-
Genes May 2024The incidence of ulcerative colitis (UC) has increased globally. As a complex disease, the genetic predisposition for UC could be estimated by the polygenic risk score...
The incidence of ulcerative colitis (UC) has increased globally. As a complex disease, the genetic predisposition for UC could be estimated by the polygenic risk score (PRS), which aggregates the effects of a large number of genetic variants in a single quantity and shows promise in identifying individuals at higher lifetime risk of UC. Here, based on a cohort of 2869 UC cases and 2900 controls with genotype array datasets, we used PRSice-2 to calculate PRS, and systematically analyzed factors that could affect the power of PRS, including GWAS summary statistics, population stratification, and impact of variants. After leveraging a stepwise condition analysis, we eventually established the best PRS model, achieving an AUC of 0.713. Meanwhile, samples in the top 20% of the PRS distribution had a risk of UC more than ten times higher than samples in the lowest 20% (OR = 10.435, 95% CI 8.571-12.703). Our analyses demonstrated that including population-enriched, more disease-associated SNPs and using GWAS summary statistics from similar ethnic background can improve the power of PRS. Strictly following the principle of focusing on one population in all aspects of generating PRS can be a cost-effective way to apply genotype-array-derived PRS to practical risk estimation.
Topics: Humans; Colitis, Ulcerative; Multifactorial Inheritance; Genetic Predisposition to Disease; Genome-Wide Association Study; Polymorphism, Single Nucleotide; White People; Female; Male; Risk Factors; Case-Control Studies; Genotype
PubMed: 38927620
DOI: 10.3390/genes15060684 -
Scientific Reports Jun 2024The objective of this study was to investigate the association between a Parkinson's disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age...
The objective of this study was to investigate the association between a Parkinson's disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD. We included data from 4367 patients with idiopathic PD, 159 patients with GBA1-PD, and 3090 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The association between PGS and lifestyle factors on AAO was assessed with linear and Cox proportional hazards models. The PGS showed a negative association with AAO (β = - 1.07, p = 6 × 10) in patients with idiopathic PD. The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p = 0.0001), 44% (p < 2 × 10), and 55% (p < 2 × 10), compared to no use. An additive effect of aspirin (β = 7.62, p = 9 × 10) and PGS (β = - 1.58, p = 0.0149) was found for AAO without an interaction (p = 0.9993) in the linear regressions, and similar effects were seen for tobacco. In contrast, no association between aspirin intake and AAO was found in GBA1-PD (p > 0.05). In our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect.
Topics: Humans; Parkinson Disease; Female; Male; Middle Aged; Aged; Life Style; Age of Onset; Multifactorial Inheritance; Genetic Predisposition to Disease; Proportional Hazards Models; Glucosylceramidase; Case-Control Studies; Risk Factors; Aspirin
PubMed: 38918550
DOI: 10.1038/s41598-024-65640-x -
ELife Jun 2024LD score regression (LDSC) is a method to estimate narrow-sense heritability from genome-wide association study (GWAS) summary statistics alone, making it a fast and...
LD score regression (LDSC) is a method to estimate narrow-sense heritability from genome-wide association study (GWAS) summary statistics alone, making it a fast and popular approach. In this work, we present interaction-LD score (i-LDSC) regression: an extension of the original LDSC framework that accounts for interactions between genetic variants. By studying a wide range of generative models in simulations, and by re-analyzing 25 well-studied quantitative phenotypes from 349,468 individuals in the UK Biobank and up to 159,095 individuals in BioBank Japan, we show that the inclusion of a -interaction score (i.e. interactions between a focal variant and proximal variants) recovers genetic variance that is not captured by LDSC. For each of the 25 traits analyzed in the UK Biobank and BioBank Japan, i-LDSC detects additional variation contributed by genetic interactions. The i-LDSC software and its application to these biobanks represent a step towards resolving further genetic contributions of sources of non-additive genetic effects to complex trait variation.
Topics: Genome-Wide Association Study; Humans; Japan; United Kingdom; Polymorphism, Single Nucleotide; Models, Genetic; Phenotype; Genetic Variation; Multifactorial Inheritance; Biological Specimen Banks
PubMed: 38913556
DOI: 10.7554/eLife.90459 -
BMC Plant Biology Jun 2024Downy mildew is the most relevant disease of quinoa and the most widespread. Though, little is known about the genetics of resistance to this disease. The objective of...
Genome-wide association study, combined with bulk segregant analysis, identify plant receptors and defense related genes as candidate genes for downy mildew resistance in quinoa.
BACKGROUND
Downy mildew is the most relevant disease of quinoa and the most widespread. Though, little is known about the genetics of resistance to this disease. The objective of this study was to identify the genomic regions controlling downy mildew resistance in quinoa and candidate genes for this trait. With this aim we carried out a GWAS analysis in a collection formed by 211 quinoa accessions from different origins. This approach was combined with inheritance studies and Bulk Segregant Analysis (BSA) in a segregating population.
