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ELife Oct 2021A theoretical framework predicts that using polygenic screening to select embryos against traits that depend on many genes has few benefits.
A theoretical framework predicts that using polygenic screening to select embryos against traits that depend on many genes has few benefits.
Topics: Multifactorial Inheritance; Phenotype
PubMed: 34635204
DOI: 10.7554/eLife.73193 -
Current Cardiology Reports Jul 2021Coronary artery disease (CAD) is a common disease globally attributable to the interplay of complex genetic and lifestyle factors. Here, we review how genomic sequencing... (Review)
Review
PURPOSE OF THE REVIEW
Coronary artery disease (CAD) is a common disease globally attributable to the interplay of complex genetic and lifestyle factors. Here, we review how genomic sequencing advances have broadened the fundamental understanding of the monogenic and polygenic contributions to CAD and how these insights can be utilized, in part by creating polygenic risk estimates, for improved disease risk stratification at the individual patient level.
RECENT FINDINGS
Initial studies linking premature CAD with rare familial cases of elevated blood lipids highlighted high-risk monogenic contributions, predominantly presenting as familial hypercholesterolemia (FH). More commonly CAD genetic risk is a function of multiple, higher frequency variants each imparting lower magnitude of risk, which can be combined to form polygenic risk scores (PRS) conveying significant risk to individuals at the extremes. However, gaps remain in clinical validation of PRSs, most notably in non-European populations. With improved and more broadly utilized genomic sequencing technologies, the genetic underpinnings of coronary artery disease are being unraveled. As a result, polygenic risk estimation is poised to become a widely used and powerful tool in the clinical setting. While the use of PRSs to augment current clinical risk stratification for optimization of cardiovascular disease risk by lifestyle change or therapeutic targeting is promising, we await adequately powered, prospective studies, demonstrating the clinical utility of polygenic risk estimation in practice.
Topics: Coronary Artery Disease; Genetic Predisposition to Disease; Humans; Multifactorial Inheritance; Prospective Studies; Risk Factors
PubMed: 34196841
DOI: 10.1007/s11886-021-01540-0 -
JAMA Aug 2023
Topics: Humans; Genetic Predisposition to Disease; Genome-Wide Association Study; Multifactorial Inheritance; Risk Factors; Risk Assessment; Direct-To-Consumer Screening and Testing
PubMed: 37535347
DOI: 10.1001/jama.2023.12262 -
Trends in Genetics : TIG Jun 2023The burden of human disease lies predominantly in polygenic diseases. Since the early 2000s, genome-wide association studies (GWAS) have identified genetic variants and... (Review)
Review
The burden of human disease lies predominantly in polygenic diseases. Since the early 2000s, genome-wide association studies (GWAS) have identified genetic variants and loci associated with complex traits. These have ranged from variants in coding sequences to mutations in regulatory regions, such as promoters and enhancers, as well as mutations affecting mediators of mRNA stability and other downstream regulators, such as 5' and 3'-untranslated regions (UTRs), long noncoding RNA (lncRNA), and miRNA. Recent research advances in genetics have utilized a combination of computational techniques, high-throughput in vitro and in vivo screening modalities, and precise genome editing to impute the function of diverse classes of genetic variants identified through GWAS. In this review, we highlight the vastness of genomic variants associated with polygenic disease risk and address recent advances in how genetic tools can be used to functionally characterize them.
Topics: Humans; Genome-Wide Association Study; Multifactorial Inheritance; Genetic Predisposition to Disease; Genetic Variation; Genomics
PubMed: 36997428
DOI: 10.1016/j.tig.2023.02.014 -
Current Opinion in Psychology Jun 2019Psychiatric conditions are highly polygenic, meaning that genetic risk arises from many hundreds or thousands of genetic variants. Psychiatric genomics and psychological... (Review)
Review
Psychiatric conditions are highly polygenic, meaning that genetic risk arises from many hundreds or thousands of genetic variants. Psychiatric genomics and psychological science are increasingly using polygenic risk scoring-the integration of all common genetic variant effects into a single risk metric-to model latent risk and to predict mental health outcomes. This review discusses the use of these scores in psychology and psychiatry to date, important methodological considerations, and potential of scoring methods for informing psychological science. Polygenic risk scores can easily be added to environmental and behavioral genetic models of latent risk, making them desirable metrics for use in psychological research.
