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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 -
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 -
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 -
BMC Cancer Jan 2022Risk prediction models incorporating single nucleotide polymorphisms (SNPs) could lead to individualized prevention of colorectal cancer (CRC). However, the added value...
BACKGROUND
Risk prediction models incorporating single nucleotide polymorphisms (SNPs) could lead to individualized prevention of colorectal cancer (CRC). However, the added value of incorporating SNPs into models with only traditional risk factors is still not clear. Hence, our primary aim was to summarize literature on risk prediction models including genetic variants for CRC, while our secondary aim was to evaluate the improvement of discriminatory accuracy when adding SNPs to a prediction model with only traditional risk factors.
METHODS
We conducted a systematic review on prediction models incorporating multiple SNPs for CRC risk prediction. We tested whether a significant trend in the increase of Area Under Curve (AUC) according to the number of SNPs could be observed, and estimated the correlation between AUC improvement and number of SNPs. We estimated pooled AUC improvement for SNP-enhanced models compared with non-SNP-enhanced models using random effects meta-analysis, and conducted meta-regression to investigate the association of specific factors with AUC improvement.
RESULTS
We included 33 studies, 78.79% using genetic risk scores to combine genetic data. We found no significant trend in AUC improvement according to the number of SNPs (p for trend = 0.774), and no correlation between the number of SNPs and AUC improvement (p = 0.695). Pooled AUC improvement was 0.040 (95% CI: 0.035, 0.045), and the number of cases in the study and the AUC of the starting model were inversely associated with AUC improvement obtained when adding SNPs to a prediction model. In addition, models constructed in Asian individuals achieved better AUC improvement with the incorporation of SNPs compared with those developed among individuals of European ancestry.
CONCLUSIONS
Though not conclusive, our results provide insights on factors influencing discriminatory accuracy of SNP-enhanced models. Genetic variants might be useful to inform stratified CRC screening in the future, but further research is needed.
Topics: Adult; Area Under Curve; Asian People; Case-Control Studies; Clinical Decision Rules; Colorectal Neoplasms; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Middle Aged; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; White People
PubMed: 35030997
DOI: 10.1186/s12885-021-09143-2 -
Biological Reviews of the Cambridge... Apr 2021Evolutionary convergence provides natural opportunities to investigate how, when, and why novel traits evolve. Many convergent traits are complex, highlighting the...
Evolutionary convergence provides natural opportunities to investigate how, when, and why novel traits evolve. Many convergent traits are complex, highlighting the importance of explicitly considering convergence at different levels of biological organization, or 'multi-level convergent evolution'. To investigate multi-level convergent evolution, we propose a holistic and hierarchical framework that emphasizes breaking down traits into several functional modules. We begin by identifying long-standing questions on the origins of complexity and the diverse evolutionary processes underlying phenotypic convergence to discuss how they can be addressed by examining convergent systems. We argue that bioluminescence, a complex trait that evolved dozens of times through either novel mechanisms or conserved toolkits, is particularly well suited for these studies. We present an updated estimate of at least 94 independent origins of bioluminescence across the tree of life, which we calculated by reviewing and summarizing all estimates of independent origins. Then, we use our framework to review the biology, chemistry, and evolution of bioluminescence, and for each biological level identify questions that arise from our systematic review. We focus on luminous organisms that use the shared luciferin substrates coelenterazine or vargulin to produce light because these organisms convergently evolved bioluminescent proteins that use the same luciferins to produce bioluminescence. Evolutionary convergence does not necessarily extend across biological levels, as exemplified by cases of conservation and disparity in biological functions, organs, cells, and molecules associated with bioluminescence systems. Investigating differences across bioluminescent organisms will address fundamental questions on predictability and contingency in convergent evolution. Lastly, we highlight unexplored areas of bioluminescence research and advances in sequencing and chemical techniques useful for developing bioluminescence as a model system for studying multi-level convergent evolution.
Topics: Biological Evolution; Multifactorial Inheritance; Phenotype
PubMed: 33306257
DOI: 10.1111/brv.12672 -
Seminars in Neurology Feb 2020Meniere's disease (MD) is a set of uncommon disorders with core phenotype of tinnitus, episodic vertigo, and sensorineural hearing loss. MD shows a genetic...
Meniere's disease (MD) is a set of uncommon disorders with core phenotype of tinnitus, episodic vertigo, and sensorineural hearing loss. MD shows a genetic predisposition and a family history is found in 10% cases, with an autosomal dominant inheritance pattern. It is a multifactorial condition whose onset and development are triggered by the combined effect of genetic and environmental factors. Histopathological studies have associated MD with the accumulation of endolymph in the cochlea and the vestibular organs. However, endolymphatic hydrops does not fully explain the persistence of tinnitus, hearing loss progression, or the frequency of vertigo attacks.There are several comorbidities associated with MD, such as migraine, anxiety, autoimmune, and autoinflammatory disorders, adding more complexity to the phenotype. This "extended phenotype" can make the diagnosis and clinical management more complex, but it could also lead to a better characterization, understanding, and treatment of MD patients.We have conducted a systematic review on MD to update current knowledge, focusing on its mechanisms, diagnosis, comorbidities, and practical management.
Topics: Gene-Environment Interaction; Humans; Meniere Disease
PubMed: 31887752
DOI: 10.1055/s-0039-3402065 -
Clinical and Translational Medicine Jan 2022
Meta-Analysis
Topics: Alcohol Drinking; Genetic Loci; Genome-Wide Association Study; Heroin; Humans; Methamphetamine; Multifactorial Inheritance
PubMed: 35075802
DOI: 10.1002/ctm2.659 -
Journal of Affective Disorders May 2022Understanding the genetic underpinnings of antidepressant treatment response in unipolar major depressive disorder (MDD) can be useful in identifying patients at risk... (Review)
Review
BACKGROUND
Understanding the genetic underpinnings of antidepressant treatment response in unipolar major depressive disorder (MDD) can be useful in identifying patients at risk for poor treatment response or treatment resistant depression. A polygenic risk score (PRS) is a useful tool to explore genetic liability of a complex trait such as antidepressant treatment response. Here, we review studies that use PRSs to examine genetic overlap between any trait and antidepressant treatment response in unipolar MDD.
METHODS
A systematic search of literature was conducted in PubMed, Embase, and PsycINFO. Our search included studies examining associations between PRSs of psychiatric as well as non-psychiatric traits and antidepressant treatment response in patients with unipolar MDD. A quality assessment of the included studies was performed.
RESULTS
In total, eleven articles were included which contained PRSs for 30 traits. Studies varied in sample size and endpoints used for antidepressant treatment response. Overall, PRSs for attention-deficit hyperactivity disorder, the personality trait openness, coronary artery disease, obesity, and stroke have been associated with antidepressant treatment response in patients with unipolar MDD.
LIMITATIONS
The endpoints used by included studies differed significantly, therefore it was not possible to perform a meta-analysis.
CONCLUSIONS
Associations between a PRS and antidepressant treatment response have been reported for a number of traits in patients with unipolar MDD. PRSs could be informative to predict antidepressant treatment response in this population, given advances in the field. Most importantly, there is a need for larger study cohorts and the use of standardized outcome measures.
Topics: Antidepressive Agents; Depression; Depressive Disorder, Major; Humans; Multifactorial Inheritance; Risk Factors
PubMed: 35151671
DOI: 10.1016/j.jad.2022.02.015