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American Journal of Human Genetics Feb 2023It has been 15 years since the advent of the genome-wide association study (GWAS) era. Here, we review how this experimental design has realized its promise by... (Review)
Review
It has been 15 years since the advent of the genome-wide association study (GWAS) era. Here, we review how this experimental design has realized its promise by facilitating an impressive range of discoveries with remarkable impact on multiple fields, including population genetics, complex trait genetics, epidemiology, social science, and medicine. We predict that the emergence of large-scale biobanks will continue to expand to more diverse populations and capture more of the allele frequency spectrum through whole-genome sequencing, which will further improve our ability to investigate the causes and consequences of human genetic variation for complex traits and diseases.
Topics: Humans; Genome-Wide Association Study; Gene Frequency; Genetics, Population; Multifactorial Inheritance; Polymorphism, Single Nucleotide
PubMed: 36634672
DOI: 10.1016/j.ajhg.2022.12.011 -
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 -
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 2021Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric... (Review)
Review
Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene-environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
Topics: Chromosome Mapping; DNA Copy Number Variations; Depressive Disorder, Major; Genetic Loci; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Phenotype
PubMed: 33682643
DOI: 10.1017/S0033291721000441 -
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 -
Science (New York, N.Y.) Sep 2021Over the next decade, the primary challenge in human genetics will be to understand the biological mechanisms by which genetic variants influence phenotypes, including... (Review)
Review
Over the next decade, the primary challenge in human genetics will be to understand the biological mechanisms by which genetic variants influence phenotypes, including disease risk. Although the scale of this challenge is daunting, better methods for functional variant interpretation will have transformative consequences for disease diagnosis, risk prediction, and the development of new therapies. An array of new methods for characterizing variant impact at scale, using patient tissue samples as well as in vitro models, are already being applied to dissect variant mechanisms across a range of human cell types and environments. These approaches are also increasingly being deployed in clinical settings. We discuss the rationale, approaches, applications, and future outlook for characterizing the molecular and cellular effects of genetic variants.
Topics: Disease; Gene Expression Regulation; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Techniques; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomics; Humans; Molecular Sequence Annotation; Multifactorial Inheritance; Phenotype; Quantitative Trait Loci
PubMed: 34554789
DOI: 10.1126/science.abi8207 -
Schizophrenia Research Mar 2020Genome-wide association studies (GWAS) have proved to be a powerful approach for gene discovery in schizophrenia; their findings have important implications not just for... (Review)
Review
Genome-wide association studies (GWAS) have proved to be a powerful approach for gene discovery in schizophrenia; their findings have important implications not just for our understanding of the genetic architecture of the disorder, but for the potential applications of personalised medicine through improved classification and targeted interventions. In this article we review the current status of the GWAS literature in schizophrenia including functional annotation methods and polygenic risk scoring, as well as the directions and challenges of future research. We consider recent findings in East Asian populations and the advancements from trans-ancestry analysis, as well as the insights gained from research looking across psychiatric disorders.
Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Schizophrenia
PubMed: 31780348
DOI: 10.1016/j.schres.2019.10.048 -
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 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 -
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