RESULTS
GWAS analysis identified 26 genomic regions associated with the trait. Inheritance studies in a F population segregating for resistance revealed the existence of a major single dominant gene controlling downy mildew complete resistance in quinoa accession PI614911. Through BSA, this gene was found to be located in chromosome 4, in a region also identified by GWAS. Furthermore, several plant receptors and resistance genes were found to be located into the genomic regions identified by GWAS and are postulated as candidate genes for resistance.
CONCLUSIONS
Until now, little was known about the genetic control of downy mildew resistance in quinoa. A previous inheritance study suggested that resistance to this disease was a quantitative polygenic trait and previous GWAS analyses were unable to identify accurate markers for this disease. In our study we demonstrate the existence of, at least, one major gene conferring resistance to this disease, identify the genomic regions involved in the trait and provide plausible candidate genes involved in defense. Therefore, this study significantly increases our knowledge about the genetics of downy mildew resistance and provides relevant information for breeding for this important trait.
Topics: Genome-Wide Association Study; Plant Diseases; Disease Resistance; Chenopodium quinoa; Genes, Plant
PubMed: 38910245
DOI: 10.1186/s12870-024-05302-2 -
Human Genomics Jun 2024We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in...
INTRODUCTION
We previously identified a genetic subtype (C4) of type 2 diabetes (T2D), benefitting from intensive glycemia treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Here, we characterized the population of patients that met the C4 criteria in the UKBiobank cohort.
RESEARCH DESIGN AND METHODS
Using our polygenic score (PS), we identified C4 individuals in the UKBiobank and tested C4 status with risk of developing T2D, cardiovascular disease (CVD) outcomes, and differences in T2D medications.
RESULTS
C4 individuals were less likely to develop T2D, were slightly older at T2D diagnosis, had lower HbA1c values, and were less likely to be prescribed T2D medications (P < .05). Genetic variants in MAS1 and IGF2R, major components of the C4 PS, were associated with fewer overall T2D prescriptions.
CONCLUSION
We have confirmed C4 individuals are a lower risk subpopulation of patients with T2D.
Topics: Humans; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; United Kingdom; Multifactorial Inheritance; Aged; Phenotype; Cardiovascular Diseases; Genetic Predisposition to Disease; Glycated Hemoglobin; Biological Specimen Banks; Polymorphism, Single Nucleotide
PubMed: 38909264
DOI: 10.1186/s40246-024-00639-z -
International Journal of Molecular... May 2024Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual...
Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with a poorly understood genetic basis. Our goal was to identify gene variants associated with these glaucoma types by assessing the mutational burden in 76 matrix metalloproteinase-related genes. We studied 101 childhood glaucoma patients with no identified monogenic alterations using next-generation sequencing. Gene expression was assessed through immunohistochemistry. Functional analysis of selected gene variants was conducted in cultured cells and in zebrafish. Patients presented a higher proportion of rare variants in four metalloproteinase-related genes, including and , compared to controls. ADAMTSL4 protein expression was observed in the anterior segment of both the adult human and zebrafish larvae's eye, including tissues associated with glaucoma. In HEK-293T cells, expression of four ADAMTSL4 variants identified in this study showed that two variants (p.Arg774Trp and p.Arg98Trp) accumulated intracellularly, inducing endoplasmic reticulum stress. Additionally, overexpressing these ADAMTSL4 variants in zebrafish embryos confirmed partial loss-of-function effects for p.Ser719Leu and p.Arg1083His. Double heterozygous functional suppression of and zebrafish orthologs resulted in reduced volume of both the anterior eye chamber and lens within the chamber, supporting a genetic interaction between these genes. Our findings suggest that accumulation of partial functional defects in matrix metalloproteinase-related genes may contribute to increased susceptibility to early-onset glaucoma and provide further evidence supporting the notion of a complex genetic inheritance pattern underlying the disease.
Topics: Humans; Animals; Zebrafish; Glaucoma; Child; Male; Female; Child, Preschool; HEK293 Cells; Genetic Predisposition to Disease; Mutation; Matrix Metalloproteinases; ADAMTS Proteins; Adolescent; Infant; Zebrafish Proteins; Endoplasmic Reticulum Stress
PubMed: 38891949
DOI: 10.3390/ijms25115757 -
Scientific Reports Jun 2024Type 2 diabetes (T2D) is caused by both genetic and environmental factors and is associated with an increased risk of cardiorenal complications and mortality. Though...
Type 2 diabetes (T2D) is caused by both genetic and environmental factors and is associated with an increased risk of cardiorenal complications and mortality. Though disproportionately affected by the condition, African Americans (AA) are largely underrepresented in genetic studies of T2D, and few estimates of heritability have been calculated in this race group. Using genome-wide association study (GWAS) data paired with phenotypic data from ~ 19,300 AA participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, Genetics of Hypertension Associated Treatments (GenHAT) study, and the Electronic Medical Records and Genomics (eMERGE) network, we estimated narrow-sense heritability using two methods: Linkage-Disequilibrium Adjusted Kinships (LDAK) and Genome-Wide Complex Trait Analysis (GCTA). Study-level heritability estimates adjusting for age, sex, and genetic ancestry ranged from 18% to 34% across both methods. Overall, the current study narrows the expected range for T2D heritability in this race group compared to prior estimates, while providing new insight into the genetic basis of T2D in AAs for ongoing genetic discovery efforts.
