ORCID Profile
0000-0001-5608-2293
Current Organisation
University of South Australia
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Publisher: Proceedings of the National Academy of Sciences
Date: 08-09-2014
Abstract: We identify several common genetic variants associated with cognitive performance using a two-stage approach: we conduct a genome-wide association study of educational attainment to generate a set of candidates, and then we estimate the association of these variants with cognitive performance. In older Americans, we find that these variants are jointly associated with cognitive health. Bioinformatics analyses implicate a set of genes that is associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. In addition to the substantive contribution, this work also serves to show a proxy-phenotype approach to discovering common genetic variants that is likely to be useful for many phenotypes of interest to social scientists (such as personality traits).
Publisher: Springer Science and Business Media LLC
Date: 04-05-2016
DOI: 10.1038/HDY.2016.25
Publisher: Springer Science and Business Media LLC
Date: 12-2012
DOI: 10.1038/NATURE11677
Publisher: Oxford University Press (OUP)
Date: 22-12-2016
DOI: 10.1093/HMG/DDW380
Publisher: Springer Science and Business Media LLC
Date: 27-02-2020
DOI: 10.1038/S41525-020-0118-3
Abstract: We conducted DNA methylation association analyses using Illumina 450K data from whole blood for an Australian amyotrophic lateral sclerosis (ALS) case–control cohort (782 cases and 613 controls). Analyses used mixed linear models as implemented in the OSCA software. We found a significantly higher proportion of neutrophils in cases compared to controls which replicated in an independent cohort from the Netherlands (1159 cases and 637 controls). The OSCA MOMENT linear mixed model has been shown in simulations to best account for confounders. When combined in a methylation profile score, the 25 most-associated probes identified by MOMENT significantly classified case–control status in the Netherlands s le (area under the curve, AUC = 0.65, CI 95% = [0.62–0.68], p = 8.3 × 10 −22 ). The maximum AUC achieved was 0.69 (CI 95% = [0.66–0.71], p = 4.3 × 10 −34 ) when cell-type proportion was included in the predictor.
Publisher: Springer Science and Business Media LLC
Date: 04-06-2019
DOI: 10.1038/S41598-019-44765-4
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1 . Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46 , showed significant differential methylation in an extended cohort of ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF , DPP6 , RAMP3 , and CCS , which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2015
Publisher: Springer Science and Business Media LLC
Date: 18-11-2019
Publisher: Oxford University Press (OUP)
Date: 23-08-2011
DOI: 10.1093/HMG/DDR375
Publisher: Oxford University Press (OUP)
Date: 04-2015
DOI: 10.1093/IJE/DYV094
Publisher: CSIRO Publishing
Date: 2007
DOI: 10.1071/EA06123
Abstract: Two quantitative trait loci (QTL) for mouse bodyweight have previously been reported on mouse chromosomes (MMU) 4 and 11 from crosses of a highly fecund and large mouse strain, Inbred Quackenbush-Swiss 5 (QSi5) and C57Bl/6J. QSi5 has now been crossed with CBA/CaH to produce 1128 F2 mice to confirm the existence and effect of these QTL. In total, 226 mice from the upper and lower deciles for bodyweight were genotyped using 12 microsatellite markers covering MMU4 and MMU11. Regression and maximum likelihood based interval mapping by either including all mice (ungenotyped mice were treated as having missing genotypes) or including only selectively genotyped mice in the analyses were used to estimate the positions and effects of the QTL. The results confirmed the existence and effects of both QTL. Although all methods estimated the same QTL positions, the QTL effects were overestimated compared with the estimates using a suggested method (maximum likelihood by including all mice in the analysis). However, the overestimated QTL effects could be mathematically corrected. Since the confidence intervals of both QTL are still too large for positional cloning, an advanced intercross line is being bred for finely mapping these bodyweight QTL.
