Association Studies Research Articles

Causal associations between childhood obesity and delayed puberty or height: a bidirectional two-sample Mendelian randomization study.

Childhood obesity is thought to influence pubertal development, according to observational studies. However, the exact causal relationship remains unclear due to the complexity of factors affecting pubertal development. To explore the association between exposure (childhood obesity) and outcome (delayed puberty, height), we utilized various methods, including inverse-variance weighted (IVW), weighted median, weighted mode, and MR Egger regression. Additionally, sensitivity analyses were conducted using MR-Egger, MR-PRESSO, Cochran's Q, and leave-one-out techniques to ensure the robustness of the results. Additionally, reverse MR analysis was conducted to explore potential reverse causation. The IVW analysis revealed no significant genetic causal link between childhood obesity and delayed puberty or height (all P>0.05). In the reverse analysis, height had a causal association with childhood obesity (OR=0.85, 95 % CI=0.76-0.96). The Cochran's Q test highlighted heterogeneity in the results concerning childhood obesity and height (p<0.05). But the MR-Egger intercept and MR-PRESSO test confirmed no impact the results pleiotropic bias, supported by leave-one-out sensitivity analysis. Our study found no significant genetic causal association between childhood obesity and delayed puberty or height. However, height was causally associated with childhood obesity. Future research should utilize advanced analytical methods to better understand the determinants of pubertal development.

Fibroblast growth factor 23 and outcomes of atrial fibrillation: from clinical association to genetic evidence.

Fibroblast growth factor 23 (FGF23) has been implicated in the occurrence of atrial fibrillation (AF), but its prognostic value in AF patients remains unclear. A total of 35 197 AF patients with available follow-up data (3.56, 0.47-8.92 years) from the UK Biobank were included. Clinical association between serum FGF23 and AF-related outcomes including mortality, heart failure (HF), ischaemic stroke, and dementia were analysed using multivariable Cox regression. In those passed quality control for array sequencing, polygenic score for FGF23 (PGSFGF23) was calculated as genetic instrument, and the association between PGSFGF23 and the occurrence of endpoints after first AF diagnosis were further explored. In 886 patients who diagnosed AF at or prior to the enrolment, elevated serum FGF23 levels were significantly associated with an increased risk of all-cause (37% increase per standard deviation) and cardiovascular (40% increase per standard deviation) mortality and HF (43% increase per standard deviation). A total of 35 197 patients were available for genetic array sequencing data. Using polygenic score including seven independent SNPs reaching genome-wide significance threshold, genetic association analysis indicated that increased PGSFGF23 is associated with reduced risk of HF but increased risk of all-cause mortality and ischaemic stroke. Our findings suggest that FGF23 is a potential biomarker for accessing AF-related outcomes. The paradoxical association between genetic FGF23 and serum FGF23 level highlights the need for further investigation to elucidate the underlying mechanisms.

Functional impairment in COPD can be predicted using genomic-derived data

ObjectiveReduced functional capacity and muscle weakness are two major contributors to functional impairment in chronic obstructive pulmonary disease (COPD). The underlying causes of functional impairment are poorly understood and, therefore,...

Elite Alleles of EPE1 Identified via Genome-wide Association Studies Increase Panicle Elongation Length in Rice.

Panicle elongation length (PEL), which determines panicle exsertion, is an important outcrossing-related trait. Mining genes controlling PEL in rice (Oryza sativa L.) has great practical significance in breeding cytoplasmic male sterility (CMS) lines with increased PEL and simplified, high-efficiency seed production. Genome-wide association studies (GWAS) were performed on the PELs of 440 rice accessions in 2022 and 2023, considering 3.17million single-nucleotide polymorphisms (SNPs) to detect the effects of different genes on PEL. A total of five quantitative trait loci (QTLs) significantly associated with PEL were detected in both years by using the general linear model (GLM) and the mixed linear model (MLM). Notably, our study identified a previously unreported QTL, qPE2.1. Three candidate genes associated with PEL were predicted by non-synonymous SNPs and functional annotation. We characterize one gibberellin (GA)-related gene, LOC_Os02g41954 (OsGA2ox9), which encodes gibberellin 2-beta-dioxygenase 7 located in the cell membrane and nucleus. Gibberellin 2-oxidase (GA2ox) has been reported to control GA levels by inactivating GA via 2-β hydroxylation. Compared with the short PELs of wild plants, mutant plants with Cas9-induced knockout (KO) of OsGA2ox9 exhibit long PELs. Therefore, OsGA2ox9 was identified as the key gene controlling PEL in rice. Haplotype analysis showed that the two polymorphisms of HapD cause amino acid residue changes from phenylalanine to leucine (F/L43) and isoleucine to phenylalanine (I/F52), which lead to the enhancement of panicle exsertion; therefore, we renamed this gene ENHANCED PANICLE EXSERTION (EPE1). Our study showed that EPE1 (OsGA2ox9) negatively regulated GA4 content in rice. Elite alleles of EPE1 can be used to further improve PEL in CMS lines to increase the outcrossing rate and yield or seed production in hybrid rice breeding.

