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NeuroImage. Clinical 2020Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to... (Review)
Review
Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to investigate changes in white matter microstructure in Alzheimer's Disease. This paper aims to systematically review studies that examined the effect of Alzheimer's risk genes on white matter microstructure. We assimilated findings from 37 studies and reviewed their diffusion pre-processing and analysis methods. Most studies estimate the diffusion tensor (DT) and compare derived quantitative measures such as fractional anisotropy and mean diffusivity between groups. Those with increased AD genetic risk are associated with reduced anisotropy and increased diffusivity across the brain, most notably the temporal and frontal lobes, cingulum and corpus callosum. Structural abnormalities are most evident amongst those with established Alzheimer's Disease. Recent studies employ signal representations and analysis frameworks beyond DT MRI but show that dMRI overall lacks specificity to disease pathology. However, as the field advances, these techniques may prove useful in pre-symptomatic diagnosis or staging of Alzheimer's disease.
Topics: Alzheimer Disease; Anisotropy; Brain; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Humans; White Matter
PubMed: 32758801
DOI: 10.1016/j.nicl.2020.102359 -
Journal of Affective Disorders Aug 2022Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ) share clinical features and genetic bases. Magnetic Resonance Imaging (MRI) studies... (Review)
Review
The effect of polygenic risk scores for major depressive disorder, bipolar disorder and schizophrenia on morphological brain measures: A systematic review of the evidence.
BACKGROUND
Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ) share clinical features and genetic bases. Magnetic Resonance Imaging (MRI) studies assessing the effect of polygenic risk score (PRS) for psychiatric disorders on brain structure show heterogeneous results. Therefore, we provided an overview of the existing evidence on the association between PRS for MDD, BD and SCZ and MRI abnormalities in clinical and healthy populations.
METHODS
A search on PubMed, Web of Science and Scopus was performed to identify the studies exploring the effect of PRS for MDD, BD and SCZ on MRI measures. A total of 25 studies were included (N = 13 on healthy individuals and N = 12 on clinical populations).
RESULTS
Both in affected and unaffected individuals, PRS for BD and SCZ showed either positive or negative correlations with cortical thickness (CT), mostly involving fronto-temporal areas, whereas PRS for MDD was associated with cortical alterations in prefrontal regions in healthy subjects.
LIMITATIONS
The heterogeneity in the methods limits the conclusions of this review.
CONCLUSIONS
Overall the evidence on the effect of PRS for MDD, BD and SCZ on brain is considerably heterogeneous and far to be conclusive. However, from the results emerged that PRS for MDD, BD and SCZ were associated with widespread cortical abnormalities in all the populations explored, suggesting that genetic risk for MDD, BD and SCZ might affect neurodevelopmental processes, resulting in cortical alterations that transcend diagnostic boundaries and seem to be independent from the clinical status.
Topics: Bipolar Disorder; Brain; Depressive Disorder, Major; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Risk Factors; Schizophrenia
PubMed: 35533776
DOI: 10.1016/j.jad.2022.05.007 -
Genetics in Medicine : Official Journal... Sep 2022Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a...
PURPOSE
Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention.
METHODS
We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB).
RESULTS
Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, P = 5.75E-9). Combining PRS19 with age and body mass index improved discriminatory power (Manchester study: AUC = 0.79, 95% CI = 0.76-0.82; UKBB: AUC =0.75, 95% CI = 0.73-0.76).
CONCLUSION
An endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.
Topics: Female; Humans; Endometrial Neoplasms; Genetic Predisposition to Disease; Genome-Wide Association Study; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors
PubMed: 35704044
DOI: 10.1016/j.gim.2022.05.014 -
Journal of Alzheimer's Disease : JAD 2020Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are...
BACKGROUND
Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual's risk alleles, have been used to draw inferences about the pathological processes underpinning AD.
OBJECTIVE
This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration.
METHODS
We searched the literature from July 2008-July 2018 following PRISMA guidelines.
RESULTS
57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes.
CONCLUSION
PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity.
Topics: Alzheimer Disease; Genetic Predisposition to Disease; Genetic Testing; Humans; Multifactorial Inheritance; Precision Medicine
PubMed: 32250305
DOI: 10.3233/JAD-191233 -
Comprehensive Psychiatry Jan 2019Genome wide association studies (GWAS) of schizophrenia allow the generation of Polygenic Risk Scores (PRS). PRS can be used to determine the contribution to altered...
BACKGROUND
Genome wide association studies (GWAS) of schizophrenia allow the generation of Polygenic Risk Scores (PRS). PRS can be used to determine the contribution to altered brain structures in this disorder, which have been well described. However, findings from studies using PRS to predict brain structural changes in schizophrenia have been inconsistent. We therefore performed a systematic review to determine the association between schizophrenia PRS and brain structure.
