-
Cold Spring Harbor Perspectives in... Jul 2018Overwhelming evidence exists that lifelong exercise is associated with a longer health span, delaying the onset of 40 chronic conditions/diseases. What is beginning to... (Review)
Review
Overwhelming evidence exists that lifelong exercise is associated with a longer health span, delaying the onset of 40 chronic conditions/diseases. What is beginning to be learned is the molecular mechanisms by which exercise sustains and improves quality of life. The current review begins with two short considerations. The first short presentation concerns the effects of endurance exercise training on cardiovascular fitness, and how it relates to improved health outcomes. The second short section contemplates emerging molecular connections from endurance training to mental health. Finally, approximately half of the remaining review concentrates on the relationships between type 2 diabetes, mitochondria, and endurance training. It is now clear that physical training is complex biology, invoking polygenic interactions within cells, tissues/organs, systems, with remarkable cross talk occurring among the former list.
Topics: Cardiorespiratory Fitness; Diabetes Mellitus, Type 2; Exercise; Healthy Lifestyle; Humans; Mental Health; Mitochondria; Multifactorial Inheritance; Prognosis; Quality of Life
PubMed: 28507196
DOI: 10.1101/cshperspect.a029694 -
Molecular Psychiatry Apr 2019Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders.... (Review)
Review
Decades of research show that genes play an vital role in the etiology of attention deficit hyperactivity disorder (ADHD) and its comorbidity with other disorders. Family, twin, and adoption studies show that ADHD runs in families. ADHD's high heritability of 74% motivated the search for ADHD susceptibility genes. Genetic linkage studies show that the effects of DNA risk variants on ADHD must, individually, be very small. Genome-wide association studies (GWAS) have implicated several genetic loci at the genome-wide level of statistical significance. These studies also show that about a third of ADHD's heritability is due to a polygenic component comprising many common variants each having small effects. From studies of copy number variants we have also learned that the rare insertions or deletions account for part of ADHD's heritability. These findings have implicated new biological pathways that may eventually have implications for treatment development.
Topics: Attention Deficit Disorder with Hyperactivity; DNA Copy Number Variations; Genetic Linkage; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance
PubMed: 29892054
DOI: 10.1038/s41380-018-0070-0 -
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 -
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 -
Brain : a Journal of Neurology Feb 2023Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk...
Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.
Topics: Humans; Genome-Wide Association Study; Multifactorial Inheritance; Multiple Sclerosis; Epigenesis, Genetic; European People; Risk Factors; Genetic Predisposition to Disease; Phenotype
PubMed: 35253861
DOI: 10.1093/brain/awac092 -
Clinica E Investigacion En... May 2021For decades, familial hypertriglyceridemia (HTG) has been considered a specific entity characterized by an increase in VLDL particles and an autosomal dominant...
For decades, familial hypertriglyceridemia (HTG) has been considered a specific entity characterized by an increase in VLDL particles and an autosomal dominant inheritance pattern. In the genomics era, it has been proven that familial HTG, although it could be grouped in families, had a polygenic inheritance in which the phenotype would be determined by concomitant environmental factors. Hence its inclusion in the group of polygenic HTGs. Clinically, they are characterized by moderate HTG, with the consequent increase in cardiovascular risk, and in rare cases, by severe HTG with risk of acute pancreatitis. Treatment will be based on controlling environmental factors, implementing hygienic-dietetic measures and sometimes drugs, to reduce cardiovascular risk in moderate HTGs and acute pancreatitis risk in severe HTGs.
Topics: Acute Disease; Humans; Hyperlipoproteinemia Type IV; Hypertriglyceridemia; Multifactorial Inheritance; Pancreatitis; Triglycerides
PubMed: 34006352
DOI: 10.1016/j.arteri.2020.12.014 -
Proceedings of the National Academy of... Aug 2023Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to...
Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.
Topics: Child; Humans; Autism Spectrum Disorder; Multifactorial Inheritance; Parents; Whole Genome Sequencing; Language Development Disorders; Genetic Predisposition to Disease
PubMed: 37506195
DOI: 10.1073/pnas.2215632120