Publisher: Wiley
Date: 11-01-2022
DOI: 10.1111/ENE.15237
Abstract: The aim was to evaluate urinary neopterin, a marker of pro‐inflammatory state, as a potential biomarker of disease prognosis and progression in amyotrophic lateral sclerosis (ALS) and to compare its utility to urinary neurotrophin receptor p75 extracellular domain (p75 ECD ). This was an observational study including 21 healthy controls and 46 people with ALS, 29 of whom were s led longitudinally. Neopterin and p75 ECD were measured using enzyme‐linked immunoassays. Baseline and longitudinal changes in clinical measures, neopterin and urinary p75 ECD were examined, and prognostic utility was explored by survival analysis. At baseline, urinary neopterin was higher in ALS compared to controls (181.7 ± 78.9 μmol/mol creatinine vs. 120.4 ± 60.8 μmol/mol creatinine, p = 0.002, Welch's t test) and correlated with the Revised ALS Functional Rating Scale ( r = −0.36, p = 0.01). Combining previously published urinary p75 ECD results from 22 ALS patients with a further 24 ALS patients, baseline urinary p75 ECD was also higher compared to healthy controls (6.0 ± 2.7 vs. 3.2 ± 1.0 ng/mg creatinine, p 0.0001) and correlated with the Revised ALS Functional Rating Scale ( r = −0.36, p = 0.01). Urinary neopterin and p75 ECD correlated with each other at baseline ( r = 0.38, p = 0.009). In longitudinal analysis, urinary neopterin increased on average (±SE) by 6.8 ± 1.1 µmol/mol creatinine per month ( p 0.0001) and p75 ECD by 0.19 ± 0.02 ng/mg creatinine per month ( p 0.0001) from diagnosis in 29 ALS patients. Urinary neopterin holds promise as marker of disease progression in ALS and is worthy of future evaluation for its potential to predict response to anti‐inflammatory therapies.
Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41588-021-00973-1
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 in iduals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2023
DOI: 10.1038/S41467-023-36281-X
Abstract: Cross-ancestry genetic correlation is an important parameter to understand the genetic relationship between two ancestry groups. However, existing methods cannot properly account for ancestry-specific genetic architecture, which is erse across ancestries, producing biased estimates of cross-ancestry genetic correlation. Here, we present a method to construct a genomic relationship matrix (GRM) that can correctly account for the relationship between ancestry-specific allele frequencies and ancestry-specific allelic effects. Through comprehensive simulations, we show that the proposed method outperforms existing methods in the estimations of SNP-based heritability and cross-ancestry genetic correlation. The proposed method is further applied to anthropometric and other complex traits from the UK Biobank data across ancestry groups. For obesity, the estimated genetic correlation between African and European ancestry cohorts is significantly different from unity, suggesting that obesity is genetically heterogenous between these two ancestries.
Publisher: Wiley
Date: 11-06-2023
DOI: 10.1002/RMV.2466
Abstract: Genome‐wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with susceptibility and severity of coronavirus disease 2019 (COVID‐19). However, identified SNPs are inconsistent across studies, and there is no compelling consensus that COVID‐19 status is determined by genetic factors. Here, we conducted a systematic review and meta‐analysis to determine the effect of genetic factors on COVID‐19. A random‐effect meta‐analysis was performed to estimate pooled odds ratios (ORs) of SNP effects, and SNP‐based heritability (SNP‐h 2 ) of COVID‐19. The analyses were performed using meta‐R package, and Stata version 17. The meta‐analysis included a total of 96,817 COVID‐19 cases and 6,414,916 negative controls. The meta‐analysis showed that a cluster of highly correlated 9 SNPs ( R 2 0.9) at 3p21.31 gene locus covering LZTFL1 and SLC6A20 genes was significantly associated with COVID‐19 severity, with a pooled OR of 1.8 [1.5–2.0]. Meanwhile, another 3 SNPs (rs2531743‐G, rs2271616‐T, and rs73062389‐A) within the locus was associated with COVID‐19 susceptibility, with pooled estimates of 0.95 [0.93–0.96], 1.23 [1.19–1.27] and 1.15 [1.13–1.17], respectively. Interestingly, SNPs associated with susceptibility and SNPs associated with severity in this locus are in linkage equilibrium ( R 2 0.026). The SNP‐h 2 on the liability scale for severity and susceptibility was estimated at 7.6% (Se = 3.2%) and 4.6% (Se = 1.5%), respectively. Genetic factors contribute to COVID‐19 susceptibility and severity. In the 3p21.31 locus, SNPs that are associated with susceptibility are not in linkage disequilibrium (LD) with SNPs that are associated with severity, indicating within‐locus heterogeneity.