Topics: Humans; Mental Disorders; Models, Statistical; Molecular Biology; Multifactorial Inheritance; Outcome Assessment, Health Care; Psychiatry; Risk Factors
PubMed: 30339992
DOI: 10.1016/j.copsyc.2018.09.002 -
Current Psychiatry Reports Aug 2017We will describe the success of recent genome-wide association studies that identify genetic variants associated with depression and outline the strategies used to... (Review)
Review
PURPOSE OF REVIEW
We will describe the success of recent genome-wide association studies that identify genetic variants associated with depression and outline the strategies used to reduce heterogeneity and increase sample size.
RECENT FINDINGS
The CONVERGE consortium identified two genetic associations by focusing on a sample of Chinese women with recurrent severe depression. Three other loci have been found in Europeans by combining cohorts with clinical diagnosis and measures of depressive symptoms to increase sample size. 23andMe identified 15 loci associated with depression using self-report of clinical diagnosis in a study of over 300,000 individuals. The first genetic associations with depression have been identified, and this number is now expected to increase linearly with sample size, as seen in other polygenic disorders. These loci provide invaluable insights into the biology of depression and exciting opportunities to develop new biomarkers and therapeutic targets.
Topics: Depression; Depressive Disorder, Major; Genetic Variation; Genome-Wide Association Study; Humans; Multifactorial Inheritance; White People
PubMed: 28608123
DOI: 10.1007/s11920-017-0803-9 -
Nature Human Behaviour May 2023Polygenic indices (PGIs) are increasingly used to identify individuals at risk of developing disease and are advocated as screening tools for personalized medicine and...
Polygenic indices (PGIs) are increasingly used to identify individuals at risk of developing disease and are advocated as screening tools for personalized medicine and education. Here we empirically assess rank concordance between PGIs created with different construction methods and discovery samples, focusing on cardiovascular disease and educational attainment. We find Spearman rank correlations between 0.17 and 0.93 for cardiovascular disease, and 0.40 and 0.83 for educational attainment, indicating highly unstable rankings across different PGIs for the same trait. Potential consequences for personalized medicine and gene-environment (G × E) interplay are illustrated using data from the UK Biobank. Simulations show how rank discordance mainly derives from a limited discovery sample size and reveal a tight link between the explained variance of a PGI and its ranking precision. We conclude that PGI-based ranking is highly dependent on PGI choice, such that current PGIs do not have the desired precision to be used routinely for personalized intervention.
Topics: Humans; Cardiovascular Diseases; Multifactorial Inheritance
PubMed: 36914805
DOI: 10.1038/s41562-023-01544-6 -
International Journal of Molecular... Sep 2021Syncope, defined as a transient loss of consciousness caused by transient global cerebral hypoperfusion, affects 30-40% of humans during their lifetime. Vasovagal... (Review)
Review
Syncope, defined as a transient loss of consciousness caused by transient global cerebral hypoperfusion, affects 30-40% of humans during their lifetime. Vasovagal syncope (VVS) is the most common cause of syncope, the etiology of which is still unclear. This review summarizes data on the genetics of VVS, describing the inheritance pattern of the disorder, candidate gene association studies and genome-wide studies. According to this evidence, VVS is a complex disorder, which can be caused by the interplay between genetic factors, whose contribution varies from monogenic Mendelian inheritance to polygenic inherited predisposition, and external factors affecting the monogenic (resulting in incomplete penetrance) and polygenic syncope types.
Topics: Genetic Predisposition to Disease; Humans; Inheritance Patterns; Multifactorial Inheritance; Syncope, Vasovagal
PubMed: 34638656
DOI: 10.3390/ijms221910316 -
ELife Mar 2019Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.
Great care is needed when interpreting claims about the genetic basis of human variation based on data from genome-wide association studies.
Topics: Biological Specimen Banks; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Selection, Genetic; United Kingdom
PubMed: 30895925
DOI: 10.7554/eLife.45380 -
Journal of Atherosclerosis and... Dec 2020
Topics: Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Humans; Hypertriglyceridemia; Multifactorial Inheritance; Mutation
PubMed: 32493883
DOI: 10.5551/jat.ED133