Understanding the genomic architecture and molecular mechanisms of cognitive functioning in healthy individuals is critical for developing tailored interventions to enhance cognitive functioning, as ...well as for identifying targets for treating impaired cognition. There has been substantial progress in uncovering the genetic composition of the general cognitive ability (g). However, there is an ongoing debate whether executive functioning (EF)-another key predictor of cognitive health and performance, is separable from general g. To provide an analytical review on existing findings on genetic influences on the relationship between g and EF, we re-analysed a subset of genome-wide association studies (GWAS) from the GWAS catalogue that used measures of g and EF as outcomes in non-clinical populations. We identified two sets of single nucleotide polymorphisms (SNPs) associated with g (1,372 SNPs across 12 studies), and EF (300 SNPs across 5 studies) at p<5x10.sup.-6 . A comparative analysis of GWAS-identified g and EF SNPs in high linkage disequilibrium (LD), followed by pathway enrichment analyses suggest that g and EF are overlapping but separable at genetic variant and molecular pathway levels, however more evidence is required to characterize the genetic overlap/distinction between the two constructs. While not without limitations, these findings may have implications for navigating further research towards translatable genetic findings for cognitive remediation, enhancement, and augmentation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The UK Biobank cognitive assessment data has been a significant resource for researchers looking to investigate predictors and modifiers of cognitive abilities and associated health outcomes in the ...general population. Given the diverse nature of this data, researchers use different approaches - from the use of a single test to composing the general intelligence score,
, across the tests. We argue that both approaches are suboptimal - one being too specific and the other one too general - and suggest a novel multifactorial solution to represent cognitive abilities.
Using a combined Exploratory Factor (EFA) and Exploratory Structural Equation Modeling Analyses (ESEM) we developed a three-factor model to characterize an underlying structure of nine cognitive tests selected from the UK Biobank using a Cattell-Horn-Carroll framework. We first estimated a series of probable factor solutions using the maximum likelihood method of extraction. The best solution for the EFA-defined factor structure was then tested using the ESEM approach with the aim of confirming or disconfirming the decisions made.
We determined that a three-factor model fits the UK Biobank cognitive assessment data best. Two of the three factors can be assigned to
with a clear distinction between
and
. The third factor was identified as a
factor.
This study characterizes cognitive assessment data in the UK Biobank and delivers an alternative view on its underlying structure, suggesting that the three factor model provides a more granular solution than
that can further be applied to study different facets of cognitive functioning in relation to health outcomes and to further progress examination of its biological underpinnings.
Abstract Cognitive impairment, or decline, is not only a feature of Alzheimer׳s disease and other forms of dementia but also normal ageing. Abundant evidence from epidemiological studies points ...towards perturbed inflammatory mechanisms in aged individuals, though the cause–effect nature of this apparent relationship is difficult to establish. Genetic association studies focusing on polymorphism in and around inflammatory genes represent a viable approach to establish whether inflammatory mechanisms might play a causal role in cognitive decline, whilst also enabling the identification of specific genes potentially influencing specific cognitive facets. Thus, here we provide a review of published genetic association studies investigating inflammatory genes in the context of cognitive decline in elderly, non-demented, samples. Numerous candidate gene association studies have been performed to date, focusing almost exclusively on genes encoding major cytokines. Some of these studies report significant cognitive domain-specific associations implicating Interleukin 1β (IL1β) (rs16944), Tumour Necrosis Factor α (TNFα) (rs1800629) and C-reactive protein (CRP) in various domains of cognitive function. However, the majority of these studies are lacking in statistical power and have other methodological limitations, suggesting some of them may have yielded false positive results. Genome-wide association studies have implicated less direct and less obvious regulators of inflammatory processes (i.e., PDE7A , HS3ST4, SPOCK3), indicating that a shift away from the major cytokine-encoding genes in future studies will be important. Furthermore, better cohesion across studies with regards to the cognitive test batteries administered to participants along with the continued application of longitudinal designs will be vital.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objectives:
Timely and accurate assessments of disease burden are essential for developing effective national health policies. We used the Global Burden of Disease Study 2015 to examine burden due to ...mental and substance use disorders in Australia.
