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International Journal of General... 2023Acne vulgaris (AV) ranks among the common chronic inflammatory disorders that impact the sebaceous components of hair follicles. Acne vulgaris is characterised by... (Review)
Review
Acne vulgaris (AV) ranks among the common chronic inflammatory disorders that impact the sebaceous components of hair follicles. Acne vulgaris is characterised by cardinal manifestations such as the presence of pimples, nodules, pustules, and cysts, which have the potential to lead to the development of acne scarring and pigmentation. The phenomenon is influenced by polygenic inheritance or can be ascribed to the interplay between multiple genes and environmental factors. In recent years, some researchers have found that some genes (such as IL, TNF, RETN, CYP family, MMPs and TIMPs genes et al) are associated with acne vulgaris and may affect the progression and prognosis of the disease. The number of reviews addressing acne-associated genetic variants, however, is limited. In that case, we have compiled a list of prevalent genes associated with acne in recent times. This helps us understand acne's genetic basis and lets us step in early for people prone to severe acne, lowering the chance of acne scars.
PubMed: 37662507
DOI: 10.2147/IJGM.S421835 -
Nature Communications Apr 2024Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to... (Meta-Analysis)
Meta-Analysis
Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.
Topics: Humans; DNA-Binding Proteins; Genetic Predisposition to Disease; Genome-Wide Association Study; Gout; Heart Failure; Hypertension; Hyperuricemia; Mendelian Randomization Analysis; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Transcriptome; Uric Acid
PubMed: 38658550
DOI: 10.1038/s41467-024-47805-4 -
European Journal of Epidemiology Sep 2023Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the...
Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the associations between higher levels of PA and better aerobic fitness and a lower risk for CMDs. We aimed to study how PA genotype associates with self-reported PA, aerobic fitness, cardiometabolic risk factors and diseases. PA genotype, which combined variation in over one million of gene variants, was composed using the SBayesR polygenic scoring methodology. First, we constructed a polygenic risk score for PA in the Trøndelag Health Study (N = 47,148) using UK Biobank single nucleotide polymorphism-specific weights (N = 400,124). The associations of the PA PRS and continuous variables were analysed using linear regression models and with CMD incidences using Cox proportional hazard models. The results showed that genotypes predisposing to higher amount of PA were associated with greater self-reported PA (Beta [B] = 0.282 MET-h/wk per SD of PRS for PA, 95% confidence interval [CI] = 0.211, 0.354) but not with aerobic fitness. These genotypes were also associated with healthier cardiometabolic profile (waist circumference [B = -0.003 cm, 95% CI = -0.004, -0.002], body mass index [B = -0.002 kg/m, 95% CI = -0.004, -0.001], high-density lipoprotein cholesterol [B = 0.004 mmol/L, 95% CI = 0.002, 0.006]) and lower incidence of hypertensive diseases (Hazard Ratio [HR] = 0.97, 95% CI = 0.951, 0.990), stroke (HR = 0.94, 95% CI = 0.903, 0.978) and type 2 diabetes (HR = 0.94, 95 % CI = 0.902, 0.970). Observed associations were independent of self-reported PA. These results support earlier findings suggesting small pleiotropic effects between PA and CMDs and provide new evidence about associations of polygenic inheritance of PA and intermediate cardiometabolic risk factors.
Topics: Humans; Cardiometabolic Risk Factors; Diabetes Mellitus, Type 2; Exercise; Hypertension; Multifactorial Inheritance; Genetic Risk Score
PubMed: 37603226
DOI: 10.1007/s10654-023-01029-w -
Nucleic Acids Research Jul 2023Polygenic risk scores (PRSs) are expected to play a critical role in precision medicine. Currently, PRS predictors are generally based on linear models using summary...
Polygenic risk scores (PRSs) are expected to play a critical role in precision medicine. Currently, PRS predictors are generally based on linear models using summary statistics, and more recently individual-level data. However, these predictors mainly capture additive relationships and are limited in data modalities they can use. We developed a deep learning framework (EIR) for PRS prediction which includes a model, genome-local-net (GLN), specifically designed for large-scale genomics data. The framework supports multi-task learning, automatic integration of other clinical and biochemical data, and model explainability. When applied to individual-level data from the UK Biobank, the GLN model demonstrated a competitive performance compared to established neural network architectures, particularly for certain traits, showcasing its potential in modeling complex genetic relationships. Furthermore, the GLN model outperformed linear PRS methods for Type 1 Diabetes, likely due to modeling non-additive genetic effects and epistasis. This was supported by our identification of widespread non-additive genetic effects and epistasis in the context of T1D. Finally, we constructed PRS models that integrated genotype, blood, urine, and anthropometric data and found that this improved performance for 93% of the 290 diseases and disorders considered. EIR is available at https://github.com/arnor-sigurdsson/EIR.
Topics: Humans; Genetic Predisposition to Disease; Genome, Human; Genome-Wide Association Study; Genomics; Genotype; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Risk Factors; Models, Genetic
PubMed: 37224538
DOI: 10.1093/nar/gkad373 -
Neuroscience and Biobehavioral Reviews Oct 2023Attention-deficit/hyperactivity disorder (ADHD) co-occurs with many other psychiatric disorders and traits. In this review, we summarize and interpret the existing... (Review)
Review
Attention-deficit/hyperactivity disorder (ADHD) co-occurs with many other psychiatric disorders and traits. In this review, we summarize and interpret the existing literature on the genetic architecture of these comorbidities based on hypothesis-generating approaches. Quantitative genetic studies indicate that genetic factors play a substantial role in the observed co-occurrence of ADHD with many different disorders and traits. Molecular genetic correlations derived from genome-wide association studies and results of studies based on polygenic risk scores confirm the general pattern but provide effect estimates that are smaller than those from twin studies. The identification of the specific genetic variants and biological pathways underlying co-occurrence using genome-wide approaches is still in its infancy. The first analyses of causal inference using genetic data support causal relationships between ADHD and comorbid disorders, although bidirectional effects identified in some instances point to complex relationships. While several issues in the methodology and inferences from the results are still to be overcome, this review shows that the co-occurrence of ADHD with many psychiatric disorders and traits is genetically interpretable.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Genome-Wide Association Study; Phenotype; Risk Factors; Multifactorial Inheritance
PubMed: 37451654
DOI: 10.1016/j.neubiorev.2023.105313 -
JAMA Network Open Oct 2023Colorectal cancer (CRC) risk varies widely in the population at average risk without a family history, but there are no established routines for translating this...
