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Frontiers in Endocrinology 2024Insulin resistance (IR) and beta cell dysfunction are the major drivers of type 2 diabetes (T2D). Genome-Wide Association Studies (GWAS) on IR have been predominantly...
Insulin resistance (IR) and beta cell dysfunction are the major drivers of type 2 diabetes (T2D). Genome-Wide Association Studies (GWAS) on IR have been predominantly conducted in European populations, while Middle Eastern populations remain largely underrepresented. We conducted a GWAS on the indices of IR (HOMA2-IR) and beta cell function (HOMA2-%B) in 6,217 non-diabetic individuals from the Qatar Biobank (QBB; Discovery cohort; n = 2170, Replication cohort; n = 4047) with and without body mass index (BMI) adjustment. We also developed polygenic scores (PGS) for HOMA2-IR and compared their performance with a previously derived PGS for HOMA-IR (PGS003470). We replicated 11 loci that have been previously associated with HOMA-IR and 24 loci that have been associated with HOMA-%B, at nominal statistical significance. We also identified a novel locus associated with beta cell function near gene, tagged by rs61552983 ( = 4.38 × 10). Moreover, our best performing PGS (Q-PGS4; Adj R = 0.233 ± 0.014; = 1.55 x 10) performed better than PGS003470 (Adj R = 0.194 ± 0.014; = 5.45 x 10) in predicting HOMA2-IR in our dataset. This is the first GWAS on HOMA2 and the first GWAS conducted in the Middle East focusing on IR and beta cell function. Herein, we report a novel locus in that is implicated in beta cell dysfunction. Inclusion of under-represented populations in GWAS has potentials to provide important insights into the genetic architecture of IR and beta cell function.
Topics: Humans; Insulin Resistance; Genome-Wide Association Study; Female; Male; Middle Aged; Multifactorial Inheritance; Diabetes Mellitus, Type 2; Adult; Qatar; Polymorphism, Single Nucleotide; Insulin-Secreting Cells; Aged; Body Mass Index; Cohort Studies; Genetic Predisposition to Disease
PubMed: 38938516
DOI: 10.3389/fendo.2024.1384103 -
BMC Psychiatry Jun 2024The inclusion of biomarkers could improve diagnostic accuracy of attention-deficit/hyperactivity disorder (ADHD). One potential biomarker is the ADHD polygenic score...
BACKGROUND
The inclusion of biomarkers could improve diagnostic accuracy of attention-deficit/hyperactivity disorder (ADHD). One potential biomarker is the ADHD polygenic score (PGS), a measure of genetic liability for ADHD. This study aimed to investigate if the ADHD PGS can provide additional information alongside ADHD rating scales and examination of family history of ADHD to distinguish between ADHD cases and controls.
METHODS
Polygenic scores were calculated for 576 adults with ADHD and 530 ethnically matched controls. ADHD PGS was used alongside scores from the Wender-Utah Rating Scale (WURS) and the Adult ADHD Self-Report Scale (ASRS) as predictors of ADHD diagnosis in a set of nested logistic regression models. These models were compared by likelihood ratio (LR) tests, Akaike information criterion corrected for small samples (AICc), and Lee R². These analyses were repeated with family history of ADHD as a covariate in all models.
RESULTS
The ADHD PGS increased the variance explained of the ASRS by 0.58% points (pp) (R = 61.11%, R=61.69%), the WURS by 0.61pp (R = 77.33%, R= 77.94%), of ASRS and WURS together by 0.57pp (R=80.84%, R=81.40%), and of self-reported family history by 1.40pp (R = 28.06%, R=29.46%). These increases were statistically significant, as measured by LR tests and AICc.
CONCLUSION
We found that the ADHD PGS contributed additional information to common diagnostic aids. However, the increase in variance explained was small, suggesting that the ADHD PGS is currently not a clinically useful diagnostic aid. Future studies should examine the utility of ADHD PGS in ADHD prediction alongside non-genetic risk factors, and the diagnostic utility of the ADHD PGS should be evaluated as more genetic data is accumulated and computational tools are further refined.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Male; Female; Multifactorial Inheritance; Adult; Psychiatric Status Rating Scales; Case-Control Studies; Genetic Predisposition to Disease; Self Report; Middle Aged
PubMed: 38937684
DOI: 10.1186/s12888-024-05925-7 -
Journal of Economic Entomology Jun 2024Fall armyworm (FAW) Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a global pest causing damage to several crops. However, its management using chemical...
First report of resistance in Spodoptera frugiperda (Lepidoptera: Noctuidae) to lambda-cyhalothrin from Pakistan: baseline susceptibility, selection, occurrence of cross-resistance, realized heritability, and inheritance mode of resistance.
