-
Current Opinion in Genetics &... Jun 2020Over the past few years several methodological and data-driven advances have greatly improved our ability to robustly detect genomic signatures of selection in humans.... (Review)
Review
Over the past few years several methodological and data-driven advances have greatly improved our ability to robustly detect genomic signatures of selection in humans. New methods applied to large samples of present-day genomes provide increased power, while ancient DNA allows precise estimation of timing and tempo. However, despite these advances, we are still limited in our ability to translate these signatures into understanding about which traits were actually under selection, and why. Combining information from different populations and timescales may allow interpretation of selective sweeps. Other modes of selection have proved more difficult to detect. In particular, despite strong evidence of the polygenicity of most human traits, evidence for polygenic selection is weak, and its importance in recent human evolution remains unclear. Balancing selection and archaic introgression seem important for the maintenance of potentially adaptive immune diversity, but perhaps less so for other traits.
Topics: Adaptation, Physiological; DNA, Ancient; Evolution, Molecular; Genomics; History, Ancient; Humans; Multifactorial Inheritance; Phenotype; Selection, Genetic
PubMed: 32745952
DOI: 10.1016/j.gde.2020.06.003 -
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 -
Evolution; International Journal of... Feb 2022The first Editor of Evolution was Ernst Mayr. His foreword to the first issue of Evolution published in 1947 framed evolution as a "problem of interaction" that was just... (Review)
Review
The first Editor of Evolution was Ernst Mayr. His foreword to the first issue of Evolution published in 1947 framed evolution as a "problem of interaction" that was just beginning to be studied in this broad context. First, I explore progress and prospects on understanding the subsidiary interactions identified by Mayr, including interactions between parts of organisms, between individuals and populations, between species, and between the organism and its abiotic environment. Mayr's overall "problem of interaction" framework is examined in the context of coevolution within and among levels of biological organization. This leads to a comparison in the relative roles of biotic versus abiotic agents of selection and fluctuating versus directional selection, followed by stabilizing selection in shaping the genomic architecture of adaptation. Oligogenic architectures may be typical for traits shaped more by fluctuating selection and biotic selection. Conversely, polygenic architectures may be typical for traits shaped more by directional followed by stabilizing selection and abiotic selection. The distribution of effect sizes and turnover dynamics of adaptive alleles in these scenarios deserves further study. Second, I review two case studies on the evolution of acquired toxicity in animals, one involving cardiac glycosides obtained from plants and one involving bacterial virulence factors horizontally transferred to animals. The approaches used in these studies and the results gained directly flow from Mayr's vision of an evolutionary biology that revolves around the "problem of interaction."
Topics: Acclimatization; Adaptation, Physiological; Animals; Biological Evolution; Multifactorial Inheritance; Phenotype; Selection, Genetic
PubMed: 35040122
DOI: 10.1111/evo.14432 -
Cells Nov 2021Scientifically interesting as well as practically important phenotypes often belong to the realm of complex traits. To the extent that these traits are hereditary, they... (Review)
Review
Scientifically interesting as well as practically important phenotypes often belong to the realm of complex traits. To the extent that these traits are hereditary, they are usually 'highly polygenic'. The study of such traits presents a challenge for researchers, as the complex genetic architecture of such traits makes it nearly impossible to utilise many of the usual methods of reverse genetics, which often focus on specific genes. In recent years, thousands of genome-wide association studies (GWAS) were undertaken to explore the relationships between complex traits and a large number of genetic factors, most of which are characterised by tiny effects. In this review, we aim to familiarise 'wet biologists' with approaches for the interpretation of GWAS results, to clarify some issues that may seem counterintuitive and to assess the possibility of using GWAS results in experiments on various complex traits.
Topics: Biomedical Research; Follow-Up Studies; Genome-Wide Association Study; Humans; Molecular Sequence Annotation; Multifactorial Inheritance; Publications
PubMed: 34831407
DOI: 10.3390/cells10113184 -
Molecular Psychiatry Mar 2021There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this...
There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated (r = 0.10, n = 874, p = 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) (r = 0.17, n = 874, p = 6.5 × 10 FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms (b = 0.006, 90% CIs = 0.001, 0.019) and BMI (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI (b = 0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.
Topics: Attention Deficit Disorder with Hyperactivity; Body Mass Index; Humans; Impulsive Behavior; Multifactorial Inheritance; Reward
PubMed: 31227801
DOI: 10.1038/s41380-019-0444-y -
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 -
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 -
International Journal of Molecular... Mar 2020Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an... (Review)
Review
Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.
Topics: Animals; Brugada Syndrome; Humans; Ion Channels; Multifactorial Inheritance; Mutation; Sarcomeres
PubMed: 32121523
DOI: 10.3390/ijms21051687 -
Schizophrenia Bulletin Nov 2023Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to...
BACKGROUND AND HYPOTHESIS
Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes.
STUDY DESIGN
We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score.
STUDY RESULTS
After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores.
CONCLUSIONS
Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.
Topics: Humans; Endophenotypes; Psychotic Disorders; Schizophrenia; Bipolar Disorder; Multifactorial Inheritance; Risk Factors; Genetic Predisposition to Disease
PubMed: 37582581
DOI: 10.1093/schbul/sbad088 -
American Journal of Human Genetics Jul 2023In polygenic score (PGS) analysis, the coefficient of determination (R) is a key statistic to evaluate efficacy. R is the proportion of phenotypic variance explained by...
In polygenic score (PGS) analysis, the coefficient of determination (R) is a key statistic to evaluate efficacy. R is the proportion of phenotypic variance explained by the PGS, calculated in a cohort that is independent of the genome-wide association study (GWAS) that provided estimates of allelic effect sizes. The SNP-based heritability (h, the proportion of total phenotypic variances attributable to all common SNPs) is the theoretical upper limit of the out-of-sample prediction R. However, in real data analyses R has been reported to exceed h, which occurs in parallel with the observation that h estimates tend to decline as the number of cohorts being meta-analyzed increases. Here, we quantify why and when these observations are expected. Using theory and simulation, we show that if heterogeneities in cohort-specific h exist, or if genetic correlations between cohorts are less than one, h estimates can decrease as the number of cohorts being meta-analyzed increases. We derive conditions when the out-of-sample prediction R will be greater than h and show the validity of our derivations with real data from a binary trait (major depression) and a continuous trait (educational attainment). Our research calls for a better approach to integrating information from multiple cohorts to address issues of between-cohort heterogeneity.
Topics: Humans; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Multifactorial Inheritance; Phenotype; Computer Simulation
PubMed: 37379836
DOI: 10.1016/j.ajhg.2023.06.006