IMPORTANCE
Colorectal cancer (CRC) risk varies widely in the population at average risk without a family history, but there are no established routines for translating this variation into personalized starting ages of screening.
OBJECTIVE
To illustrate derivation of risk-adapted starting ages of CRC screening based on the concept of risk advancement period (RAP) using sex and a polygenic risk score (PRS) as an example.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included participants in the UK Biobank study recruited in England, Wales, and Scotland between March 13, 2006, and October 1, 2010. Participants were aged 40 to 69 years, with no previous bowel cancer screening and no family history of CRC. Follow-up of cancer data was completed February 29, 2020, for England and Wales and January 31, 2021, for Scotland. The censoring date for death data was September 30, 2021, for England and Wales and October 31, 2021, for Scotland.
EXPOSURES
Data on age, sex, and family history were collected at the baseline interview. A PRS was calculated based on 139 CRC-related risk loci.
MAIN OUTCOMES AND MEASURES
Hazard ratios (HRs) of sex and PRS with CRC risk and mortality were estimated using Cox proportional hazards regression models and were translated to RAPs to quantify how many years of age earlier or later men and individuals in higher or lower PRS deciles would reach risks comparable with those of the reference group (ie, women or those in the 5th and 6th PRS deciles).
RESULTS
Among 242 779 participants (median age, 55 [IQR, 48-61] years; 55.7% women), 2714 incident CRC cases were identified during a median follow-up of 11.2 (IQR, 10.5-11.8) years and 758 deaths during a median follow-up of 12.8 (IQR, 12.0-13.4) years. The HRs of CRC risk were 1.57 (95% CI, 1.46-1.70) for men vs women and ranged from 0.51 (95% CI, 0.41-0.62) to 2.29 (95% CI, 2.01-2.62) across PRS deciles compared with the reference. The RAPs were 5.6 (95% CI, 4.6-6.6) years for men vs women and ranged from -8.4 (95% CI, -11.0 to -5.9) to 10.3 (95% CI, 8.5-12.1) years across PRS deciles compared with the reference deciles. Risk-adapted starting ages of screening would vary by 24 years between men in the highest PRS decile and women in the lowest PRS decile. Similar results were obtained regarding CRC mortality.
CONCLUSIONS AND RELEVANCE
In this large cohort study including women and men at average risk of CRC, risk-adapted starting ages of screening strongly varied by sex and a PRS. The RAP concept could easily accommodate additional factors for defining personalized starting ages of screening.
Topics: Male; Humans; Female; Middle Aged; Early Detection of Cancer; Cohort Studies; Risk Factors; England; Multifactorial Inheritance; Neoplasms
PubMed: 37878311
DOI: 10.1001/jamanetworkopen.2023.39670 -
BMC Medical Genomics Jul 2023Polygenic Risk Scores (PRS) (also known as polygenic scores, genetic risk scores or polygenic indexes) capture genetic contributions of a multitude of markers that...
Polygenic Risk Scores (PRS) (also known as polygenic scores, genetic risk scores or polygenic indexes) capture genetic contributions of a multitude of markers that characterise complex traits. Although their likely application to precision medicine remains to be established, promising advances have included their ability to stratify high risk individuals and targeted screening interventions. Current PRS have been mostly optimised for individuals of Northern European ancestries. If PRS are to become widespread as a tool for healthcare applications, more diverse populations and greater capacity for derived interventions need to be accomplished. In this editorial we aim to attract submissions from the research community that highlight current challenges in development of PRS applications at scale. We also welcome manuscripts that delve into the ethical, social and legal implications that the implementation of PRS may generate.
Topics: Humans; Genetic Predisposition to Disease; Multifactorial Inheritance; Risk Factors; Genomics; White People; Genome-Wide Association Study
PubMed: 37507694
DOI: 10.1186/s12920-023-01615-7 -
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 -
Nature Communications Aug 2023We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic...
We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.
Topics: Humans; Multifactorial Inheritance; Genomics; Phenotype; RNA, Messenger; Research Personnel
PubMed: 37604891
DOI: 10.1038/s41467-023-40569-3 -
Molecular Psychiatry Dec 2023Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population...
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li was developed in the International Consortium of Lithium Genetics cohort (ConLiGen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li was positively associated with lithium treatment response in the ConLiGen cohort, in both the categorical (P = 9.8 × 10, R = 1.9%) and continuous (P = 6.4 × 10, R = 2.6%) outcomes. Compared to bipolar patients in the 1 decile of the risk distribution, individuals in the 10 decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10, R = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
Topics: Bipolar Disorder; Humans; Female; Male; Multifactorial Inheritance; Adult; Middle Aged; Lithium; Treatment Outcome; Bayes Theorem; Genome-Wide Association Study; Glutamic Acid; Cohort Studies; Lithium Compounds; Acetylcholine; Polymorphism, Single Nucleotide; Antimanic Agents
PubMed: 37433967
DOI: 10.1038/s41380-023-02149-1