-
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 -
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 -
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 -
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 -
Genetics in Medicine : Official Journal... Jun 2013Advances in genomics have near-term impact on diagnosis and management of monogenic disorders. For common complex diseases, the use of genomic information from multiple... (Review)
Review
Advances in genomics have near-term impact on diagnosis and management of monogenic disorders. For common complex diseases, the use of genomic information from multiple loci (polygenic model) is generally not useful for diagnosis and individual prediction. In principle, the polygenic model could be used along with other risk factors in stratified population screening to target interventions. For example, compared to age-based criterion for breast, colorectal, and prostate cancer screening, adding polygenic risk and family history holds promise for more efficient screening with earlier start and/or increased frequency of screening for segments of the population at higher absolute risk than an established screening threshold; and later start and/or decreased frequency of screening for segments of the population at lower risks. This approach, while promising, faces formidable challenges for building its evidence base and for its implementation in practice. Currently, it is unclear whether or not polygenic risk can contribute enough discrimination to make stratified screening worthwhile. Empirical data are lacking on population-based age-specific absolute risks combining genetic and non-genetic factors, on impact of polygenic risk genes on disease natural history, as well as information on comparative balance of benefits and harms of stratified interventions. Implementation challenges include difficulties in integration of this information in the current health-care system in the United States, the setting of appropriate risk thresholds, and ethical, legal, and social issues. In an era of direct-to-consumer availability of personal genomic information, the public health and health-care systems need to prepare for an evidence-based integration of this information into population screening.
Topics: Evidence-Based Medicine; Female; Genetic Testing; Genomics; Humans; Male; Mass Screening; Multifactorial Inheritance; Neoplasms; Precision Medicine
PubMed: 23412608
DOI: 10.1038/gim.2012.182 -
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 -
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 -
Annals of Human Biology Feb 2023Like other complex phenotypes, human height reflects a combination of environmental and genetic factors, but is notable for being exceptionally easy to measure. Height... (Review)
Review
CONTEXT
Like other complex phenotypes, human height reflects a combination of environmental and genetic factors, but is notable for being exceptionally easy to measure. Height has therefore been commonly used to make observations later generalised to other phenotypes though the appropriateness of such generalisations is not always considered.
OBJECTIVES
We aimed to assess height's suitability as a model for other complex phenotypes and review recent advances in height genetics with regard to their implications for complex phenotypes more broadly.
METHODS
We conducted a comprehensive literature search in PubMed and Google Scholar for articles relevant to the genetics of height and its comparatibility to other phenotypes.
RESULTS
Height is broadly similar to other phenotypes apart from its high heritability and ease of measurment. Recent genome-wide association studies (GWAS) have identified over 12,000 independent signals associated with height and saturated height's common single nucleotide polymorphism based heritability of height within a subset of the genome in individuals similar to European reference populations.
CONCLUSIONS
Given the similarity of height to other complex traits, the saturation of GWAS's ability to discover additional height-associated variants signals potential limitations to the omnigenic model of complex-phenotype inheritance, indicating the likely future power of polygenic scores and risk scores, and highlights the increasing need for large-scale variant-to-gene mapping efforts.
Topics: Humans; Multifactorial Inheritance; Genome-Wide Association Study; Phenotype; Genome, Human; Polymorphism, Single Nucleotide
PubMed: 37343163
DOI: 10.1080/03014460.2023.2215546