Transcriptome-Wide Association Study Identified Novel Blood Tissue Gene Biomarkers for Prostate Cancer Risk.

A number of susceptibility genes in prostate tissue have been identified to be associated with prostate cancer (PCa) risk. However, the reported genes based on assessing prostate tissue could not fully explain PCa genetic susceptibility. It is believed that genes functioning in the immune system may fill in the gap of some missing heritability. To study potential susceptibility genes acting in such pathways, we performed a transcriptome-wide association study (TWAS) of 79,194 PCa cases and 61,112 control of European ancestry by using three sets of gene expression prediction models of blood tissue. A total of 470 genes were associated at false discovery rates-corrected p-value < 0.05, of which 51 were implicated as likely causal genes based on fine-mapping analysis. Compared with previous literature, 133 novel genes were reported for the first time. Of the identified genes, five (CREB3L4, GSTP1, MAPK3, NKX3-1, and PIK3C2B) were enriched in a PCa signaling pathway, and 128 genes were enriched in five PCa categories. Importantly, 13 genes (SCP2, LMNA, ZNF148, H2AFV, TACC1, FLII, SUPT4H1, CD300LF, MYO9B, COX6B1, CTSA, EP300, and TSPO) showed consistent effect directions for the measured levels in circulating immune cells between PCa cases and controls, and 14 genes (SLC39A1, ZBTB7B, TRIM59, NCEH1, N4BP2, TAGAP, TACC1, TRAF1, AIP, SECTM1, C18orf54, ZNF793, YIF1B, and TSPO) showed consistency for levels in blood exosomes between PCa patients and controls. The identified blood-based candidate susceptibility genes provide further insights into the genetic basis of PCa risk.

Immune cells: Mediators in the metabolites and Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that predominantly affects elderly individuals across the globe. While genetic, environmental, and lifestyle factors are known to influence the onset of AD, the underlying mechanisms remain unclear. To elucidate the intricate interplay between metabolites and immune cell activation in the ethology of AD, and to determine their collective impact on AD risk. We conducted a comprehensive analysis of genome-wide association studies data to examine the relationships between metabolites, immune cell phenotypes, and the risk of AD. Our study encompassed a comprehensive examination involving 731 distinct immune cell types, 1400 metabolites, and a large cohort comprising10,520 AD cases with 401,661 controls. We employed univariate Mendelian randomization to assess bidirectional relationships between metabolites and AD, metabolites and immune cells, as well as immune cells and AD. Subsequently, multivariate Mendelian randomization was then applied to evaluate the potential mediating role of immune cells on the relationship between metabolites and AD. Specific metabolites, the histidine/pyruvate ratio and homoarginine, were positively associated with the risk of AD, mediated by immune cells. Conversely, 4-hydroxycoumarin and glycolithocholate sulfate showed protective associations against AD. Immune cell markers, CD64 on monocytes and HLA DR on CD14+ CD16- monocytes were linked to higher AD risk, while CD33dim HLA DR+ CD11b- myeloid cells and HLA DR on CD8+ T cells were protective. This study highlights the critical role of immune cells in the pathogenesis of AD, demonstrating how their interaction with specific metabolites influences disease risk.

Causal associations between immune cells and psychiatric disorders: a bidirectional mendelian randomization analysis.