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2021
DOI: 10.1101/2021.04.17.21255471
Abstract: Homeostatic control of blood glucose requires different physiological responses in the fasting and post-prandial states. We reasoned that glucose measurements under non-standardised conditions (random glucose RG) may capture erse glucoregulatory processes more effectively than previous genome-wide association studies (GWAS) of fasting glycaemia or after standardised glucose loads. Through GWAS meta-analysis of RG in 493,036 in iduals without diabetes of erse ethnicities we identified 128 associated loci represented by 162 distinct signals, including 14 with sex-dimorphic effects, 9 discovered through trans-ethnic analysis, and 70 novel signals for glycaemic traits. Novel RG loci were particularly enriched in expression in the ileum and colon, indicating a prominent role for the gastrointestinal tract in the control of blood glucose. Functional studies and molecular dynamics simulations of coding variants of GLP1R , a well-established type 2 diabetes treatment target, provided a genetic framework for optimal selection of GLP-1R agonist therapy. We also provided new evidence from Mendelian randomisation that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Thus, our approach based on RG GWAS provided wide-ranging insights into the biology of glucose regulation, diabetes complications and the potential for treatment stratification.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2013
Abstract: Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type–restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type–specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type–restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.
Publisher: Oxford University Press (OUP)
Date: 02-06-2017
DOI: 10.1093/NDT/GFW215
Abstract: Iron depletion is a known consequence of chronic kidney disease (CKD), but there is contradicting epidemiological evidence on whether iron itself affects kidney function and whether its effect is protective or detrimental in the general population. While epidemiological studies tend to be affected by confounding and reverse causation, Mendelian randomization (MR) can provide unconfounded estimates of causal effects by using genes as instruments. We performed an MR study of the effect of serum iron levels on estimated glomerular filtration rate (eGFR), using genetic variants known to be associated with iron. MR estimates of the effect of iron on eGFR were derived based on the association of each variant with iron and eGFR from two large genome-wide meta-analyses on 48 978 and 74 354 in iduals. We performed a similar MR analysis for ferritin, which measures iron stored in the body, using variants associated with ferritin. A combined MR estimate across all variants showed a 1.3% increase in eGFR per standard deviation increase in iron (95% confidence interval 0.4–2.1% P = 0.004). The results for ferritin were consistent with those for iron. Secondary MR analyses of the effects of iron and ferritin on CKD did not show significant associations but had very low statistical power. Our study suggests a protective effect of iron on kidney function in the general population. Further research is required to confirm this causal association, investigate it in study populations at higher risk of CKD and explore its underlying mechanism of action.
Publisher: Springer Science and Business Media LLC
Date: 09-2023
Publisher: Future Medicine Ltd
Date: 02-2009
DOI: 10.2217/14622416.10.2.181
Abstract: In the last 2 years, the effort to identify genes affecting common diseases and complex traits has been accelerated through the use of genome-wide association studies (GWAS). The availability of existing large collections of linkage data paved the way for the use of family-based GWAS. Although most published GWAS used population-based designs, family-based designs have played an important role, particularly in replication stages. Family-based designs offer advantages in terms of quality control, the robustness to population stratification and the ability to perform genetic analyses that cannot be achieved using a s le of unrelated in iduals, such as testing for the effect of imprinted genes on phenotypes, testing whether a genetic variant is inherited or de novo and combined linkage and association analysis.
Publisher: Elsevier BV
Date: 10-2010
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1086/522934
Publisher: American Diabetes Association
Date: 23-02-2015
DOI: 10.2337/DB14-0988
Abstract: Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese in iduals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 in iduals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P & 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the & -year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the & -year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
Publisher: Elsevier BV
Date: 2009
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.ATHEROSCLEROSIS.2006.04.024
Abstract: Twin studies are used extensively to decompose the variance of a trait, mainly to estimate the heritability of the trait. A second purpose of such studies is to estimate to what extent the non-genetic variance is shared or specific to in iduals. To a lesser extent the twin studies have been used in bivariate or multivariate analysis to elucidate common genetic factors to two or more traits. In the present study the variances of traits related to lipid metabolism is decomposed in a relatively large Danish twin population, including bivariate analysis to detect possible common genetic factors of the traits. The heritabilities of apolipoprotein B and E, cholesterol, LDL, and high density lipoprotein (HDL) were significant in the general population, although gender-specific levels and significance were detected. Heritabilities of apolipoprotein A1, triglycerides, and very low density protein (VLDL) were only significant when the population was stratified according to gender.
