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  1. Article: Accidental Brothers: The Story of Twins Exchanged at Birth and the Power of Nature and Nurture Nancy L. Segal and Yesika S. Montoya (2018), St. Martin's Press, 352 pp., hardcover ISBN 9781250101907, ebook ISBN 9781250101914.

    Lupton, Michelle K

    Twin research and human genetics : the official journal of the International Society for Twin Studies

    2018  Volume 21, Issue 4, Page(s) 330–331

    Language English
    Publishing date 2018-07-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 2182682-1
    ISSN 1839-2628 ; 1832-4274
    ISSN (online) 1839-2628
    ISSN 1832-4274
    DOI 10.1017/thg.2018.44
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  2. Article ; Online: Advanced patient-specific microglia cell models for pre-clinical studies in Alzheimer's disease.

    Cuní-López, Carla / Stewart, Romal / Oikari, Lotta E / Nguyen, Tam Hong / Roberts, Tara L / Sun, Yifan / Guo, Christine C / Lupton, Michelle K / White, Anthony R / Quek, Hazel

    Journal of neuroinflammation

    2024  Volume 21, Issue 1, Page(s) 50

    Abstract: Background: Alzheimer's disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no consistent clinical benefit. Neuroinflammation ... ...

    Abstract Background: Alzheimer's disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no consistent clinical benefit. Neuroinflammation is a major contributor to neurodegeneration and hence, microglia, the brain's resident immune cells, are an attractive target for potentially more effective therapeutic strategies. However, there is no current in vitro model system that captures AD patient-specific microglial characteristics using physiologically relevant and experimentally flexible culture conditions.
    Methods: To address this shortcoming, we developed novel 3D Matrigel-based monocyte-derived microglia-like cell (MDMi) mono-cultures and co-cultures with neuro-glial cells (ReNcell VM). We used single-cell RNA sequencing (scRNAseq) analysis to compare the transcriptomic signatures of MDMi between model systems (2D, 3D and 3D co-culture) and against published human microglia datasets. To demonstrate the potential of MDMi for use in personalized pre-clinical strategies, we generated and characterized MDMi models from sixteen AD patients and matched healthy controls, and profiled cytokine responses upon treatment with anti-inflammatory drugs (dasatinib and spiperone).
    Results: MDMi in 3D exhibited a more branched morphology and longer survival in culture compared to 2D. scRNAseq uncovered distinct MDMi subpopulations that exhibit higher functional heterogeneity and best resemble human microglia in 3D co-culture. AD MDMi in 3D co-culture showed altered cell-to-cell interactions, growth factor and cytokine secretion profiles and responses to amyloid-β. Drug testing assays revealed patient- and model-specific cytokine responses.
    Conclusion: Our study presents a novel, physiologically relevant and AD patient-specific 3D microglia cell model that opens avenues towards improving personalized drug development strategies in AD.
    MeSH term(s) Humans ; Alzheimer Disease/pathology ; Microglia/metabolism ; Neuroglia/metabolism ; Amyloid beta-Peptides/metabolism ; Cytokines/metabolism
    Chemical Substances Amyloid beta-Peptides ; Cytokines
    Language English
    Publishing date 2024-02-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-024-03037-3
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  3. Article ; Online: Genetic evidence that the causal association of educational attainment with reduced risk of Alzheimer's disease is driven by intelligence.

    Thorp, Jackson G / Mitchell, Brittany L / Gerring, Zachary F / Ong, Jue-Sheng / Gharahkhani, Puya / Derks, Eske M / Lupton, Michelle K

    Neurobiology of aging

    2022  Volume 119, Page(s) 127–135

    Abstract: Alzheimer's disease (AD) is predicted to affect 132 million people by 2050. Targeting modifiable lifestyle risk factors that are associated with an increased risk of AD could prevent a large proportion of dementia cases, allowing people to reach the end ... ...

