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Pigment Cell & Melanoma Research Jan 2020Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome-wide linkage studies and genome-wide... (Review)
Review
Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome-wide linkage studies and genome-wide association studies in European ancestry cases identified over 50 vitiligo susceptibility loci, defining a model of melanocyte-directed autoimmunity. Vitiligo heritability is exceedingly high, ~2/3 coming from common and ~1/3 from rare genomic variants; ~20% of vitiligo risk is environmental. Vitiligo genetic risk is polygenic, with greater additive risk in multiplex vitiligo families than simplex cases. Vitiligo age-of-onset is bimodal, also involving a major genetic component; a MHC enhancer haplotype confers extreme risk for vitiligo (OR 8.1) and early disease onset, increasing expression of HLA-DQB1 mRNA and HLA-DQ protein and thus perhaps facilitating presentation of triggering antigens. Vitiligo triggering also involves a major environmental component; dramatic delay in vitiligo age-of-onset, especially from 1973 to 2004, suggests that exposure or response to a key vitiligo environmental trigger diminished during this period. Together, these findings provide deep understanding of vitiligo pathogenesis and genetic architecture, suggesting that vitiligo represents a tractable model for investigating complex disease genetic architecture and predictive aspects of personalized medicine.
Topics: Age of Onset; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Risk Factors; Vitiligo
PubMed: 31743585
DOI: 10.1111/pcmr.12848 -
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 -
Journal of Advanced Nursing Aug 2019
Topics: Female; Genetic Predisposition to Disease; Humans; Male; Multifactorial Inheritance; Nurse-Patient Relations
PubMed: 30950539
DOI: 10.1111/jan.14020 -
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 -
Trends in Genetics : TIG Feb 2023Traditional classification of genetic diseases as monogenic and polygenic has lagged far behind scientific progress. In this opinion article, we propose and define a new... (Review)
Review
Traditional classification of genetic diseases as monogenic and polygenic has lagged far behind scientific progress. In this opinion article, we propose and define a new terminology, genetically transitional disease (GTD), referring to cases where a large-effect mutation is necessary, but not sufficient, to cause disease. This leads to a working disease nosology based on gradients of four types of genetic architecture: monogenic, polygenic, GTD, and mixed. We present four scenarios under which GTD may occur; namely, subsets of traditionally Mendelian disease, modifiable Tier 1 monogenic conditions, variable penetrance, and situations where a genetic mutational spectrum produces qualitatively divergent pathologies. The implications of the new nosology in precision medicine are discussed, in which therapeutic options may target the molecular cause or the disease phenotype.
Topics: Humans; Genomic Medicine; Phenotype; Mutation; Multifactorial Inheritance; Genetic Predisposition to Disease
PubMed: 36564319
DOI: 10.1016/j.tig.2022.11.002 -
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 -
The Behavioral and Brain Sciences Sep 2023It is a hotly contested issue whether polygenic scores should play a major role in the social sciences. Here, we defend a methodologically pluralist stance in which...
It is a hotly contested issue whether polygenic scores should play a major role in the social sciences. Here, we defend a methodologically pluralist stance in which sociogenomics should abandon its hype and recognize that it suffers from all the methodological difficulties of the social sciences, yet nevertheless maintain an optimistic stance toward a more cautious use.
Topics: Humans; Social Sciences; Multifactorial Inheritance
PubMed: 37695016
DOI: 10.1017/S0140525X22002345 -
Genes Sep 2023Non-syndromic cleft lip with or without palate (NSCL/P) is a prevalent birth defect that affects 1/500-1/1400 live births globally. The genetic basis of NSCL/P is... (Review)
Review
Non-syndromic cleft lip with or without palate (NSCL/P) is a prevalent birth defect that affects 1/500-1/1400 live births globally. The genetic basis of NSCL/P is intricate and involves both genetic and environmental factors. In the past few years, various genetic inheritance models have been proposed to elucidate the underlying mechanisms of NSCL/P. These models range from simple monogenic inheritance to more complex polygenic inheritance. Here, we present a comprehensive overview of the genetic inheritance model of NSCL/P exemplified by representative genes and regions from both monogenic and polygenic perspectives. We also summarize existing association studies and corresponding loci of NSCL/P within the Chinese population and highlight the potential of utilizing polygenic risk scores for risk stratification of NSCL/P. The potential application of polygenic models offers promising avenues for improved risk assessment and personalized approaches in the prevention and management of NSCL/P individuals.
Topics: Humans; Cleft Lip; Cleft Palate; Multifactorial Inheritance; Inheritance Patterns
PubMed: 37895208
DOI: 10.3390/genes14101859 -
Trends in Genetics : TIG Jul 2021The adaptation of populations to local environments often relies on the selection of optimal values for polygenic traits. Here, we first summarize the results obtained... (Review)
Review
The adaptation of populations to local environments often relies on the selection of optimal values for polygenic traits. Here, we first summarize the results obtained from different quantitative genetics and population genetics models, about the genetic architecture of polygenic traits and their response to directional selection. We then highlight the contribution of systems biology to the understanding of the molecular bases of polygenic traits and the evolution of gene regulatory networks involved in these traits. Finally, we discuss the need for a unifying framework merging the fields of population genetics, quantitative genetics and systems biology to better understand the molecular bases of polygenic traits adaptation.
Topics: Adaptation, Physiological; Evolution, Molecular; Gene Regulatory Networks; Genetic Variation; Genetics, Population; Humans; Multifactorial Inheritance; Quantitative Trait Loci; Selection, Genetic
PubMed: 33892958
DOI: 10.1016/j.tig.2021.03.005 -
Biological Psychiatry Jul 2019Genetics provides two major opportunities for understanding human disease-as a transformative line of etiological inquiry and as a biomarker for heritable diseases. In... (Review)
Review
Genetics provides two major opportunities for understanding human disease-as a transformative line of etiological inquiry and as a biomarker for heritable diseases. In psychiatry, biomarkers are very much needed for both research and treatment, given the heterogenous populations identified by current phenomenologically based diagnostic systems. To date, however, useful and valid biomarkers have been scant owing to the inaccessibility and complexity of human brain tissue and consequent lack of insight into disease mechanisms. Genetic biomarkers are therefore especially promising for psychiatric disorders. Genome-wide association studies of common diseases have matured over the last decade, generating the knowledge base for increasingly informative individual-level genetic risk prediction. In this review, we discuss fundamental concepts involved in computing genetic risk with current methods, strengths and weaknesses of various approaches, assessments of utility, and applications to various psychiatric disorders and related traits. Although genetic risk prediction has become increasingly straightforward to apply and common in published studies, there are important pitfalls to avoid. At present, the clinical utility of genetic risk prediction is still low; however, there is significant promise for future clinical applications as the ancestral diversity and sample sizes of genome-wide association studies increase. We discuss emerging data and methods aimed at improving the value of genetic risk prediction for disentangling disease mechanisms and stratifying subjects for epidemiological and clinical studies. For all applications, it is absolutely critical that polygenic risk prediction is applied with appropriate methodology and control for confounding to avoid repeating some mistakes of the candidate gene era.
Topics: Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Humans; Mental Disorders; Multifactorial Inheritance; Predictive Value of Tests; Risk Assessment
PubMed: 30737014
DOI: 10.1016/j.biopsych.2018.12.015