Extensive researches illuminate a potential interplay between immune traits and psychiatric disorders. However, whether there is the causal relationship between the two remains an unresolved question. We conducted a two-sample bidirectional mendelian randomization by utilizing summary data of 731 immune cell traits from genome-wide association studies (GCST90001391-GCST90002121)) and 11 psychiatric disorders including attention deficit/hyperactivity disorder (ADHD), anxiety disorder, autism spectrum disorder (ASD), bipolar disorder (BIP), anorexia nervosa (AN), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), Tourette syndrome (TS), post-traumatic stress disorder (PTSD), schizophrenia (SCZ), and substance use disorders (cannabis) (SUD) from the Psychiatric Genomics Consortium (PGC). A total of four types of immune signatures (median fluorescence intensities [MFI], relative cell [RC], absolute cell [AC], and morphological parameters [MP]) were included. Effect estimates were obtained by using the inverse-variance-weighted (IVW), weighted median method, Mendelian randomization (MR)-Egger, and corrected by false discovery rate. Outliers were evaluated through the leave-one-out technique. Horizontal pleiotropy was assessed using the MR pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger intercept tests. MR analysis results suggested several immune cell subtypes were casually associated with psychiatric disorders. It was found that CD33br HLA DR + CD14 - AC (Myeloid cell, AC) may contribute to decreasing the risk of BIP (odds ratio [OR] = 0.9179, confidence interval [CI] = 0.8829-0.9542, PFDR = 7.06 × 10-3), and likewise, CD38 on transitional (B cell, MFI) also showed negative causal effect on SCZ risk (OR = 0.9551, CI = 0.9330-0.9776, PFDR = 0.0441). While IgD - CD27 - %lymphocyte (B cell, RC) has causal effect on increasing BIP risk (OR = 1.0184, CI = 1.0079-1.0291, PFDR = 0.0201). In addition, HLA DR + + monocyte %monocyte (TBNK, RC) is likely to increase AN onset (OR = 1.0746, CI = 1.0324-1.1186, PFDR = 0.0506), and CCR2 on CD14 - CD16 + monocyte (Monocyte, MFI) may contribute to PTSD (OR = 1.0591, CI = 1.0275-1.0917, PFDR = 0.0369). Sensitivity analysis revealed consistency of results. Our research elucidates there may be causal links between immune traits and the onset of psychiatric disorders, which established a groundwork for the prospective clinical utilization of immune cells as markers for the diagnosis and early intervention of psychiatric disorders.

Associations between common genetic variants and income provide insights about the socio-economic health gradient.

We conducted a genome-wide association study on income among individuals of European descent (N = 668,288) to investigate the relationship between socio-economic status and health disparities. We identified 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes (the Income Factor). Our polygenic index captures 1-5% of income variance, with only one fourth due to direct genetic effects. A phenome-wide association study using this index showed reduced risks for diseases including hypertension, obesity, type 2 diabetes, depression, asthma and back pain. The Income Factor had a substantial genetic correlation (0.92, s.e. = 0.006) with educational attainment. Accounting for the genetic overlap of educational attainment with income revealed that the remaining genetic signal was linked to better mental health but reduced physical health and increased risky behaviours such as drinking and smoking. These findings highlight the complex genetic influences on income and health.

Interplay between BMI, neutrophil, triglyceride and uric acid: a case-control study and bidirectional multivariate mendelian randomization analysis

BackgroundThis study aims to explore the interplay between body mass index (BMI), neutrophils, triglyceride levels, and uric acid (UA). Understanding the causal correlation between UA and health indicators, specifically its association with the body’s inflammatory conditions, is crucial for preventing and managing various diseases.MethodsA retrospective analysis was conducted on 4,286 cases utilizing the Spearman correlation method. BMI, neutrophil count, and triglyceride levels were determined as key exposure factors. To further investigate the causal correlation, a two-sample Mendelian randomization(MR) design was utilized, leveraging data from genome-wide association study (GWAS). Within this framework, and multivariable Mendelian randomization(MVMR) was applied to explore the linkage between multiple genetic variants and complex traits.ResultsThe study primarily focused on UA, employing genetic variation as a natural tool to assess the causal impact of various factors on UA. Spearman correlation analysis revealed significant association between UA and BMI (ρ = 0.230,p<0.01), neutrophils (ρ = 0.164,p<0.01), and triglyceride levels (ρ = 0.154,p<0.01). Additionally, two-sample MR analysis affirmed a reciprocal causal association between neutrophils and UA (OR = 1.035,95%CI:1.009–1.061,p = 0.008), as well as positive causal connection between UA and both BMI (OR = 1.083,95%CI:1.042–1.126,p<0.001) and triglyceride levels (OR = 1.090,95%CI:1.037–1.146,p<0.001). Neutrophils also demonstrated a positive causal linkage with BMI (OR = 1.034,95%CI:1.009–1.078,p = 0.012) and triglyceride levels (OR = 1.077,95%CI:1.033–1.122,p<0.001), and BMI exhibited a similar causal association with triglyceride levels (OR = 1.300,95%CI:1.212–1.385,p<0.001). These findings shed light on the causal networks connecting UA, BMI, neutrophils, and triglyceride levels. By integrating Spearman correlation analysis with various MR study designs, this study provided a robust framework for identifying key factors influencing hyperuricemia and related health issues, thereby enhancing our understanding of the interplay between inflammatory markers and these health indicators.ConclusionsOur study presents strong evidence of the complex interconnection between BMI, neutrophils, triglyceride, and UA, revealing complex causal links and highlighting potential inflammatory states as key mediators. The findings may contribute to a better understanding of these factors and potentially lead to improved clinical outcomes and patients’ health.

