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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 -
Genes Jul 2023Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number... (Review)
Review
Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur "later in life". The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification.
Topics: Humans; Heterozygote; Inheritance Patterns; Knowledge; Multifactorial Inheritance; Protein Processing, Post-Translational
PubMed: 37628614
DOI: 10.3390/genes14081562 -
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 Obesity (2005) Jun 2024The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when...
BACKGROUND/OBJECTIVE
The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance.
METHODS
Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service.
RESULTS
We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance.
CONCLUSION
Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found.
Topics: Humans; Male; Adolescent; Obesity, Morbid; Adult; Exome Sequencing; Pedigree; Female; Genetic Predisposition to Disease; Mutation; Penetrance; United Kingdom; Pakistan; Multifactorial Inheritance
PubMed: 38297031
DOI: 10.1038/s41366-024-01476-9 -
Annual Review of Clinical Psychology May 2022In the second half of the twentieth century, twin and family studies established beyond a reasonable doubt that all forms of psychopathology are substantially heritable... (Review)
Review
In the second half of the twentieth century, twin and family studies established beyond a reasonable doubt that all forms of psychopathology are substantially heritable and highly polygenic. These conclusions were simultaneously an important theoretical advance and a difficult methodological obstacle, as it became clear that heritability is universal and undifferentiated across forms of psychopathology, and the radical polygenicity of genetic effects limits the biological insight provided by genetically informed studies at the phenotypic level. The paradigm-shifting revolution brought on by the Human Genome Project has recapitulated the great methodological promise and the profound theoretical difficulties of the twin study era. We review these issues using the rubric of genetic architecture, which we define as a search for specific genetic insight that adds to the general conclusion that psychopathology is heritable and polygenic. Although significant problems remain, we see many promising avenues for progress.
Topics: Genome-Wide Association Study; Humans; Mental Disorders; Multifactorial Inheritance
PubMed: 34982569
DOI: 10.1146/annurev-clinpsy-081219-091234 -
Current Opinion in Lipidology Apr 2022: Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been... (Review)
Review
PURPOSE OF REVIEW
: Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been investigated to characterize its genetic basis. Despite almost half a century of searching, a single gene cause for the phenotype has not yet been identified.
RECENT FINDINGS
: Recent studies using next-generation genetic analytic methods confirm that FCH has a polygenic basis, with a clear large contribution from the accumulation of small-to-moderate effect common single nucleotide polymorphisms (SNPs) throughout the genome that is associated with raising TG, and probably also those raising LDL cholesterol. On the other hand, rare monogenic variants, such as those causing familial hypercholesterolemia, play a negligible role, if any. Genetic profiling suggests that patients with FCH and hypertriglyceridemia share a strong polygenic basis and show a similar profile of multiple TG-raising common SNPs.
SUMMARY
: Recent progress in genomics has shown that most if not all of the genetic susceptibility to FCH is polygenic in nature. Future research should include larger cohort studies, with wider ancestral diversity, ancestry-specific polygenic scores, and investigation of epigenetic and lifestyle factors to help further elucidate the causative agents at play in cases where the genetic etiology remains to be defined.
Topics: Cholesterol, LDL; Humans; Hyperlipidemia, Familial Combined; Hyperlipidemias; Multifactorial Inheritance; Triglycerides
PubMed: 34690300
DOI: 10.1097/MOL.0000000000000796 -
Nature Human Behaviour Sep 2023Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have...
Personality and cognitive function are heritable mental traits whose genetic foundations may be distributed across interconnected brain functions. Previous studies have typically treated these complex mental traits as distinct constructs. We applied the 'pleiotropy-informed' multivariate omnibus statistical test to genome-wide association studies of 35 measures of neuroticism and cognitive function from the UK Biobank (n = 336,993). We identified 431 significantly associated genetic loci with evidence of abundant shared genetic associations, across personality and cognitive function domains. Functional characterization implicated genes with significant tissue-specific expression in all tested brain tissues and brain-specific gene sets. We conditioned independent genome-wide association studies of the Big 5 personality traits and cognitive function on our multivariate findings, boosting genetic discovery in other personality traits and improving polygenic prediction. These findings advance our understanding of the polygenic architecture of these complex mental traits, indicating a prominence of pleiotropic genetic effects across higher order domains of mental function such as personality and cognitive function.