Methods:
For each of the 20 mental and substance use disorders included in Global Burden of Disease Study 2015, systematic reviews of epidemiological data were conducted, and data modelled using a Bayesian meta-regression tool to produce prevalence estimates by age, sex, geography and year. Prevalence for each disorder was then combined with a disorder-specific disability weight to give years lived with disability, as a measure of non-fatal burden. Fatal burden was measured as years of life lost due to premature mortality which were calculated by combining the number of deaths due to a disorder with the life expectancy remaining at the time of death. Disability-adjusted life years were calculated by summing years lived with disability and years of life lost to give a measure of total burden. Uncertainty was calculated around all burden estimates.
Results:
Mental and substance use disorders were the leading cause of non-fatal burden in Australia in 2015, explaining 24.3% of total years lived with disability, and were the second leading cause of total burden, accounting for 14.6% of total disability-adjusted life years. There was no significant change in the age-standardised disability-adjusted life year rates for mental and substance use disorders from 1990 to 2015.
Conclusion:
Global Burden of Disease Study 2015 found that mental and substance use disorders were leading contributors to disease burden in Australia. Despite several decades of national reform, the burden of mental and substance use disorders remained largely unchanged between 1990 and 2015. To reduce this burden, effective population-level preventions strategies are required in addition to effective interventions of sufficient duration and coverage.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The contributions of genetic variation and the environment to gene expression may change across the lifespan. However, few studies have investigated the heritability of blood gene expression in older ...adults. The current study therefore aimed to investigate this question in a community sample of older adults. A total of 246 adults (71 MZ and 52 DZ twins, 69.91% females; mean age-75.79 ± 5.44) were studied. Peripheral blood gene expression was assessed using Illumina microarrays. A heritability analysis was performed using structural equation modelling. There were 5269 probes (19.9%) from 4603 unique genes (23.9%) (total 26,537 probes from 19,256 genes) that were significantly heritable (mean h
= 0.40). A pathway analysis of the top 10% of significant genes showed enrichment for the immune response and ageing-associated genes. In a comparison with two other gene expression twin heritability studies using adults from across the lifespan, there were 38 out of 9479 overlapping genes that were significantly heritable. In conclusion, our study found ~24% of the available genes for analysis were heritable in older adults, with only a small number common across studies that used samples from across adulthood, indicating the importance of examining gene expression in older age groups.
•Genome-wide gene expression signature of depression identifies potential novel mechanisms and treatment targets.•57 brain and 21 peripheral DEGs are replicated at genome-wide level in ...depression.•Functional overlap between brain and periphery links depression and CVD.•Dermal fibroblasts are a promising experimental model for depression biomarker research.•Gene PXMP2 is a proposed novel candidate for pathophysiology of depression.
There is a growing body of research investigating the gene expression signature of depression at the genome-wide level, with potential for the discovery of novel pathophysiological mechanisms of depression. However, heterogeneity of depression, dynamic nature of gene expression patterns and various sources of noise have resulted in inconsistent findings. We systematically review the current state of transcriptome profiling of depression in the brain and peripheral tissues with a particular focus on replicated findings at the single gene level. By examining 16 brain regions and 5 cell types from the periphery, we identified 57 replicated differentially expressed genes in the brain and 21 in peripheral tissues. Functional overlap between brain and periphery strongly implicates shared pathways in a comorbid phenotype of depression and cardiovascular disease. The findings highlight dermal fibroblasts as a promising experimental model for depression biomarker research, provide partial support for all major theories of depression and suggest a novel candidate gene, PXMP2, which plays a critical role in lipid and reactive oxygen species metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The molecular factors involved in the pathophysiology of major depressive disorder (MDD) remain poorly understood. One approach to examine the molecular basis of MDD is co-expression network ...analysis, which facilitates the examination of complex interactions between expression levels of individual genes and how they influence biological pathways affected in MDD. Here, we applied an unsupervised gene-network based approach to a prospective experimental design using microarray genome-wide gene expression from the peripheral whole blood of older adults. We utilised the Sydney Memory and Ageing Study (sMAS, N = 521) and the Older Australian Twins Study (OATS, N = 186) as discovery and replication cohorts, respectively. We constructed networks using Weighted Gene Co-expression Network Analysis (WGCNA), and correlated identified modules with four subtypes of depression: single episode, current, recurrent, and lifetime MDD. Four modules of highly co-expressed genes were associated with recurrent MDD (N = 27) in our discovery cohort (FDR<0.2), with no significant findings for a single episode, current or lifetime MDD. Functional characterisation of these modules revealed a complex interplay between dysregulated protein processing in the endoplasmic reticulum (ER), and innate and adaptive immune response signalling, with possible involvement of pathogen-related pathways. We were underpowered to replicate findings at the network level in an independent cohort (OATS), however; we found a significant overlap for 9 individual genes with similar co-expression and dysregulation patterns associated with recurrent MDD in both cohorts. Overall, our findings support other reports on dysregulated immune response and protein processing in the ER in MDD and provide novel insights into the pathophysiology of depression.