Publisher: Springer Science and Business Media LLC
Date: 12-07-2007
DOI: 10.1007/S00125-007-0758-1
Abstract: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic and environmental factors influencing this cluster in a general population of twin pairs. A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. All endophenotypes showed moderate to high heritability (0.31-0.69) and small common environmental variance (0.05-0.21). In general, genetic and phenotypic correlations between the endophenotypes were strong only within sets of physiologically similar endophenotypes, but weak to moderate for other pairs of endophenotypes. However, moderate correlations between insulin resistance indices and either obesity-related endophenotypes or triacylglycerol levels indicated that some common genetic backgrounds are shared between those components. We demonstrated that, in a general population, the endophenotypes associated with the metabolic syndrome apparently do not share a substantial common genetic or familial environmental background.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2015
DOI: 10.1038/NG.3285
Abstract: Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of in idual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-01-2015
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JAAC.2021.11.035
Abstract: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for s le overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. The meta-analysis of overall internalizing symptoms (INT Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood s les will be key in paving the way to future GWAS success.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2006
DOI: 10.1007/S10519-006-9086-3
Abstract: The classification of twin pairs based on zygosity into monozygotic (MZ) or dizygotic (DZ) twins is the basis of most twin analyses. When zygosity information is unavailable, a normal finite mixture distribution (mixture distribution) model can be used to estimate components of variation for continuous traits. The main assumption of this model is that the observed phenotypes on a twin pair are bivariately normally distributed. Any deviation from normality, in particular kurtosis, could produce biased estimates. Using computer simulations and analyses of a wide range of phenotypes from the U.K. Twins' Early Developments Study (TEDS), where zygosity is known, properties of the mixture distribution model were assessed. Simulation results showed that, if normality assumptions were satisfied and the s le size was large (e.g., 2,000 pairs), then the variance component estimates from the mixture distribution model were unbiased and the standard deviation of the difference between heritability estimates from known and unknown zygosity in the range of 0.02-0.20. Unexpectedly, the estimates of heritability of 10 variables from TEDS using the mixture distribution model were consistently larger than those from the conventional (known zygosity) model. This discrepancy was due to violation of the bivariate normality assumption. A leptokurtic distribution of pair difference was observed for all traits (except non-verbal ability scores of MZ twins), even when the univariate distribution of the trait was close to normality. From an independent s le of Australian twins, the heritability estimates for IQ variables were also larger for the mixture distribution model in six out of eight traits, consistent with the observed kurtosis of pair difference. While the known zygosity model is quite robust to the violation of the bivariate normality assumption, this novel finding of widespread kurtosis of the pair difference may suggest that this assumption for analysis of quantitative trait in twin studies may be incorrect and needs revisiting. A possible explanation of widespread kurtosis within zygosity groups is heterogeneity of variance, which could be caused by genetic or environmental factors. For the mixture distribution model, violation of the bivariate normality assumption will produce biased estimates.
Publisher: Oxford University Press (OUP)
Date: 2012
DOI: 10.1038/AJH.2011.163
Publisher: Springer Science and Business Media LLC
Date: 25-09-2014
Publisher: Springer Science and Business Media LLC
Date: 08-04-2022
Publisher: Elsevier BV
Date: 02-2012
Publisher: Springer Science and Business Media LLC
Date: 11-10-2009
DOI: 10.1038/NG.456
Publisher: Springer Science and Business Media LLC
Date: 09-2009
DOI: 10.1038/IJO.2009.168
Publisher: Cold Spring Harbor Laboratory
Date: 15-03-2021
DOI: 10.1101/2021.03.12.21253159
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced in iduals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: Cambridge University Press (CUP)
Date: 12-2015
DOI: 10.1017/THG.2015.87
Abstract: Monozygotic (MZ) twins provide a natural system for investigating developmental plasticity and the potential epigenetic origins of disease. A major difference in the intrauterine environment between MZ pairs is whether they share a common placenta or have separate placentas. Using DNA methylation measured at ,000 points in the genome on the Illumina HumanMethylation450 array, we demonstrate that the co-twins of MZ pairs (average age of 14) that shared a common placenta ( n = 18 pairs) have more similar DNA methylation levels in blood throughout the genome relative to those with separate placentas ( n = 16 pairs). Functional annotation of the genomic regions that show significantly different correlation between monochorionic (MC) and dichorionic (DC) MZ pairs found an over-representation of genes involved in the regulation of transcription, neuronal development, and cellular differentiation. These results support the idea that prenatal environmental exposures may have a lasting effect on an in idual's epigenetic landscape, and the potential for these changes to have functional consequences.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2014
DOI: 10.1038/MP.2012.184
Publisher: Cold Spring Harbor Laboratory
Date: 13-09-2020
DOI: 10.1101/2020.09.11.20175026
Abstract: Internalising symptoms in childhood and adolescence are as heritable as adult depression and anxiety, yet little is known of their molecular basis. This genome-wide association meta-analysis of internalising symptoms included repeated observations from 64,641 in iduals, aged between 3 and 18. The N-weighted meta-analysis of overall internalising symptoms (INT overall ) detected no genome-wide significant hits and showed low SNP heritability (1.66%, 95% confidence intervals 0.84-2.48%, N effective =132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalising symptoms showing the highest heritability (5.63%, 95% confidence intervals 3.08-8.18%). Additive genetic effects on internalising symptoms appeared stable over age, with overlapping estimates of SNP heritability from early-childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the wellbeing spectrum (| r g | 0.70), as well as with insomnia, loneliness, attention-deficit hyperactivity disorder, autism, and childhood aggression (range | r g |=0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. The pattern of genetic correlations suggests that childhood and adolescent internalising symptoms share substantial genetic vulnerabilities with adult internalising disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalising symptoms over time and the high comorbidity amongst childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood s les will be key in paving the way to future GWAS success.