Fall armyworm (FAW) Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a global pest causing damage to several crops. However, its management using chemical control is a challenge due to its capacity to evolve resistance to insecticides. After 6 generations of selection with lambda-cyhalothrin, the LC50 for the insecticide-resistant strain (Lambda-Sel) was 486 ppm, higher than that of the field strain (FAW-MUL) (7.5 ppm), susceptible laboratory strain (Lab-PK) (0.46 ppm), and laboratory unselected strain (UNSEL) (5.26 ppm). Laboratory selection with lambda-cyhalothrin increased resistance from 16.3- to 1056.52-fold and 1.43- to 92.4-fold to lambda-cyhalothrin compared to Lab-PK and UNSEL strains, respectively. The selected strain of S. frugiperda (Lambda-Sel) presented low cross-resistance to chlorpyrifos, moderate to deltamethrin and indoxacarb, very low to spinosad, and no cross-resistance to emamectin benzoate. The realized heritability (h2) of lambda-cyhalothrin resistance in the Lambda-Sel strain was very high (0.88). The reciprocal cross progenies of F1 (Lambda-Sel ♀ × Lab-PK ♂), F1' (Lambda-Sel ♂ × Lab-PK ♀), BC1 (F1 ♀ × Lambda-Sel ♂), and BC2 (F1 ♀ × Lab-PK ♂) showed high resistance ratios of 545.64-, 396.52-, 181.18-, and 146.54-fold, respectively compared to Lab-PK. The degree of dominance values for lambda-cyhalothrin in F1 and F1' indicates incompletely dominant resistance. The difference between observed and expected mortality in backcross populations (BC1 and BC2) revealed a polygenic resistance. In conclusion, the resistance to lambda-cyhalothrin was autosomal, incompletely dominant, and polygenic. These findings provide new insights for insect resistance management strategies to mitigate the occurrence of resistance in this global pest.
PubMed: 38936423
DOI: 10.1093/jee/toae132 -
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 -
Urolithiasis Jun 2024Approximately 80% of kidney stone diseases contain calcium. Inherited genetic factors are among the variables that influence the development of calcium-containing kidney...
Identification of novel genetic susceptibility loci for calcium-containing kidney stone disease by genome-wide association study and polygenic risk score in a Taiwanese population.
Approximately 80% of kidney stone diseases contain calcium. Inherited genetic factors are among the variables that influence the development of calcium-containing kidney stone diseases (CKSD). Previous genome-wide association studies (GWAS) on stone diseases have been reported worldwide; however, these are not focused on calcium-containing stones. We conducted a GWAS to identify germline genetic polymorphisms associated with CKSD in a Medical Center in Taiwan; hence, this study was based primarily on a hospital-based database. CKSD was diagnosed using the chart records. Patients infected with urea-splitting-microorganisms and those with at least two urinary pH value below 5.5 were excluded. None of the patients had cystic stones based on stone analysis. Those over 40 years of age with no history of CKSD and no microscopic hematuria on urinalysis were considered as controls. The DNA isolated from the blood of 14,934 patients (63.7% male and 36.3% female) with CKSD and 29,868 controls (10,830 men and 19,038 women) at a medical center was genotyped for approximately 714,457 single nucleotide polymorphisms (SNPs) with minor allele frequency of ≥ 0.05. We used PLINK 1.9 to calculate the polygenic risk score (PRS) to investigate the association between CKSD and controls. The accuracy of the PRS was verified by dividing it into the training and testing groups. The statistical analyses were calculated with the area under the curve (AUC) using IBM SPSS version 22. We identified 432 susceptibility loci that reached a genome-wide threshold of P < 1.0 × 10. A total of 132 SNPs reached a threshold of P < 5 × 10 using a stricter definition of significance on chromosomes 4, 13, 16, 17, and 18. At the top locus of our study, SNPs in DGKH, PDILT, BCAS3, and ABCG2 have been previously reported. RN7SKP27, HDAC4, PCDH15, AP003068.2, and NFATC1 were novel findings in this study. PRS was adjusted for sex and age, resulting in an AUC of 0.65. The number of patients in the top quartile of PRS was 1.39 folds in the risk of CKSD than patients in the bottom quartile. Our data identified the significance of GWAS for patients with CKSD in a hospital-based study. The PRS also had a high AUC for discriminating patients with CKSD from controls. A total of 132 SNP loci of SNPs significantly associated with the development of CKSD. This first survey, which focused on patients with CKSD, will provide novel insights specific to CKSD and its potential clinical biomarkers.
Topics: Humans; Genome-Wide Association Study; Female; Male; Genetic Predisposition to Disease; Kidney Calculi; Middle Aged; Polymorphism, Single Nucleotide; Taiwan; Adult; Multifactorial Inheritance; Calcium; Aged; Case-Control Studies; Genetic Loci; Gene Frequency; Genetic Risk Score
PubMed: 38896256
DOI: 10.1007/s00240-024-01577-0 -
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