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Molecular Diagnosis & Therapy Dec 2020Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes... (Review)
Review
Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes substantially to mortality in the United States by increasing the risk for type 2 diabetes, cardiovascular-related diseases, and other comorbidities. Despite environmental changes over past decades, including increases in high-calorie foods and sedentary lifestyles, there is very clear evidence of a genetic predisposition to obesity risk. Childhood obesity cases can be categorized in one of two ways: syndromic or non-syndromic. Syndromic obesity includes disorders such as Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome. Non-syndromic cases of obesity can be further separated into rarer instances of monogenic obesity and much more common forms of polygenic obesity. The advent of genome-wide association studies (GWAS) and next-generation sequencing has driven significant advances in our understanding of the genetic contribution to childhood obesity. Many rare and common genetic variants have been shown to contribute to the heritability in obesity, although the molecular mechanisms underlying most of these variants remain unclear. An important caveat of GWAS efforts is that they do not strictly represent gene target discoveries, rather simply the uncovering of robust genetic signals. One clear example of this is with progress in understanding the key obesity signal harbored within an intronic region of the FTO gene. It has been shown that the non-coding region in which the variant actually resides in fact influences the expression of genes distal to FTO instead, specifically IRX3 and IRX5. Such discoveries suggest that associated non-coding variants can be embedded within or next to one gene, but commonly influence the expression of other, more distal effector genes. Advances in genetics and genomics are therefore contributing to a deeper understanding of childhood obesity, allowing for development of clinical tools and therapeutic agents.
Topics: Child; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Pediatric Obesity; Risk Factors
PubMed: 33006084
DOI: 10.1007/s40291-020-00496-1 -
International Journal of Molecular... Sep 2019Opioid addiction is a chronic and complex disease characterized by relapse and remission. In the past decade, the opioid epidemic or opioid crisis in the United States... (Review)
Review
Opioid addiction is a chronic and complex disease characterized by relapse and remission. In the past decade, the opioid epidemic or opioid crisis in the United States has raised public awareness. Methadone, buprenorphine, and naloxone have proven their effectiveness in treating addicted individuals, and each of them has different effects on different opioid receptors. Classic and molecular genetic research has provided valuable information and revealed the possible mechanism of individual differences in vulnerability for opioid addiction. The polygenic risk score based on the results of a genome-wide association study (GWAS) may be a promising tool to evaluate the association between phenotypes and genetic markers across the entire genome. A novel gene editing approach, clustered, regularly-interspaced short palindromic repeats (CRISPR), has been widely used in basic research and potentially applied to human therapeutics such as mental illness; many applications against addiction based on CRISPR are currently under research, and some are successful in animal studies. In this article, we summarized the biological mechanisms of opioid addiction and medical treatments, and we reviewed articles about the genetics of opioid addiction, the promising approach to predict the risk of opioid addiction, and a novel gene editing approach. Further research on medical treatments based on individual vulnerability is needed.
Topics: Gene Editing; Genetic Predisposition to Disease; Genetic Therapy; Humans; Multifactorial Inheritance; Opioid-Related Disorders; Risk Factors
PubMed: 31480739
DOI: 10.3390/ijms20174294 -
Psychological Medicine Oct 2021Obsessive-compulsive disorder (OCD) is a psychiatric disorder with multiple symptom dimensions (e.g. contamination, symmetry). OCD clusters in families and decades of... (Review)
Review
BACKGROUND
Obsessive-compulsive disorder (OCD) is a psychiatric disorder with multiple symptom dimensions (e.g. contamination, symmetry). OCD clusters in families and decades of twin studies clearly demonstrate an important role for genetics in the etiology of the disorder.
METHODS
In this review, we summarize the genetic epidemiology and molecular genetic studies of OCD and obsessive-compulsive symptoms.