    Abstract Alzheimer's disease (AD) is predicted to affect 132 million people by 2050. Targeting modifiable lifestyle risk factors that are associated with an increased risk of AD could prevent a large proportion of dementia cases, allowing people to reach the end of their life dementia free. However, evidence obtained from the observational studies does not take into account how risk factors are correlated with one another, and whether they causally contribute to increased AD risk. In this study, we determine whether the relationship between previously speculated AD risk factors and AD susceptibility is consistent with causality using large-scale genetic data. We focus on educational attainment (EA), intelligence and household income which have been previously shown to be causally associated with AD. Using GWAS-by-subtraction and Multivariable Mendelian Randomization we show that of these, only the cognitive component of EA (intelligence) is independently causally associated with AD. This work has ramifications for the modifiability of lifestyle risk factors for AD.
    MeSH term(s) Alzheimer Disease/etiology ; Alzheimer Disease/genetics ; Educational Status ; Genome-Wide Association Study ; Humans ; Intelligence/genetics ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide ; Risk Factors
    Language English
    Publishing date 2022-07-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 604505-4
    ISSN 1558-1497 ; 0197-4580
    ISSN (online) 1558-1497
    ISSN 0197-4580
    DOI 10.1016/j.neurobiolaging.2022.07.011
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  4. Article ; Online: An analysis of genetically regulated gene expression across multiple tissues implicates novel gene candidates in Alzheimer's disease.

    Gerring, Zachary F / Lupton, Michelle K / Edey, Daniel / Gamazon, Eric R / Derks, Eske M

    Alzheimer's research & therapy

    2020  Volume 12, Issue 1, Page(s) 43

    Abstract: Introduction: Genome-wide association studies (GWAS) have successfully identified multiple independent genetic loci that harbour variants associated with Alzheimer's disease, but the exact causal genes and biological pathways are largely unknown.: ... ...

    Abstract Introduction: Genome-wide association studies (GWAS) have successfully identified multiple independent genetic loci that harbour variants associated with Alzheimer's disease, but the exact causal genes and biological pathways are largely unknown.
    Methods: To prioritise likely causal genes associated with Alzheimer's disease, we used S-PrediXcan to integrate expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression (GTEx) study and CommonMind Consortium (CMC) with Alzheimer's disease GWAS summary statistics. We meta-analysed the GTEx results using S-MultiXcan, prioritised disease-implicated loci using a computational fine-mapping approach, and performed a biological pathway analysis on the gene-based results.
    Results: We identified 126 tissue-specific gene-based associations across 48 GTEx tissues, targeting 50 unique genes. Meta-analysis of the tissue-specific associations identified 73 genes whose expression was associated with Alzheimer's disease. Additional analyses in the dorsolateral prefrontal cortex from the CMC identified 12 significant associations, 8 of which also had a significant association in GTEx tissues. Fine-mapping of causal gene sets prioritised gene candidates in 10 Alzheimer's disease loci with strong evidence for causality. Biological pathway analyses of the meta-analysed GTEx data and CMC data identified a significant enrichment of Alzheimer's disease association signals in plasma lipoprotein clearance, in addition to multiple immune-related pathways.
    Conclusions: Gene expression data from brain and peripheral tissues can improve power to detect regulatory variation underlying Alzheimer's disease. However, the associations in peripheral tissues may reflect tissue-shared regulatory variation for a gene. Therefore, future functional studies should be performed to validate the biological meaning of these associations and whether they represent new pathogenic tissues.
    MeSH term(s) Alzheimer Disease/genetics ; Gene Expression ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics
    Language English
    Publishing date 2020-04-16
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2506521-X
    ISSN 1758-9193 ; 1758-9193
    ISSN (online) 1758-9193
    ISSN 1758-9193
    DOI 10.1186/s13195-020-00611-8
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  5. Article: The Effect of Genetic Predisposition to Alzheimer's Disease and Related Traits on Recruitment Bias in a Study of Cognitive Aging.

    Gomez, Lina M / Mitchell, Brittany L / McAloney, Kerrie / Adsett, Jessica / Garden, Natalie / Wood, Madeline / Diaz-Torres, Santiago / Garcia-Marin, Luis M / Breakspear, Michael / Martin, Nicholas G / Lupton, Michelle K

    Twin research and human genetics : the official journal of the International Society for Twin Studies

    2023  Volume 26, Issue 3, Page(s) 209–214

    Abstract: The recruitment of participants for research studies may be subject to bias. The Prospective Imaging Study of Ageing (PISA) aims to characterize the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD) ...