•Stratification of MDD is useful for identifying molecular signature of disease.•Transcriptome signature of MDD can be captured in the whole blood using WGCNA.•Genes involved in protein processing in ER are downregulated in recurrent MDD.•Both innate and adaptive immune systems are dysregulated in recurrent MDD.•Molecular link between infectious diseases and MDD in later life is suggested.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•Blood transcriptome is a proxy for studying biomarkers for Major Depressive Disorder (MDD).•Machine Learning (ML) is a powerful approach to identify predictive markers of MDD.•Fuzzy Forests, a ...machine learning algorithm, takes into account network structure of transcriptome data.•Transferrin receptor, TFRC, downregulated in blood, is predictive of recurrent MDD, indicating the role of immune system in MDD.
At present, no predictive markers for Major Depressive Disorder (MDD) exist. The search for such markers has been challenging due to clinical and molecular heterogeneity of MDD, the lack of statistical power in studies and suboptimal statistical tools applied to multidimensional data. Machine learning is a powerful approach to mitigate some of these limitations.
We aimed to identify the predictive markers of recurrent MDD in the elderly using peripheral whole blood from the Sydney Memory and Aging Study (SMAS) (N = 521, aged over 65) and adopting machine learning methodology on transcriptome data. Fuzzy Forests is a Random Forests-based classification algorithm that takes advantage of the co-expression network structure between genes; it allows to alleviate the problem of p >> n via reducing the dimensionality of transcriptomic feature space.
By adopting Fuzzy Forests on transcriptome data, we found that the downregulated TFRC (transferrin receptor) can predict recurrent MDD with an accuracy of 63%.
Although we corrected our data for several important confounders, we were not able to account for the comorbidities and medication taken, which may be numerous in the elderly and might have affected the levels of gene transcription.
We found that downregulated TFRC is predictive of recurrent MDD, which is consistent with the previous literature, indicating the role of the innate immune system in depression. This study is the first to successfully apply Fuzzy Forests methodology on psychiatric condition, opening, therefore, a methodological avenue that can lead to clinically useful predictive markers of complex traits.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Jerusalem, Israel, from 30 October 2016 to 3 November 2016. A total of ...372 participants gathered to discuss the latest findings in the field. The following report was written by early career investigator travel awardees, and student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the presentations during the conference, and contains some of the major notable new findings reported.
The Australian population aged 70 and above is increasing and imposing new challenges for policy makers and providers to deliver accessible, appropriate and affordable health care. We examine ...pre-COVID patterns of health loss between 1990 and 2019 to inform policies and practices.
Using the standardised methodology framework and analytical strategies from GBD 2019 methodologies, we estimated mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life years (DALYs), life expectancy at age 70 and above (LE-70), and healthy life expectancy (HALE-70) in Australia comparing them globally and with high socio-demographic index (SDI) groups.
DALY rates have been improving steadily over the past 30 years among Australians aged 70 and above. Decreases in DALY rates were primarily attributed to a fall in YLLs attributable to cardiovascular diseases (60%) and chronic respiratory disorders (30.2%) and transport injuries (56.9%), while the non-fatal burden remained stable from 1990 to 2019. According to the DALY rates, the top five leading causes are ischemic heart disease, Alzheimer's disease, COPD, stroke, and falls, where falls exhibited the largest increase since 1990.
This study provides an in-depth report on the main causes of mortality and disability in Australia's population aged 70 and above. It sheds light on the shifts in burden over three decades, emphasising the need for the Australian health system to enhance its readiness in addressing the escalating demands of an ageing population. These findings establish pre-COVID baseline estimates for Australia's population aged 70 and above, informing healthcare preparedness.
Bill & Melinda Gates Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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