METHODS
Following PRISMA systematic review guidelines, databases were searched for literature using key search terms. Inclusion criteria for the discovery sample required case-control schizophrenia GWAS summary statistics from European populations. The target sample was required to be of European ancestry, and have brain structure and genotype information. Quality assessment of the publications was conducted using the Mixed Methods Appraisal Tool for quantitative non-randomised studies.
MAIN FINDINGS
A total of seven studies were found to be eligible for review. Five studies found no significant association and two studies found a significant association of schizophrenia PRS with total brain, reduced white matter volume, and globus pallidus volume. However, the latter studies were conducted using smaller discovery (n = 9394 n = 12,462) and target samples compared to the studies with substantially larger discovery (n = 33,636 n = 43,008) and target samples where no association was observed. Taken together, the results suggest that schizophrenia PRS are not significantly associated with brain structural changes in this disorder.
CONCLUSIONS
The lack of significant association between schizophrenia PRS and brain structural changes may indicate that intermediate phenotypes other than brain structure should be the focus of future work. Alternatively, however, the lack of association found here may point to limitations of the current evidence-base, and so point to the need for future better powered studies.
Topics: Brain; Case-Control Studies; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Multifactorial Inheritance; Phenotype; Risk Factors; Schizophrenia
PubMed: 30529765
DOI: 10.1016/j.comppsych.2018.11.014 -
Archives of Oral Biology Dec 2019To present a genetic and protein interaction analysis associated with dental caries.
OBJECTIVE
To present a genetic and protein interaction analysis associated with dental caries.
MATERIAL AND METHODS
The first step was to conduct a systematic literature review (SLR) through an electronic database search. Case-controls that reported associations between genes and dental caries were the main type of study design used as inclusion criteria, retrieved from the PubMed and the Virtual Health Library databases, comprising the chronological range from 1982 to 2017. The SLR was guided by PRISMA protocol and the methodological quality of the studies was established through Newcastle-Ottawa Scale (NOS). In the second step, the String Protein Interaction (SPI) approach was used to analyze protein interaction (by esyN software) and also the Ingenuity Pathway Analysis (IPA) to check biological pathways associated with dental caries genes.
RESULTS
A total of 51 articles were included to perform this SLR, describing a number of 27 genes associated with dental caries development. At the genetic level, 23 genes have at least one other gene with which they interact. The genes TUFT1, VDR, TFIP11, LTF, HLA-DRB1, MMP2, MMP3 and MUC5B were shown to be connected in interactive networks by at least 10 other genes.
CONCLUSION
It is essential to apprehend the multifactorial pattern of inheritance in human disease. This study presents pathways which may be directly correlated with several dental caries phenotype and this contributes to a better understanding of this disease, opening up a wider range of biotechnology options for its effective control in the future.
Topics: Case-Control Studies; Dental Caries; Genetic Predisposition to Disease; Humans; Phenotype; Proteins
PubMed: 31476523
DOI: 10.1016/j.archoralbio.2019.104522 -
Human Genetics Nov 2022Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic,... (Review)
Review
Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.
Topics: Genetic Predisposition to Disease; Genomic Medicine; Genomics; Humans; Multifactorial Inheritance; Risk Factors
PubMed: 35488921
DOI: 10.1007/s00439-022-02452-x -
Annals of Palliative Medicine Aug 2022Ischaemic stroke is a common neurological disease and a leading cause of severe disability and death in developed countries. In most cases, stroke is thought to be a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ischaemic stroke is a common neurological disease and a leading cause of severe disability and death in developed countries. In most cases, stroke is thought to be a multifactorial disorder or complex trait for which classic patterns of inheritance cannot be shown. Xuesaitong is one of the most commonly used medicines for treating ischemic stroke in China. However, compared to the conventional therapy, the effectiveness and safety of Xuesaitong for ischemic stroke needs to be further systematically reviewed and determined.
METHODS
Relevant randomized controlled trials (RCTs) examining the use of the Xuesaitong soft capsule in the treatment of patients with ischemic stroke were identified from databases, including the China National Knowledge Infrastructure, Wanfang, PubMed, Embase, and Web of Science databases. Next, 2 researchers independently extracted information from the included studies, analyzed the data using STATA 15.0 software, and evaluated the quality of the included studies using RevMan 5.3.
RESULTS
A total of 17 RCTs (comprising 1,942 patients with ischemic stroke) were included in the meta-analysis. The meta-analysis results showed that the Xuesaitong soft capsule treatment increased patients' total effective rate compared to conventional or other drug treatments, and improved patients' Clinical Severity Score (CSS scores) or Barthel index (BI) score. A further subgroup analysis stratified by different treatment times showed that Xuesaitong soft capsule treatment at 4 and 8 weeks improved CSS scores more than treatment at 2 weeks in patients with ischemic stroke. Additionally, the Xuesaitong soft capsule also significantly improved plasma viscosity, whole-blood viscosity at high and low shear rates, fibrinogen, hematocrit, and the effect on traditional Chinese medicine (TCM) single symptoms or signs in patients with ischemic stroke.