    Abstract The recruitment of participants for research studies may be subject to bias. The Prospective Imaging Study of Ageing (PISA) aims to characterize the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). Participants approached to take part in PISA were selected from existing cohort studies with available genomewide genetic data for both successfully and unsuccessfully recruited participants, allowing us to investigate the genetic contribution to voluntary recruitment, including the genetic predisposition to AD. We use a polygenic risk score (PRS) approach to test to what extent the genetic risk for AD, and related risk factors predict participation in PISA. We did not identify a significant association of genetic risk for AD with study participation, but we did identify significant associations with PRS for key causal risk factors for AD, IQ, household income and years of education. We also found that older and female participants were more likely to take part in the study. Our findings highlight the importance of considering bias in key risk factors for AD in the recruitment of individuals for cohort studies.
    MeSH term(s) Adult ; Humans ; Female ; Alzheimer Disease/genetics ; Genetic Predisposition to Disease ; Prospective Studies ; Cognitive Aging ; Australia/epidemiology ; Phenotype
    Language English
    Publishing date 2023-07-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2182682-1
    ISSN 1839-2628 ; 1832-4274
    ISSN (online) 1839-2628
    ISSN 1832-4274
    DOI 10.1017/thg.2023.26
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  6. Article ; Online: Functional re-organization of hippocampal-cortical gradients during naturalistic memory processes.

    Borne, Léonie / Tian, Ye / Lupton, Michelle K / van der Meer, Johan N / Jeganathan, Jayson / Paton, Bryan / Koussis, Nikitas / Guo, Christine C / Robinson, Gail A / Fripp, Jurgen / Zalesky, Andrew / Breakspear, Michael

    NeuroImage

    2023  Volume 271, Page(s) 119996

    Abstract: The functional organization of the hippocampus mirrors that of the cortex, changing smoothly along connectivity gradients and abruptly at inter-areal boundaries. Hippocampal-dependent cognitive processes require flexible integration of these hippocampal ... ...

    Abstract The functional organization of the hippocampus mirrors that of the cortex, changing smoothly along connectivity gradients and abruptly at inter-areal boundaries. Hippocampal-dependent cognitive processes require flexible integration of these hippocampal gradients into functionally related cortical networks. To understand the cognitive relevance of this functional embedding, we acquired fMRI data while participants viewed brief news clips, either containing or lacking recently familiarized cues. Participants were 188 healthy mid-life adults and 31 adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD). We employed a recently developed technique - connectivity gradientography - to study gradually changing patterns of voxel to whole brain functional connectivity and their sudden transitions. We observed that functional connectivity gradients of the anterior hippocampus map onto connectivity gradients across the default mode network during these naturalistic stimuli. The presence of familiar cues in the news clips accentuates a stepwise transition across the boundary from the anterior to the posterior hippocampus. This functional transition is shifted in the posterior direction in the left hippocampus of individuals with MCI or AD. These findings shed new light on the functional integration of hippocampal connectivity gradients into large-scale cortical networks, how these adapt with memory context and how these change in the presence of neurodegenerative disease.
    MeSH term(s) Adult ; Humans ; Neurodegenerative Diseases ; Memory ; Hippocampus ; Magnetic Resonance Imaging ; Brain ; Alzheimer Disease ; Cognitive Dysfunction
    Language English
    Publishing date 2023-03-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1147767-2
    ISSN 1095-9572 ; 1053-8119
    ISSN (online) 1095-9572
    ISSN 1053-8119
    DOI 10.1016/j.neuroimage.2023.119996
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  7. Article ; Online: Evaluation of Brain-Body Health in Individuals With Common Neuropsychiatric Disorders.

    Tian, Ye Ella / Di Biase, Maria A / Mosley, Philip E / Lupton, Michelle K / Xia, Ying / Fripp, Jurgen / Breakspear, Michael / Cropley, Vanessa / Zalesky, Andrew

    JAMA psychiatry

    2023  Volume 80, Issue 6, Page(s) 567–576

    Abstract: Importance: Physical health and chronic medical comorbidities are underestimated, inadequately treated, and often overlooked in psychiatry. A multiorgan, systemwide characterization of brain and body health in neuropsychiatric disorders may enable ... ...

