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American Journal of Medical Genetics.... Jul 2024Debates about the prospective clinical use of polygenic risk scores (PRS) have grown considerably in the last years. The potential benefits of PRS to improve patient... (Review)
Review
Debates about the prospective clinical use of polygenic risk scores (PRS) have grown considerably in the last years. The potential benefits of PRS to improve patient care at individual and population levels have been extensively underlined. Nonetheless, the use of PRS in clinical contexts presents a number of unresolved ethical challenges and consequent normative gaps that hinder their optimal implementation. Here, we conducted a systematic review of reasons of the normative literature discussing ethical issues and moral arguments related to the use of PRS for the prevention and treatment of common complex diseases. In total, we have included and analyzed 34 records, spanning from 2013 to 2023. The findings have been organized in three major themes: in the first theme, we consider the potential harms of PRS to individuals and their kin. In the theme "Threats to health equity," we consider ethical concerns of social relevance, with a focus on justice issues. Finally, the theme "Towards best practices" collects a series of research priorities and provisional recommendations to be considered for an optimal clinical translation of PRS. We conclude that the use of PRS in clinical care reinvigorates old debates in matters of health justice; however, open questions, regarding best practices in clinical counseling, suggest that the ethical considerations applicable in monogenic settings will not be sufficient to face PRS emerging challenges.
Topics: Humans; Multifactorial Inheritance; Genetic Predisposition to Disease; Morals; Genetic Testing; Risk Assessment; Genetic Counseling; Risk Factors; Genetic Risk Score
PubMed: 38450933
DOI: 10.1002/ajmg.a.63584 -
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 -
Journal of Psychiatric Research Nov 2022Early identification of attention-deficit/hyperactivity disorder (ADHD) is critical for mitigating the many negative functional outcomes associated with its diagnosis.... (Meta-Analysis)
Meta-Analysis Review
Early identification of attention-deficit/hyperactivity disorder (ADHD) is critical for mitigating the many negative functional outcomes associated with its diagnosis. Because of the strong genetic basis of ADHD, the use of polygenic risk scores (PRS) could potentially aid in the early identification of ADHD and associated outcomes. Therefore, a systematic search of the literature on the association between ADHD and PRS in pediatric populations was conducted. All articles were screened for a priori inclusion and exclusion criteria, and, after careful review, 33 studies were included in our systematic review and 16 studies with extractable data were included in our meta-analysis. The results of the review were categorized into three common themes: the associations between ADHD-PRS with 1) the diagnosis of ADHD and ADHD symptoms 2) comorbid psychopathology and 3) cognitive and educational outcomes. Higher ADHD-PRS were associated with increased odds of having a diagnosis (OR = 1.37; p<0.001) and more symptoms of ADHD (β = 0.06; p<0.001). While ADHD-PRS were associated with a persistent diagnostic trajectory over time in the systematic review, the meta-analysis did not confirm these findings (OR = 1.09; p = 0.62). Findings showed that ADHD-PRS were associated with increased odds for comorbid psychopathology such as anxiety/depression (OR = 1.16; p<0.001) and irritability/emotional dysregulation (OR = 1.14; p<0.001). Finally, while the systematic review showed that ADHD-PRS were associated with a variety of negative cognitive outcomes, the meta-analysis showed no significant association (β = 0.08; p = 0.07). Our review of the available literature suggests that ADHD-PRS, together with risk factors, may contribute to the early identification of children with suspected ADHD and associated disorders.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Comorbidity; Humans; Longitudinal Studies; Multifactorial Inheritance; Risk Factors
PubMed: 35988304
DOI: 10.1016/j.jpsychires.2022.07.032 -
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 -
Schizophrenia Bulletin Sep 2022Schizophrenia has been robustly associated with multiple genetic and environmental risk factors. Childhood adversity is one of the most widely replicated environmental... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND HYPOTHESIS
Schizophrenia has been robustly associated with multiple genetic and environmental risk factors. Childhood adversity is one of the most widely replicated environmental risk factors for schizophrenia, but it is unclear if schizophrenia genetic risk alleles contribute to this association.
STUDY DESIGN
In this systematic review and meta-analysis, we assessed the evidence for gene-environment correlation (genes influence likelihood of environmental exposure) between schizophrenia polygenic risk score (PRS) and reported childhood adversity. We also assessed the evidence for a gene-environment interaction (genes influence sensitivity to environmental exposure) in relation to the outcome of schizophrenia and/or psychosis. This study was registered on PROSPERO (CRD42020182812). Following PRISMA guidelines, a search for relevant literature was conducted using Cochrane, MEDLINE, PsycINFO, Web of Science, and Scopus databases until February 2022. All studies that examined the association between schizophrenia PRS and childhood adversity were included.