Publisher: Frontiers Media SA
Date: 09-03-2022
DOI: 10.3389/FGENE.2022.759309
Abstract: Metabolic syndrome is a group of heritable metabolic traits that are highly associated with type 2 diabetes (T2DM). Classical interventions to T2DM include in idual self-management of environmental risk factors, such as improving diet quality, increasing physical activity, and reducing smoking and alcohol consumption, which decreases the risk of developing metabolic syndrome. However, it is poorly understood how the phenotypes of diabetes-related metabolic traits change with respect to lifestyle modifications at the in idual level. In the analysis, we used 12 diabetes-related metabolic traits and eight lifestyle covariates from the UK Biobank comprising 288,837 white British participants genotyped for 1,133,273 genome-wide single nucleotide polymorphisms. We found 16 GxE interactions. Modulation of genetic effects by physical activity was seen for four traits (glucose, HbA1c, C-reactive protein, systolic blood pressure) and by alcohol and smoking for three (BMI, glucose, waist–hip ratio and BMI and diastolic and systolic blood pressure, respectively). We also found a number of significant phenotypic modulations by the lifestyle covariates, which were not attributed to the genetic effects in the model. Overall, modulation in the metabolic risk in response to the level of lifestyle covariates was clearly observed, and its direction and magnitude were varied depending on in idual differences. We also showed that the metabolic risk inferred by our model was notably higher in T2DM prospective cases than controls. Our findings highlight the importance of in idual genetic differences in the prevention and management of diabetes and suggest that the one-size-fits-all approach may not benefit all.
Publisher: Oxford University Press (OUP)
Date: 10-06-2011
DOI: 10.1093/HMG/DDR272
Publisher: Cold Spring Harbor Laboratory
Date: 21-07-2023
DOI: 10.1101/2023.07.20.549816
Abstract: The use of polygenic risk score (PRS) models has transformed the field of genetics by enabling the prediction of complex traits and diseases based on an in idual’s genetic profile. However, the impact of genotype-environment interaction (GxE) on the performance and applicability of PRS models remains a crucial aspect to be explored. Currently, existing GxE PRS models are often inappropriately used, which can result in inflated type 1 error rates and compromised results. In this study, we propose a novel GxE PRS model that correctly incorporates the GxE component to analyze complex traits and diseases. Through extensive simulations, we demonstrate that our proposed model outperforms existing models in terms of controlling type 1 error rates and enhancing statistical power. Furthermore, we apply the proposed model to real data, and report significant GxE effects. Specifically, we highlight the impact of our model on both quantitative and binary traits. For quantitative traits, we uncover the GxE modulation of genetic effects on body mass index (BMI) by alcohol intake frequency (ALC). In the case of binary traits, we identify the GxE modulation of genetic effects on hypertension (HYP) by waist-to-hip ratio (WHR). These findings underscore the importance of employing a robust model that effectively controls type 1 error rates, thus preventing the occurrence of spurious GxE signals. To facilitate the implementation of our approach, we have developed an innovative R software package called GxE PRS, specifically designed to detect and estimate GxE effects. Overall, our study highlights the importance of accurate GxE modeling and its implications for genetic risk prediction, while providing a practical tool to support further research in this area.