Topics: Humans; Genome-Wide Association Study; Personality; Phenotype; Multifactorial Inheritance; Cognition
PubMed: 37365406
DOI: 10.1038/s41562-023-01630-9 -
Sleep Oct 2022Sleep occurs universally and is a biological necessity for human functioning. The consequences of diminished sleep quality impact physical and physiological systems such... (Review)
Review
Sleep occurs universally and is a biological necessity for human functioning. The consequences of diminished sleep quality impact physical and physiological systems such as neurological, cardiovascular, and metabolic processes. In fact, people impacted by common complex diseases experience a wide range of sleep disturbances. It is challenging to uncover the underlying molecular mechanisms responsible for decreased sleep quality in many disease systems owing to the lack of suitable sleep biomarkers. However, the discovery of a genetic component to sleep patterns has opened a new opportunity to examine and understand the involvement of sleep in many disease states. It is now possible to use major genomic resources and technologies to uncover genetic contributions to many common diseases. Large scale prospective studies such as the genome wide association studies (GWAS) have successfully revealed many robust genetic signals associated with sleep-related traits. With the discovery of these genetic variants, a major objective of the community has been to investigate whether sleep-related traits are associated with disease pathogenesis and other health complications. Mendelian Randomization (MR) represents an analytical method that leverages genetic loci as proxy indicators to establish causal effect between sleep traits and disease outcomes. Given such variants are randomly inherited at birth, confounding bias is eliminated with MR analysis, thus demonstrating evidence of causal relationships that can be used for drug development and to prioritize clinical trials. In this review, we outline the results of MR analyses performed to date on sleep traits in relation to a multitude of common complex diseases.
Topics: Genome-Wide Association Study; Humans; Infant, Newborn; Mendelian Randomization Analysis; Multifactorial Inheritance; Prospective Studies; Sleep
PubMed: 35908176
DOI: 10.1093/sleep/zsac180 -
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 -
PloS One 2022The variable presentations and different phenotypes of sepsis suggest that risk of sepsis comes from many genes each having a small effect. The cumulative effect can be...
BACKGROUND
The variable presentations and different phenotypes of sepsis suggest that risk of sepsis comes from many genes each having a small effect. The cumulative effect can be used to create individual risk profile. The purpose of this study was to create a polygenic risk score and determine the genetic variants associated with sepsis.
METHODS
We sequenced ~14 million single nucleotide polymorphisms with a minimac imputation quality R2>0.3 and minor allele frequency >10-6 in patients with Sepsis-2 or Sepsis-3. Genome-wide association was performed using Firth bias-corrected logistic regression. Semi-parsimonious logistic regression was used to create polygenic risk scores and reduced regression to determine the genetic variants independently associated with sepsis.
FINDINGS
2261 patients had sepsis and 13,068 control patients did not. The polygenic risk scores had good discrimination: c-statistic = 0.752 ± 0.005 for Sepsis-2 and 0.752 ± 0.007 for Sepsis-3. We found 772 genetic variants associated with Sepsis-2 and 442 with Sepsis-3, p<0.01. After multivariate adjustment, 100 variants on 85 genes were associated with Sepsis-2 and 69 variants in 54 genes with Sepsis-3. Twenty-five variants were present in both the Sepsis-2 and Sepsis-3 groups out of 32 genes that were present in both groups. The other 7 genes had different variants present. Most variants had small effect sizes.
CONCLUSIONS
Sepsis-2 and Sepsis-3 have both separate and shared genetic variants. Most genetic variants have small effects sizes, but cumulatively, the polygenic risk scores have good discrimination.
Topics: Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Sepsis
PubMed: 35275946
DOI: 10.1371/journal.pone.0265052