RESULTS
OCD is a heritable, polygenic disorder with contributions from both common and rare variants, including de novo deleterious variations. Multiple studies have provided reliable support for a large additive genetic contribution to liability to OCD, with discrete OCD symptom dimensions having both shared and unique genetic risks. Genome-wide association studies have not produced significant results yet, likely because of small sample sizes, but larger meta-analyses are forthcoming. Both twin and genome-wide studies show that OCD shares genetic risk with its comorbid conditions (e.g. Tourette syndrome and anorexia nervosa).
CONCLUSIONS
Despite significant efforts to uncover the genetic basis of OCD, the mechanistic understanding of how genetic and environmental risk factors interact and converge at the molecular level to result in OCD's heterogeneous phenotype is still mostly unknown. Future investigations should increase ancestral genetic diversity, explore age and/or sex differences in genetic risk for OCD and expand the study of pharmacogenetics, gene expression, gene × environment interactions and epigenetic mechanisms for OCD.
Topics: Anorexia Nervosa; Humans; Multifactorial Inheritance; Obsessive-Compulsive Disorder; Phenotype; Tourette Syndrome; Twin Studies as Topic
PubMed: 34030745
DOI: 10.1017/S0033291721001744 -
Circulation Aug 2022Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk... (Review)
Review
Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation' which have been recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care-associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients.
Topics: Adult; American Heart Association; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Risk Factors
PubMed: 35862132
DOI: 10.1161/CIR.0000000000001077 -
Nature Mar 2021Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical... (Review)
Review
Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics. However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, we present the Polygenic Risk Score Reporting Standards (PRS-RS), in which we update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field. Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications. Items span detailed descriptions of study populations, statistical methods for the development and validation of PRSs and considerations for the potential limitations of these scores. In addition, we emphasize the need for data availability and transparency, and we encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.
Topics: Genetic Predisposition to Disease; Genetics, Medical; Humans; Multifactorial Inheritance; Reproducibility of Results; Risk Assessment
PubMed: 33692554
DOI: 10.1038/s41586-021-03243-6 -
Genome Medicine May 2020Genome-wide association studies have shown unequivocally that common complex disorders have a polygenic genetic architecture and have enabled researchers to identify... (Review)
Review
Genome-wide association studies have shown unequivocally that common complex disorders have a polygenic genetic architecture and have enabled researchers to identify genetic variants associated with diseases. These variants can be combined into a polygenic risk score that captures part of an individual's susceptibility to diseases. Polygenic risk scores have been widely applied in research studies, confirming the association between the scores and disease status, but their clinical utility has yet to be established. Polygenic risk scores may be used to estimate an individual's lifetime genetic risk of disease, but the current discriminative ability is low in the general population. Clinical implementation of polygenic risk score (PRS) may be useful in cohorts where there is a higher prior probability of disease, for example, in early stages of diseases to assist in diagnosis or to inform treatment choices. Important considerations are the weaker evidence base in application to non-European ancestry and the challenges in translating an individual's PRS from a percentile of a normal distribution to a lifetime disease risk. In this review, we consider how PRS may be informative at different points in the disease trajectory giving examples of progress in the field and discussing obstacles that need to be addressed before clinical implementation.
Topics: Direct-To-Consumer Screening and Testing; Genetic Predisposition to Disease; Genetic Variation; Humans; Multifactorial Inheritance; Research Design; Risk Factors
PubMed: 32423490
DOI: 10.1186/s13073-020-00742-5 -
Nature Genetics Oct 2021Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally...
Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.