Publisher: Wiley
Date: 24-07-2013
Publisher: Cold Spring Harbor Laboratory
Date: 23-11-2020
DOI: 10.1101/2020.11.22.20236505
Abstract: Metabolic syndrome is a group of heritable metabolic traits that are highly associated with type 2 diabetes (T2DM). Classical interventions to T2DM include in idual self-management of environmental risk factors such as improving diet quality, increasing physical activity and reducing smoking and alcohol consumptions, which decreases the risk of developing metabolic syndrome. However, it is poorly understood how the phenotypes of diabetes-related metabolic traits change with respect to lifestyle modifications at the in idual level. In this study, we applied a whole-genome genotype-by-environment (GxE) interaction approach to describe how intermediate traits reflecting metabolic risk are affected by genetic variations and how this genetic risk can interact with lifestyle, which can vary, conditional on in idual genetic differences. In the analysis, we used 12 diabetes-related metabolic traits and eight lifestyle covariates from the UK Biobank comprising 288,837 white British participants genotyped for 1,133,273 genome-wide single nucleotide polymorphisms. We found 17 GxE interactions, of which four modulated BMI and the others distributed across other traits. Modulation of genetic effects by physical activity was seen for four traits (glucose, HbA1c, C-reactive protein, systolic blood pressure), and by alcohol and smoking for three (BMI, glucose, waist-hip ratio and BMI, diastolic and systolic blood pressure, respectively). We also found a number of significant phenotypic modulations by the lifestyle covariates, which were not attributed to the genetic effects in the model. Overall, modulation in the metabolic risk in response to the level of lifestyle covariates was clearly observed, and its direction and magnitude were varied depending on in idual differences. We also showed that the metabolic risk inferred by our model was notably higher in T2DM prospective cases than controls. Our findings highlight the importance of in idual genetic differences in the prevention and management of diabetes and suggest that the one-size-fits-all approach may not benefit all. This study has been supported by the Australian Research Council (DP 190100766, FT 160100229).
Publisher: Cambridge University Press (CUP)
Date: 12-2004
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2020
DOI: 10.1101/2020.06.04.20121061
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium. The SNP heritability of total psychiatric problems was 5.4% (SE=0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total psychiatric problem score were shared with known genetic variants for common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (r G 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (r G 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation of with intelligence, educational attainment, wellbeing, smoking, and body fat (r G 0.29).The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between psychiatric disorders and related traits.
Publisher: Oxford University Press (OUP)
Date: 18-01-2023
DOI: 10.1093/IJE/DYAC238
Abstract: Genetic and lifestyle factors are associated with cancer risk. We investigated the benefits of adhering to lifestyle advice by the World Cancer Research Fund (WCRF) with the risk of 13 types of cancer and whether these associations differ according to genetic risk using data from the UK Biobank. In 2006–2010, participants aged 37–73 years had their lifestyle assessed and were followed up for incident cancers until 2015–2019. Analyses were restricted to those of White European ancestry with no prior history of malignant cancer (n = 195 822). Polygenic risk scores (PRSs) were computed for 13 cancer types and these cancers combined (‘overall cancer’), and a lifestyle index was calculated from WCRF recommendations. Associations with cancer incidence were estimated using Cox regression, adjusting for relevant confounders. Additive and multiplicative interactions between lifestyle index and PRSs were assessed. There were 15 240 incident cancers during the 1 926 987 person-years of follow-up (median follow-up = 10.2 years). After adjusting for confounders, the lifestyle index was associated with a lower risk of overall cancer [hazard ratio per standard deviation increase (95% CI) = 0.89 (0.87, 0.90)] and of eight specific cancer types. There was no evidence of interactions on the multiplicative scale. There was evidence of additive interactions in risks for colorectal, breast, pancreatic, lung and bladder cancers, such that the recommended lifestyle was associated with greater change in absolute risk for persons at higher genetic risk (P & 0.0003 for all). The recommended lifestyle has beneficial associations with most cancers. In terms of absolute risk, the protective association is greater for higher genetic risk groups for some cancers. These findings have important implications for persons most genetically predisposed to those cancers and for targeted strategies for cancer prevention.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2008
Abstract: Most information in linkage analysis for quantitative traits comes from pairs of relatives that are phenotypically most discordant or concordant. Confounding this, within-family outliers from non-genetic causes may create false positives and negatives. We investigated the influence of within-family outliers empirically, using one of the largest genome-wide linkage scans for height. The subjects were drawn from Australian twin cohorts consisting of 8447 in iduals in 2861 families, providing a total of 5815 possible pairs of siblings in sibships. A variance component linkage analysis was performed, either including or excluding the within-family outliers. Using the entire dataset, the largest LOD scores were on chromosome 15q (LOD 2.3) and 11q (1.5). Excluding within-family outliers increased the LOD score for most regions, but the LOD score on chromosome 15 decreased from 2.3 to 1.2, suggesting that the outliers may create false negatives and false positives, although rare alleles of large effect may also be an explanation. Several regions suggestive of linkage to height were found after removing the outliers, including 1q23.1 (2.0), 3q22.1 (1.9) and 5q32 (2.3). We conclude that the investigation of the effect of within-family outliers, which is usually neglected, should be a standard quality control measure in linkage analysis for complex traits and may reduce the noise for the search of common variants of modest effect size as well as help identify rare variants of large effect and clinical significance. We suggest that the effect of within-family outliers deserves further investigation via theoretical and simulation studies.