    Abstract Importance: Physical health and chronic medical comorbidities are underestimated, inadequately treated, and often overlooked in psychiatry. A multiorgan, systemwide characterization of brain and body health in neuropsychiatric disorders may enable systematic evaluation of brain-body health status in patients and potentially identify new therapeutic targets.
    Objective: To evaluate the health status of the brain and 7 body systems across common neuropsychiatric disorders.
    Design, setting, and participants: Brain imaging phenotypes, physiological measures, and blood- and urine-based markers were harmonized across multiple population-based neuroimaging biobanks in the US, UK, and Australia, including UK Biobank; Australian Schizophrenia Research Bank; Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing; Alzheimer's Disease Neuroimaging Initiative; Prospective Imaging Study of Ageing; Human Connectome Project-Young Adult; and Human Connectome Project-Aging. Cross-sectional data acquired between March 2006 and December 2020 were used to study organ health. Data were analyzed from October 18, 2021, to July 21, 2022. Adults aged 18 to 95 years with a lifetime diagnosis of 1 or more common neuropsychiatric disorders, including schizophrenia, bipolar disorder, depression, generalized anxiety disorder, and a healthy comparison group were included.
    Main outcomes and measures: Deviations from normative reference ranges for composite health scores indexing the health and function of the brain and 7 body systems. Secondary outcomes included accuracy of classifying diagnoses (disease vs control) and differentiating between diagnoses (disease vs disease), measured using the area under the receiver operating characteristic curve (AUC).
    Results: There were 85 748 participants with preselected neuropsychiatric disorders (36 324 male) and 87 420 healthy control individuals (40 560 male) included in this study. Body health, especially scores indexing metabolic, hepatic, and immune health, deviated from normative reference ranges for all 4 neuropsychiatric disorders studied. Poor body health was a more pronounced illness manifestation compared to brain changes in schizophrenia (AUC for body = 0.81 [95% CI, 0.79-0.82]; AUC for brain = 0.79 [95% CI, 0.79-0.79]), bipolar disorder (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.57-0.58]), depression (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.58-0.58]), and anxiety (AUC for body = 0.63 [95% CI, 0.63-0.63]; AUC for brain = 0.57 [95% CI, 0.57-0.58]). However, brain health enabled more accurate differentiation between distinct neuropsychiatric diagnoses than body health (schizophrenia-other: mean AUC for body = 0.70 [95% CI, 0.70-0.71] and mean AUC for brain = 0.79 [95% CI, 0.79-0.80]; bipolar disorder-other: mean AUC for body = 0.60 [95% CI, 0.59-0.60] and mean AUC for brain = 0.65 [95% CI, 0.65-0.65]; depression-other: mean AUC for body = 0.61 [95% CI, 0.60-0.63] and mean AUC for brain = 0.65 [95% CI, 0.65-0.66]; anxiety-other: mean AUC for body = 0.63 [95% CI, 0.62-0.63] and mean AUC for brain = 0.66 [95% CI, 0.65-0.66).
    Conclusions and relevance: In this cross-sectional study, neuropsychiatric disorders shared a substantial and largely overlapping imprint of poor body health. Routinely monitoring body health and integrated physical and mental health care may help reduce the adverse effect of physical comorbidity in people with mental illness.
    MeSH term(s) Young Adult ; Humans ; Male ; Cross-Sectional Studies ; Prospective Studies ; Australia ; Brain/diagnostic imaging ; Bipolar Disorder/psychology
    Language English
    Publishing date 2023-04-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 2701203-7
    ISSN 2168-6238 ; 2168-622X
    ISSN (online) 2168-6238
    ISSN 2168-622X
    DOI 10.1001/jamapsychiatry.2023.0791
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  8. Article: Exploring the genetic relationship between hearing impairment and Alzheimer's disease.

    Mitchell, Brittany L / Thorp, Jackson G / Evans, David M / Nyholt, Dale R / Martin, Nicholas G / Lupton, Michelle K

    Alzheimer's & dementia (Amsterdam, Netherlands)

    2020  Volume 12, Issue 1, Page(s) e12108

    Abstract: Introduction: Hearing loss has been identified as the potentially largest modifiable risk factor for Alzheimer's disease (AD), estimated to account for a similar increase in AD risk as the apolipoprotein E (: Methods: We investigated the genetic ... ...