Topics: Genome, Human; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Multifactorial Inheritance; Quantitative Trait Loci; Telomere Homeostasis
PubMed: 34611362
DOI: 10.1038/s41588-021-00944-6 -
Psychological Medicine Oct 2021Bipolar disorder (BD) is a highly heritable mental disorder and is estimated to affect about 50 million people worldwide. Our understanding of the genetic etiology of BD... (Review)
Review
Bipolar disorder (BD) is a highly heritable mental disorder and is estimated to affect about 50 million people worldwide. Our understanding of the genetic etiology of BD has greatly increased in recent years with advances in technology and methodology as well as the adoption of international consortiums and large population-based biobanks. It is clear that BD is also highly heterogeneous and polygenic and shows substantial genetic overlap with other psychiatric disorders. Genetic studies of BD suggest that the number of associated loci is expected to substantially increase in larger future studies and with it, improved genetic prediction of the disorder. Still, a number of challenges remain to fully characterize the genetic architecture of BD. First among these is the need to incorporate ancestrally-diverse samples to move research away from a Eurocentric bias that has the potential to exacerbate health disparities already seen in BD. Furthermore, incorporation of population biobanks, registry data, and electronic health records will be required to increase the sample size necessary for continued genetic discovery, while increased deep phenotyping is necessary to elucidate subtypes within BD. Lastly, the role of rare variation in BD remains to be determined. Meeting these challenges will enable improved identification of causal variants for the disorder and also allow for equitable future clinical applications of both genetic risk prediction and therapeutic interventions.
Topics: Bipolar Disorder; Comorbidity; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Pharmacogenetics; Psychotic Disorders
PubMed: 33879273
DOI: 10.1017/S0033291721001252 -
Nature Genetics May 2022Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) have been conducted predominantly...
Polygenic risk scores (PRS) have attenuated cross-population predictive performance. As existing genome-wide association studies (GWAS) have been conducted predominantly in individuals of European descent, the limited transferability of PRS reduces their clinical value in non-European populations, and may exacerbate healthcare disparities. Recent efforts to level ancestry imbalance in genomic research have expanded the scale of non-European GWAS, although most remain underpowered. Here, we present a new PRS construction method, PRS-CSx, which improves cross-population polygenic prediction by integrating GWAS summary statistics from multiple populations. PRS-CSx couples genetic effects across populations via a shared continuous shrinkage (CS) prior, enabling more accurate effect size estimation by sharing information between summary statistics and leveraging linkage disequilibrium diversity across discovery samples, while inheriting computational efficiency and robustness from PRS-CS. We show that PRS-CSx outperforms alternative methods across traits with a wide range of genetic architectures, cross-population genetic overlaps and discovery GWAS sample sizes in simulations, and improves the prediction of quantitative traits and schizophrenia risk in non-European populations.
Topics: Genetic Predisposition to Disease; Genetics, Population; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Multifactorial Inheritance; Risk Factors
PubMed: 35513724
DOI: 10.1038/s41588-022-01054-7 -
Nature Feb 2023Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant...
Both common and rare genetic variants influence complex traits and common diseases. Genome-wide association studies have identified thousands of common-variant associations, and more recently, large-scale exome sequencing studies have identified rare-variant associations in hundreds of genes. However, rare-variant genetic architecture is not well characterized, and the relationship between common-variant and rare-variant architecture is unclear. Here we quantify the heritability explained by the gene-wise burden of rare coding variants across 22 common traits and diseases in 394,783 UK Biobank exomes. Rare coding variants (allele frequency < 1 × 10) explain 1.3% (s.e. = 0.03%) of phenotypic variance on average-much less than common variants-and most burden heritability is explained by ultrarare loss-of-function variants (allele frequency < 1 × 10). Common and rare variants implicate the same cell types, with similar enrichments, and they have pleiotropic effects on the same pairs of traits, with similar genetic correlations. They partially colocalize at individual genes and loci, but not to the same extent: burden heritability is strongly concentrated in significant genes, while common-variant heritability is more polygenic, and burden heritability is also more strongly concentrated in constrained genes. Finally, we find that burden heritability for schizophrenia and bipolar disorder is approximately 2%. Our results indicate that rare coding variants will implicate a tractable number of large-effect genes, that common and rare associations are mechanistically convergent, and that rare coding variants will contribute only modestly to missing heritability and population risk stratification.
Topics: Humans; Exome; Genetic Variation; Genome-Wide Association Study; Multifactorial Inheritance; Risk Factors; United Kingdom; Gene Frequency; Genetic Loci; Schizophrenia; Bipolar Disorder
PubMed: 36755099
DOI: 10.1038/s41586-022-05684-z