Publisher: Oxford University Press (OUP)
Date: 18-10-2012
DOI: 10.1093/HMG/DDR478
Publisher: Springer Science and Business Media LLC
Date: 20-06-2010
DOI: 10.1038/NG.608
Publisher: Springer Science and Business Media LLC
Date: 09-2005
DOI: 10.1007/S10519-005-3556-X
Abstract: Twin studies provide estimates of genetic and environmental contributions to cognitive ability differences, but could be based on biased s les. Here we report whole-population estimates using twins from unique mental surveys in Scotland. The Scottish Mental Surveys of 1st June 1932 (SMS1932) and 4th June 1947 (SMS1947), respectively, administered the same validated verbal reasoning test to almost everyone born in 1921 or 1936 and attending school in Scotland. There were 572 twin pairs from the SMS1932, and 517 pairs from the SMS1947. Information on zygosity was unavailable. A novel application of a mixture distribution was used to estimate genetic and environmental components of verbal reasoning variation by maximum likelihood. We found consistent heritability (approximately 0.70) and shared environment (approximately 0.21) estimates. The estimates did not change substantially when additional quantitative traits (height and weight) were added in a multivariate analysis. More generally for studies in genetics, the methodological innovation developed here implies that large (national) data collections can provide sufficient information on twin pairs to estimate genetic parameters, even without zygosity.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.JAAC.2010.10.010
Abstract: Breast-fed C-allele carriers of the rs174575 single nucleotide polymorphism in the fatty acyl desaturase 2 (FADS2) gene have been reported to show a 6.4 to 7 IQ point advantage over formula-fed C-allele carriers, with no effect of breast-feeding in GG carriers. An Australian s le was examined to determine if an interaction between breast-feeding and the rs174575 single nucleotide polymorphism had any effect on IQ. This hypothesis was tested in more than 700 families of adolescent twins assessed for IQ and breast-feeding, birth weight, and FADS2 polymorphisms, and parental socioeconomic status and education, and maternal FADS2 status. No significant evidence for a moderating effect on IQ of rs174575 C-carrier status and breast-feeding was found, and there no effects of maternal FADS2 status on offspring IQ. In addition, no main effects of any FADS2 polymorphisms on IQ were found when the genotype was kept as two-homozygote and one-heterozygote categories and indeed no evidence for effects of breast-feeding on IQ scores after controlling for parental socioeconomic status and education. The investigation was extended to two additional FADS2 polymorphisms (rs1535 and rs174583), but again, although these polymorphisms code alleles affecting fatty acid metabolism, no main or interaction effects were found on IQ. These results support the view that apparent effects of breast-feeding on IQ reflect differential likelihood of breast-feeding as a function of parental education and did not support the predicted interaction effect of FADS2 and breast-feeding on IQ.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.SCHRES.2013.03.022
Abstract: Association of rs1344706 in the ZNF804A gene (2q32.1) with schizophrenia was first reported in a genome wide scan conducted in a s le of 479 cases and replicated in 6666 cases. Subsequently, evidence by replication was obtained in several s les with European- and Asian ancestral background. We report ascertainment, clinical characterization, quality control, and determination of ancestral background of a case control s le from Indonesia, comprising 1067 cases and 1111 ancestry matched controls. Genotyping was performed using a fluorescence-based allelic discrimination assay (TaqMan SNP genotyping assay) and a newly designed PCR-RFLP assay for confirmation of rs1344706 genotypes. We confirmed association of the T-allele of rs1344706 with schizophrenia in a newly ascertained s le from Indonesia with Southeast Asian ancestral background (P=0.019, OR=1.155, 95%, CI 1.025-1.301). In addition, we studied several SNPs in the vicinity of rs1344706, for which nominally significant results had been reported. None of the association P values of the additional SNPs exceeded that of rs1344706. We provide additional evidence for association of the ZNF804A gene with schizophrenia. We conclude that rs1344706 or a yet unknown polymorphism in linkage disequilibrium is also involved in conferring susceptibility to schizophrenia in s les with different (Asian) ancestral backgrounds.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.JPSYCHIRES.2017.07.006