DISCUSSION
In summary, compared to conventional or other drug treatments, the Xuesaitong soft capsule treatment was beneficial in improving patients' TCM symptoms (e.g., crooked mouth and tongue, and dizziness) and various indicators. Further, Xuesaitong soft capsule may be a safe and effective drug for the treatment of ischemic stroke. And large-scale randomized clinical trials are needed to further confirm our findings.
Topics: Capsules; Drugs, Chinese Herbal; Humans; Ischemic Stroke; Saponins; Stroke
PubMed: 36064360
DOI: 10.21037/apm-22-748 -
Human Molecular Genetics Aug 2018We present a systematic review of genome-wide research on psychotic experience and negative symptom (PENS) traits in the community. We integrate these new findings, most...
We present a systematic review of genome-wide research on psychotic experience and negative symptom (PENS) traits in the community. We integrate these new findings, most of which have emerged over the last four years, with more established behaviour genetic and epidemiological research. The review includes the first genome-wide association studies of PENS, including a recent meta-analysis, and the first SNP heritability estimates. Sample sizes of <10 000 participants mean that no genome-wide significant variants have yet been replicated. Importantly, however, in the most recent and well-powered studies, polygenic risk score prediction and linkage disequilibrium (LD) score regression analyses show that all types of PENS share genetic influences with diagnosed schizophrenia and that negative symptom traits also share genetic influences with major depression. These genetic findings corroborate other evidence in supporting a link between PENS in the community and psychiatric conditions. Beyond the systematic review, we highlight recent work on gene-environment correlation, which appears to be a relevant process for psychotic experiences. Genes that influence risk factors such as tobacco use and stressful life events are likely to be harbouring 'hits' that also influence PENS. We argue for the acceptance of PENS within the mainstream, as heritable traits in the same vein as other sub-clinical psychopathology and personality styles such as neuroticism. While acknowledging some mixed findings, new evidence shows genetic overlap between PENS and psychiatric conditions. In sum, normal variations in adolescent and adult thinking styles, such as feeling paranoid, are heritable and show genetic associations with schizophrenia and major depression.
Topics: Adult; Affect; Bipolar Disorder; Depressive Disorder, Major; Female; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Genotype; Humans; Linkage Disequilibrium; Male; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Psychiatry; Psychometrics; Psychotic Disorders; Risk Factors; Schizophrenia
PubMed: 29741616
DOI: 10.1093/hmg/ddy157 -
Molecular Psychiatry Aug 2020Schizophrenia and other psychotic disorders are highly debilitating psychiatric conditions that lack a clear etiology and exhibit polygenic inheritance underlain by...
Schizophrenia and other psychotic disorders are highly debilitating psychiatric conditions that lack a clear etiology and exhibit polygenic inheritance underlain by pleiotropic genes. The prevailing explanation points to the interplay between predisposing genes and environmental exposure. Accumulated evidence suggests that epigenetic regulation of the genome may mediate dynamic gene-environment interactions at the molecular level by modulating the expression of psychiatric phenotypes through transcription factors. This systematic review summarizes the current knowledge linking schizophrenia and other psychotic disorders to epigenetics, based on PubMed and Web of Science database searches conducted according to the PRISMA guidelines. Three groups of mechanisms in case-control studies of human tissue (i.e., postmortem brain and bio-fluids) were considered: DNA methylation, histone modifications, and non-coding miRNAs. From the initial pool of 3,204 records, 152 studies met our inclusion criteria (11,815/11,528, 233/219, and 2,091/1,827 cases/controls for each group, respectively). Many of the findings revealed associations with epigenetic modulations of genes regulating neurotransmission, neurodevelopment, and immune function, as well as differential miRNA expression (e.g., upregulated miR-34a, miR-7, and miR-181b). Overall, actual evidence moderately supports an association between epigenetics and schizophrenia and other psychotic disorders. However, heterogeneous results and cross-tissue extrapolations call for future work. Integrating epigenetics into systems biology may critically enhance research on psychosis and thus our understanding of the disorder. This may have implications for psychiatry in risk stratification, early recognition, diagnostics, precision medicine, and other interventional approaches targeting epigenetic fingerprints.
Topics: DNA Methylation; Epigenesis, Genetic; Gene-Environment Interaction; Histones; Humans; MicroRNAs; Psychotic Disorders; Schizophrenia
PubMed: 31907379
DOI: 10.1038/s41380-019-0601-3