    Abstract Introduction: Hearing loss has been identified as the potentially largest modifiable risk factor for Alzheimer's disease (AD), estimated to account for a similar increase in AD risk as the apolipoprotein E (
    Methods: We investigated the genetic relationship between hearing loss and AD, and sought evidence for a causal relationship.
    Results: We found a significant genetic overlap between hearing impairment and AD and a polygenic risk score for AD was able to significantly predict hearing loss in an independent cohort. Additionally, regions of the genome involved in inflammation were identified to be shared between hearing difficulty and AD. However, causality tests found no significant evidence of a causal relationship between these traits in either direction.
    Discussion: Overall, these results show that the relationship between hearing difficulty and AD may, in part, be due to shared genes and immune response pathways between the traits. However, currently available data do not support a causal relationship.
    Language English
    Publishing date 2020-09-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2832898-X
    ISSN 2352-8729
    ISSN 2352-8729
    DOI 10.1002/dad2.12108
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  9. Article ; Online: ALS monocyte-derived microglia-like cells reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression.

    Quek, Hazel / Cuní-López, Carla / Stewart, Romal / Colletti, Tiziana / Notaro, Antonietta / Nguyen, Tam Hong / Sun, Yifan / Guo, Christine C / Lupton, Michelle K / Roberts, Tara L / Lim, Yi Chieh / Oikari, Lotta E / La Bella, Vincenzo / White, Anthony R

    Journal of neuroinflammation

    2022  Volume 19, Issue 1, Page(s) 58

    Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Increasing evidence indicates that neuroinflammation mediated by microglia contributes to ALS ... ...

    Abstract Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Increasing evidence indicates that neuroinflammation mediated by microglia contributes to ALS pathogenesis. This microglial activation is evident in post-mortem brain tissues and neuroimaging data from patients with ALS. However, the role of microglia in the pathogenesis and progression of amyotrophic lateral sclerosis remains unclear, partly due to the lack of a model system that is able to faithfully recapitulate the clinical pathology of ALS. To address this shortcoming, we describe an approach that generates monocyte-derived microglia-like cells that are capable of expressing molecular markers, and functional characteristics similar to in vivo human brain microglia.
    Methods: In this study, we have established monocyte-derived microglia-like cells from 30 sporadic patients with ALS, including 15 patients with slow disease progression, 6 with intermediate progression, and 9 with rapid progression, together with 20 non-affected healthy controls.
    Results: We demonstrate that patient monocyte-derived microglia-like cells recapitulate canonical pathological features of ALS including non-phosphorylated and phosphorylated-TDP-43-positive inclusions. Moreover, ALS microglia-like cells showed significantly impaired phagocytosis, altered cytokine profiles, and abnormal morphologies consistent with a neuroinflammatory phenotype. Interestingly, all ALS microglia-like cells showed abnormal phagocytosis consistent with the progression of the disease. In-depth analysis of ALS microglia-like cells from the rapid disease progression cohort revealed significantly altered cell-specific variation in phagocytic function. In addition, DNA damage and NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome activity were also elevated in ALS patient monocyte-derived microglia-like cells, indicating a potential new pathway involved in driving disease progression.
    Conclusions: Taken together, our work demonstrates that the monocyte-derived microglia-like cell model recapitulates disease-specific hallmarks and characteristics that substantiate patient heterogeneity associated with disease subgroups. Thus, monocyte-derived microglia-like cells are highly applicable to monitor disease progression and can be applied as a functional readout in clinical trials for anti-neuroinflammatory agents, providing a basis for personalised treatment for patients with ALS.
    MeSH term(s) Amyotrophic Lateral Sclerosis/pathology ; DNA Damage ; DNA-Binding Proteins/metabolism ; Disease Progression ; Humans ; Microglia/metabolism ; Monocytes/metabolism ; Neurodegenerative Diseases/metabolism ; Phagocytosis
    Chemical Substances DNA-Binding Proteins ; TARDBP protein, human
    Language English
    Publishing date 2022-02-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2156455-3
    ISSN 1742-2094 ; 1742-2094
    ISSN (online) 1742-2094
    ISSN 1742-2094
    DOI 10.1186/s12974-022-02421-1
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  10. Article: Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness.

    Roughan, William H / Campos, Adrián I / García-Marín, Luis M / Cuéllar-Partida, Gabriel / Lupton, Michelle K / Hickie, Ian B / Medland, Sarah E / Wray, Naomi R / Byrne, Enda M / Ngo, Trung Thanh / Martin, Nicholas G / Rentería, Miguel E

    Frontiers in psychiatry

    2021  Volume 12, Page(s) 643609

    Abstract: The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of ... ...

    Abstract The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study (
    Language English
    Publishing date 2021-04-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564218-2
    ISSN 1664-0640
    ISSN 1664-0640
    DOI 10.3389/fpsyt.2021.643609
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