Abstract: Lower levels of circulating iron have been associated with depression. Our objective was to investigate the phenotypic and genetic relationship between measures of circulating levels of iron (serum iron, transferrin, transferrin saturation, and ferritin) and depressive symptoms. Data were available from ongoing studies at QIMR Berghofer Medical Research Institute (QIMRB), including twin adolescents (mean age 15.1 years, standard deviation (SD) 3.2 years), and twin adults (mean age 23.2 years, SD 2.2 years). In the adolescent cohort, there were 3416 participants from 1688 families. In the adult cohort there were 9035 participants from 4533 families. We estimated heritabilities of, and phenotypic and genetic correlations between, traits. We conducted analyses that linked results from published large-scale genome-wide association studies (including iron and Major Depressive Disorder) with our study s les using single SNP and multi-SNP genetic risk score analyses, and LD score regression analyses. In both cohorts, measures of iron, transferrin, transferrin saturation, and log 10 of ferritin (L10Fer) were all highly heritable, while depressive measures were moderately heritable. In adolescents, depression measures were higher in those in the middle 10th versus top 10th percentile of transferrin saturation measures (p = 0.002). Genetic profile risk scores of the iron measures were not significantly associated with depression in study participants. LD score analyses showed no significant genetic relationship between iron and depression. Genetic factors strongly influence iron measures in adolescents and adults. Using several different strategies we find no evidence for a genetic contribution to the relationship between blood measures of iron and measures of depression.
Publisher: Elsevier BV
Date: 06-2015
Publisher: Springer Science and Business Media LLC
Date: 27-04-2022
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Oxford University Press (OUP)
Date: 06-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2019
Publisher: Springer Science and Business Media LLC
Date: 02-09-2023
Publisher: Wiley
Date: 12-2008
DOI: 10.1038/OBY.2008.440
Abstract: To estimate common and distinct genetic influences on a panel of obesity-related traits and serum leptin level in adults. In a cross-sectional study of 625 Danish, adult, healthy, monozygotic, and same-sex dizygotic twin pairs of both genders, we carried out detailed anthropometry (height, weight, waist and hip, and skin-fold thickness, body composition assessment by bioimpedance (fat mass and fat-free mass), and measurement of serum leptin level. Bivariate variance component analyses estimated the additive genetic correlations between these measurements. The genetic correlations between the traits for overall fatness (BMI and fat mass index, kg/m(2)) were 0.94 in men and 0.98 in women, and their correlations with the various local fatness measures ranged from 0.49 to 0.83 in men and from 0.70 to 0.87 in women. The correlations between the truncal measures (waist circumference and truncal skin folds) and between the peripheral measures (hip circumference and peripheral skin folds) were 0.57 and 0.47 in men and 0.71 and 0.70 in women, respectively. The correlations between the truncal and peripheral measures ranged between 0.49 and 0.72 in men and between 0.61 and 0.82 in women. For leptin vs. the various measures of overall and local fatness the correlations ranged from 0.54 to 0.74 in men and from 0.48 to 0.75 in women. All correlations were significantly <1.00. The study supports control of overall fat mass and peripheral and truncal fat mass by both shared and different genetic components, which suggests that it is important to distinguish between the different phenotypes in the search for genes involved in the development of obesity.
Publisher: Springer Science and Business Media LLC
Date: 12-07-2017
DOI: 10.1038/NCOMMS16015
Abstract: Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined s le of 195,180 in iduals and identify 16 loci associated with grip strength ( P × 10 −8 ) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres ( ACTG1 ), neuronal maintenance and signal transduction ( PEX14, TGFA, SYT1 ), or monogenic syndromes with involvement of psychomotor impairment ( PEX14, LRPPRC and KANSL1 ). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2019
Publisher: Public Library of Science (PLoS)
Date: 22-08-2022
DOI: 10.1371/JOURNAL.PONE.0273116
Abstract: Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2 , a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.
Publisher: Public Library of Science (PLoS)
Date: 15-10-2012
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2015
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2015
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2012
Funder: National Health and Medical Research Council
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