cardiovascular disease). This data-driven study has demonstrated a novel & efficient strategy for identifying genetically supported risk & protective traits to enhance the design of interventional trials targeting underlying causal factors and help accelerate the development of more effective treatments with broader clinical utility.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.JPAIN.2022.10.005
Abstract: The multiple comorbidities & dimensions of chronic pain present a formidable challenge in disentangling its aetiology. Here, we performed genome-wide association studies of 8 chronic pain types using UK Biobank data (N =4,037-79,089 cases N = 239,125 controls), followed by bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine (respectively) their genetic correlations and genetic causal proportion (GCP) parameters with 1,492 other complex traits. We report evidence of a shared genetic signature across chronic pain types as their genetic correlations and GCP directions were broadly consistent across an array of biopsychosocial traits. Across 5,942 significant genetic correlations, 570 trait pairs could be explained by a causal association (|GCP| >0.6 5% false discovery rate), including 82 traits affected by pain while 410 contributed to an increased risk of chronic pain (cf. 78 with a decreased risk) such as certain somatic pathologies (eg, musculoskeletal), psychiatric traits (eg, depression), socioeconomic factors (eg, occupation) and medical comorbidities (eg, cardiovascular disease). This data-driven phenome-wide association analysis has demonstrated a novel and efficient strategy for identifying genetically supported risk & protective traits to enhance the design of interventional trials targeting underlying causal factors and accelerate the development of more effective treatments with broader clinical utility. PERSPECTIVE: Through large-scale phenome-wide association analyses of >1,400 biopsychosocial traits, this article provides evidence for a shared genetic signature across 8 common chronic pain types. It lays the foundation for further translational studies focused on identifying causal genetic variants and pathophysiological pathways to develop novel diagnostic & therapeutic technologies and strategies.
Publisher: Elsevier BV
Date: 2023
Publisher: Cold Spring Harbor Laboratory
Date: 11-01-2019
DOI: 10.1101/518027
Abstract: Genome-wide association studies (GWAS) are an important method for mapping genetic variation underlying complex traits and diseases. Tools to visualize, annotate and analyse results from these studies can be used to generate hypotheses about the molecular mechanisms underlying the associations. The Complex-Traits Genetics Virtual Lab (CTG-VL) integrates over a thousand publicly-available GWAS summary statistics, a suite of analysis tools, visualization functions and erse data sets for genomic annotations. CTG-VL also makes available results from gene, pathway and tissue-based analyses from over 1,500 complex-traits allowing to assess pleiotropy not only at the genetic variant level but also at the gene, pathway and tissue levels. In this manuscript, we showcase the platform by analysing GWAS summary statistics of mood swings derived from UK Biobank. Using analysis tools in CTG-VL we highlight hippoc us as a potential tissue involved in mood swings, and that pathways including neuron apoptotic process may underlie the genetic associations. Further, we report a negative genetic correlation with educational attainment rG = −0.41 ± 0.018 and a potential causal effect of BMI on mood swings OR = 1.01 (95% CI = 1.00–1.02). Using CTG-VL’s database, we show that pathways and tissues associated with mood swings are also associated with neurological traits including reaction time and neuroticism, as well as traits such age at menopause and age at first live birth. CTG-VL is a platform with the most complete set of tools to carry out post-GWAS analyses. The CTG-VL is freely available at genoma.io as an online web application.
Publisher: Springer Science and Business Media LLC
Date: 06-12-2022
DOI: 10.1038/S41467-022-35158-9
Abstract: The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Public Library of Science (PLoS)
Date: 26-10-2020
DOI: 10.1371/JOURNAL.PGEN.1009154
Abstract: Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to their children. However, given the relative paucity of large-scale family-based cohorts around the world, it is difficult to demonstrate parental genetic effects on human traits, particularly at in idual loci. In this manuscript, we illustrate how parental genetic effects on offspring phenotypes, including late onset conditions, can be estimated at in idual loci in principle using large-scale genome-wide association study (GWAS) data, even in the absence of parental genotypes. Our strategy involves creating “virtual” mothers and fathers by estimating the genotypic dosages of parental genotypes using physically genotyped data from relative pairs. We then utilize the expected dosages of the parents, and the actual genotypes of the offspring relative pairs, to perform conditional genetic association analyses to obtain asymptotically unbiased estimates of maternal, paternal and offspring genetic effects. We apply our approach to 19066 sibling pairs from the UK Biobank and show that a polygenic score consisting of imputed parental educational attainment SNP dosages is strongly related to offspring educational attainment even after correcting for offspring genotype at the same loci. We develop a freely available web application that quantifies the power of our approach using closed form asymptotic solutions. We implement our methods in a user-friendly software package IMPISH ( IM puting P arental genotypes I n S iblings and H alf Siblings) which allows users to quickly and efficiently impute parental genotypes across the genome in large genome-wide datasets, and then use these estimated dosages in downstream linear mixed model association analyses. We conclude that imputing parental genotypes from relative pairs may provide a useful adjunct to existing large-scale genetic studies of parents and their offspring.