STUDY RESULTS
Seventeen of 650 identified studies met the inclusion criteria and were assessed against the Newcastle-Ottawa Scale for quality. The meta-analysis found evidence for gene-environment correlation between schizophrenia PRS and childhood adversity (r = .02; 95% CI = 0.01, 0.03; P = .001), but the effect was small and therefore likely to explain only a small proportion of the association between childhood adversity and psychosis. The 4 studies that investigated a gene-environment interaction between schizophrenia PRS and childhood adversity in increasing risk of psychosis reported inconsistent results.
CONCLUSIONS
These findings suggest that a gene-environment correlation could explain a small proportion of the relationship between reported childhood adversity and psychosis.
Topics: Adverse Childhood Experiences; Child; Gene-Environment Interaction; Humans; Multifactorial Inheritance; Risk; Schizophrenia
PubMed: 35674151
DOI: 10.1093/schbul/sbac049 -
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 -
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 -
Genetics in Medicine : Official Journal... Jun 2022Recently, preimplantation genetic testing (PGT) for polygenic conditions (PGT-P) has been introduced commercially. In view of the lack of specific guidance on this... (Review)
Review
PURPOSE
Recently, preimplantation genetic testing (PGT) for polygenic conditions (PGT-P) has been introduced commercially. In view of the lack of specific guidance on this development, we analyzed normative documents on PGT for monogenic conditions (PGT-M) to understand what we can learn from these documents for recommendations for PGT-P.
METHODS
We conducted a systematic review of normative guidelines and recommendations on PGT-M. The aim was to understand what the current consensus and disagreements are on ethical acceptability of PGT-M and how this compares with PGT-P.
RESULTS
We analyzed 38 documents by advisory committees at the national, European, and global level. In total, 2 themes were identified, which included the following: (1) what PGT is considered appropriate for and (2) who can make decisions regarding the use of PGT. Many aspects of PGT-M documents apply to PGT-P as well. Additional factors such as the fact that PGT-P screens for risk indications of multiple polygenic conditions increase ethical difficulties regarding severity, risk, autonomy, and informed decision-making.
CONCLUSION
On the basis of PGT-M normative documents, we conclude that ethical acceptability for PGT-P is limited. Our findings present various factors that have to be considered for the development of guidelines and the appropriateness of PGT.
Topics: Aneuploidy; Female; Genetic Testing; Humans; Morals; Multifactorial Inheritance; Pregnancy; Preimplantation Diagnosis
PubMed: 35341652
DOI: 10.1016/j.gim.2022.03.001 -
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 -
Pituitary Jun 2022To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogonadism (nCHH) from our centre and perform a systematic review of genetic...
PURPOSE
To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogonadism (nCHH) from our centre and perform a systematic review of genetic studies using next-generation sequencing (NGS) in nCHH.
METHODS
Sixty-eight nCHH probands from our center, and 370 nCHH probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG guidelines. Molecular diagnosis was defined as presence of a pathogenic or likely pathogenic variant in a known CHH gene following zygosity status as per known mode of genetic inheritance.
RESULT
At our centre molecular diagnosis was observed in 35.3% of probands {GNRHR:16.2%, FGFR1:7.3%, KISS1R:4.4%, GNRH1:2.9%, TACR3:2.9%, CHD7:1.4%}. Molecular diagnosis was observed more often (44.7% vs 14.3%, p = 0.026) with severe than partial reproductive-phenotype. The study adds 12 novel variants and suggests GNRHR p.Thr32Ala variant may have a founder effect. In per-patient systematic review (including our cohort), the molecular diagnosis was reached in 23.2%, ranging from 3.5 to 46.7% at different centers. The affected genes were FGFR1:6.4%, GNRHR:4.3%, PROKR2:3.6%, TACR3:1.8%, CHD7:1.6%, KISS1R:1.4%, GNRH1:1.4% and others (PROK2, SOX3, SOX10, SOX11, IL17RD, IGSF10, TAC3, ANOS1, oligogenic): < 1% each. FGFR1 was the most commonly affected gene in most cohorts except Asia, whereas PROKR2 (in China and Japan) and GNRHR (in India) were the commonest.
CONCLUSION
(s): The global molecular diagnosis rate was 23.2% in nCHH cohorts whereas that in our cohort was 35% with a higher rate (44.7%) in those with severe reproductive-phenotype. The most commonly affected gene in nCHH patients was FGFR1 globally while it was PROKR2 in East Asia and GNRHR in India.
Topics: Genotype; High-Throughput Nucleotide Sequencing; Humans; Hypogonadism; Mutation; Phenotype; Receptors, Kisspeptin-1
PubMed: 35133534
DOI: 10.1007/s11102-022-01209-z