Topics: Humans; Diabetes Mellitus, Type 2; Black or African American; Male; Female; Genome-Wide Association Study; Middle Aged; Aged; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Linkage Disequilibrium; Phenotype; Multifactorial Inheritance
PubMed: 38890458
DOI: 10.1038/s41598-024-64711-3 -
Nature Communications Jun 2024Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These risk factors, such as depression...
Approximately 40% of dementia cases could be prevented or delayed by modifiable risk factors related to lifestyle and environment. These risk factors, such as depression and vascular disease, do not affect all individuals in the same way, likely due to inter-individual differences in genetics. However, the precise nature of how genetic risk profiles interact with modifiable risk factors to affect brain health is poorly understood. Here we combine multiple data resources, including genotyping and postmortem gene expression, to map the genetic landscape of brain structure and identify 367 loci associated with cortical thickness and 13 loci associated with white matter hyperintensities (P < 5×10), with several loci also showing a significant association with cognitive function. We show that among 220 unique genetic loci associated with cortical thickness in our genome-wide association studies (GWAS), 95 also showed evidence of interaction with depression or cardiovascular conditions. Polygenic risk scores based on our GWAS of inferior frontal thickness also interacted with hypertension in predicting executive function in the Canadian Longitudinal Study on Aging. These findings advance our understanding of the genetic underpinning of brain structure and show that genetic risk for brain and cognitive health is in part moderated by treatable mid-life factors.
Topics: Humans; Genome-Wide Association Study; Depression; Cognition; Male; Brain; Cardiovascular Diseases; Female; Aged; Middle Aged; Risk Factors; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Longitudinal Studies; White Matter; Multifactorial Inheritance; Aged, 80 and over
PubMed: 38890310
DOI: 10.1038/s41467-024-49430-7 -
BMC Genomics Jun 2024Chronic Obstructive Pulmonary Disease (COPD) describes a group of progressive lung diseases causing breathing difficulties. While COPD development typically involves a...
Genome-wide association study identifies novel susceptible loci and evaluation of polygenic risk score for chronic obstructive pulmonary disease in a Taiwanese population.
BACKGROUND
Chronic Obstructive Pulmonary Disease (COPD) describes a group of progressive lung diseases causing breathing difficulties. While COPD development typically involves a complex interplay between genetic and environmental factors, genetics play a role in disease susceptibility. This study used genome-wide association studies (GWAS) and polygenic risk score (PRS) to elucidate the genetic basis for COPD in Taiwanese patients.
RESULTS
GWAS was performed on a Taiwanese COPD case-control cohort with a sample size of 5,442 cases and 17,681 controls. Additionally, the PRS was calculated and assessed in our target groups. GWAS results indicate that although there were no single nucleotide polymorphisms (SNPs) of genome-wide significance, prominent COPD susceptibility loci on or nearby genes such as WWTR1, EXT1, INTU, MAP3K7CL, MAMDC2, BZW1/CLK1, LINC01197, LINC01894, and CFAP95 (C9orf135) were identified, which had not been reported in previous studies. Thirteen susceptibility loci, such as CHRNA4, AFAP1, and DTWD1, previously reported in other populations were replicated and confirmed to be associated with COPD in Taiwanese populations. The PRS was determined in the target groups using the summary statistics from our base group, yielding an effective association with COPD (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.17, p = 0.011). Furthermore, replication a previous lung function trait PRS model in our target group, showed a significant association of COPD susceptibility with PRS of Forced Expiratory Volume in one second (FEV)/Forced Vital Capacity (FCV) (OR 0.89, 95% CI 0.83-0.95, p = 0.001).
CONCLUSIONS
Novel COPD-related genes were identified in the studied Taiwanese population. The PRS model, based on COPD or lung function traits, enables disease risk estimation and enhances prediction before suffering. These results offer new perspectives on the genetics of COPD and serve as a basis for future research.
Topics: Pulmonary Disease, Chronic Obstructive; Humans; Genome-Wide Association Study; Taiwan; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Male; Female; Aged; Multifactorial Inheritance; Case-Control Studies; Middle Aged; Risk Factors; Genetic Loci; Asian People; Genetic Risk Score
PubMed: 38886662
DOI: 10.1186/s12864-024-10526-5 -
PloS One 2024Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions....
Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS.
Topics: Humans; Male; Female; Long QT Syndrome; Middle Aged; Electrocardiography; Multifactorial Inheritance; Risk Factors; Aged; Adult; Torsades de Pointes; Case-Control Studies; Phenethylamines; Genetic Risk Score; Sulfonamides
PubMed: 38885227
DOI: 10.1371/journal.pone.0303261