Publisher: Elsevier BV
Date: 04-2022
Publisher: Springer Science and Business Media LLC
Date: 22-10-2019
Publisher: Springer Science and Business Media LLC
Date: 21-01-2022
DOI: 10.1186/S12915-021-01209-8
Abstract: Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases ( P 2× 10 −3 ). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height ( P 6× 10 −4 ), and estimated bone mineral density (eBMD, P 2× 10 −5 ). Zebrafish mutants of two human orthologues that were robustly associated with height ( COL11A2 , P =6× 10 −24 ) or eBMD ( SPP1 , P =6× 10 −20 ) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses col11a2 Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1 P160X/P160X mutants predominantly showed mineralisation defects. We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 28-05-2020
DOI: 10.1101/2020.05.26.115568
Abstract: Chronic pain (CP) is a leading cause of disability worldwide with complex aetiologies that remain elusive. Here we addressed this issue by performing a GWAS on a large UK Biobank s le (N=188,352 cases & N=69,627 controls) which identified two independent loci associated with CP near ADAMTS6 and LEMD2 . Gene-based tests revealed additional CP-associated genes ( DCAKD, NMT1, MLN, IP6K3 ). Across 1328 complex traits, 548 (41%) were genetically correlated with CP, of which 175 (13%) showed genetic causal relationships using the latent causal variable approach and Mendelian randomization. In particular, major depressive disorder, anxiety, smoking, body fat & BMI were found to increase the risk of CP, whereas diet, walking for pleasure & higher educational attainment were associated with a reduced risk (i.e., protective effect). This data-driven hypothesis-free approach has uncovered several specific risk factors that warrant further examination in longitudinal trials to help deliver effective early screening & management strategies for CP.
Publisher: Cold Spring Harbor Laboratory
Date: 03-03-2023
DOI: 10.1101/2023.03.01.23286618
Abstract: Minimum joint space width (mJSW) from 2-dimensional images provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and use them to (ii) examine causal effects of mJSW on hip osteoarthritis (HOA) risk. GWAS meta-analysis of hip mJSW derived from plain X-rays (four cohorts) or DXA (one cohort) was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA. 50,745 in iduals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci (35 novel), were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA ( β IVW -0.01 [95% CI -0.19, 0.17]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life. GWAS and MR analyses suggested one group of mJSW loci reduces HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to mJSW and HOA risk via a growth-related mechanism.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.MOLCEL.2019.05.024
Abstract: Epigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippoc al neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3' transduction. The source (donor) L1 for this insertion was slightly 5' truncated, lacked the YY1 binding site, and was highly mobile when tested in vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body.
Publisher: Cold Spring Harbor Laboratory
Date: 09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 25-02-2020
DOI: 10.1101/2020.02.21.959114
Abstract: Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to children. However, given the relative paucity of large-scale family-based cohorts around the world, it is difficult to demonstrate parental genetic effects on human traits, particularly at in idual loci. In this manuscript, we illustrate how parental genetic effects on offspring phenotypes, including late onset diseases, can be estimated at in idual loci in principle using large-scale genome-wide association study (GWAS) data, even in the absence of parental genotypes. Our strategy involves creating “virtual” mothers and fathers by estimating the genotypic dosages of parental genotypes using physically genotyped data from relative pairs. We then utilize the expected dosages of the parents, and the actual genotypes of the offspring relative pairs, to perform conditional genetic association analyses to obtain asymptotically unbiased estimates of maternal, paternal and offspring genetic effects. We develop a freely available web application that quantifies the power of our approach using closed form asymptotic solutions. We implement our methods in a user-friendly software package IMPISH ( IM puting P arental genotypes I n S iblings and H alf-Siblings) which allows users to quickly and efficiently impute parental genotypes across the genome in large genome-wide datasets, and then use these estimated dosages in downstream linear mixed model association analyses. We conclude that imputing parental genotypes from relative pairs may provide a useful adjunct to existing large-scale genetic studies of parents and their offspring.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2023
DOI: 10.1007/S00586-023-07711-7
Abstract: Causal mechanisms underlying systemic inflammation in spinal & widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder & widespread pain can be explained by shared underlying genetic variants and (ii) higher CRP levels causally contribute to these conditions. Using genome-wide association studies (GWAS) of chronic back, neck/shoulder & widespread pain ( N = 6063–79,089 cases N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 & PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations ( rG ) between these chronic pain phenotypes and CRP levels (FDR 5%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR 5%). Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain ( rG range 0.26–0.36 P ≤ 8.07E-9 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range − 0.32–0.08 P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027–0.166 P ≤ 9.82E-03 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021] P = 6.97E-04). This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies.
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2023
DOI: 10.1101/2023.06.23.23291611
Abstract: Large biobank s les provide an opportunity to integrate broad phenotyping, familial records, and molecular genetics data to study complex traits and diseases. We introduce Pearson-Aitken Family Genetic Risk Scores (PA-FGRS), a new method for estimating disease liability from patterns of diagnoses in extended, age-censored genealogical records. We then apply the method to study a paradigmatic complex disorder, Major Depressive Disorder (MDD), using the iPSYCH2015 case-cohort study of 30,949 MDD cases, 39,655 random population controls, and more than 2 million relatives. We show that combining PA-FGRS liabilities estimated from family records with molecular genotypes of probands improves the three lines of inquiry. Incorporating PA-FGRS liabilities improves classification of MDD over and above polygenic scores, identifies robust genetic contributions to clinical heterogeneity in MDD associated with comorbidity, recurrence, and severity, and can improve the power of genome-wide association studies (GWAS). Our method is flexible and easy to use and our study approaches are generalizable to other data sets and other complex traits and diseases.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 05-10-2023
Publisher: Oxford University Press (OUP)
Date: 09-06-2022
DOI: 10.1093/IJE/DYAC121
Abstract: Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized–controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR). A two-s le MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91 462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49 996 cases and 174 109 controls from a large meta-analysis) the number of stillbirths [N = 60 453 from UK Biobank (UKBB)] gestational age and pre-term birth (N = 43 568 from the 23andMe, Inc cohort) and birthweight (N = 297 356 reporting own birthweight and N = 210 248 reporting offspring’s birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-s le genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194 196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed. Both the two-s le MR and one-s le GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent. Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring.
Location: Australia
No related grants have been discovered for Mischa Lundberg.