Lipidomics-based association study reveals genomic signatures of anti-cancer qualities of pigmented rice sprouts

Lipidomics-based association study reveals genomic signatures of anti-cancer qualities of pigmented rice sprouts

A TTPA deletion is associated with Retinopathy with Vitamin E Deficiency (RVED) in the English Cocker Spaniel Dog.

Retinopathy with Vitamin E Deficiency (RVED) is a familial disease in the English Cocker Spaniel (ECS) dog breed. Ophthalmic abnormalities observed in RVED-affected ECS include lipofuscin granule deposition within the tapetal fundus and subsequent retinal degeneration resulting in visual deficits. Affected dogs may also exhibit neurological signs that include ataxia and hindlimb proprioceptive deficit. In all cases, circulating plasma concentrations of α-tocopherol are low. This study sought to investigate the genetic basis of RVED in the ECS breed. We undertook a genome-wide association study comprising 30 ECS with normal fundic examinations aged 6 years or older (controls) and 20 diagnosed with RVED (cases) and identified a statistically associated signal on chromosome 29 (Praw = 1.909×10-17). Whole genome sequencing (WGS) of two cases identified a 102bp deletion in exon 1 of the Alpha Tocopherol Transfer Protein gene (TTPA), truncating the protein by 34 amino acids. The c.23_124del variant segregated with RVED in a total of 30 cases and 43 controls. Variants in TTPA are causal for Ataxia with Vitamin E Deficiency (AVED) in humans which is a phenotypically similar disease to RVED. The identification of the canine variant is extremely significant as the availability of a DNA test will allow for identification of presymptomatic dogs and early therapeutic intervention which may prevent development of retinopathy and improve neurological signs. Breeders can also use the DNA test to efficiently eradicate the disease from this breed.

Exposome-wide association study of cognition among older adults in the national health and nutrition examination survey

Exposome-wide association study of cognition among older adults in the national health and nutrition examination survey

Mendelian randomization analysis of plasma proteins reveals potential novel tumor markers for gastric cancer

This study aimed to elucidate the potential causal relationship between 4,907 plasma proteins and the risk of gastric cancer using a two-sample Mendelian randomization approach. We utilized genome-wide association study (GWAS) data to perform two-sample Mendelian randomization analyses, treating the 4,907 plasma proteins as exposure factors and gastric cancer as the outcome. Instrumental variables for plasma proteins were selected based on strongly correlated SNPs identified through data processing and screening of the GWAS data provided by the deCode database. We employed a set of statistical methods centered on inverse variance weighting (IVW) for Mendelian randomization analysis to estimate the odds ratios (ORs) for the effects of these plasma proteins on gastric cancer susceptibility. According to the IVW method, 14 plasma proteins were associated with gastric cancer (p < 0.005). Specifically, CHST15 (OR = 0.7553, 95% CI = 0.6346 − 0.8988), L1CAM (OR = 0.7230, 95% CI = 0.5876 − 0.8896), FTMT (OR = 0.8246, 95% CI = 0.7241 − 0.9391), and PMM2 (OR = 0.5767, 95% CI = 0.3943 − 0.8433) were negatively correlated with GASTRIC CANCER, whereas ABO (OR = 1.1868, 95% CI = 1.0638 − 1.3240), FAM3D (OR = 1.2109, 95% CI = 1.0850 − 1.3515), FAM3B (OR = 1.2988, 95% CI = 1.0953 − 1.5402), ADH7 (OR = 1.3568, 95% CI = 1.1044 − 1.6670), MAP1LC3A (OR = 1.3704, 95% CI = 1.1194 − 1.6778), PGLYRP1 (OR = 1.4071, 95% CI = 1.1235 − 1.7623), PDE5A (OR = 1.7446, 95% CI = 1.2693 − 2.3978), GLUL (OR = 3.1203, 95% CI = 1.5017 − 6.4839), NFE2L1 (OR = 3.1759, 95% CI = 1.6163 − 6.2402), and MAFG (OR = 3.1945, 95% CI = 1.5329 − 6.6575) were positively correlated. Convergent results from Weighted Median and MR-Egger analyses confirmed these associations. Reverse Mendelian randomization analysis indicated that gastric cancer does not significantly alter the levels of these 14 plasma proteins (p > 0.05). Sensitivity analyses, including assessments of heterogeneity and horizontal pleiotropy, confirmed the robustness and reliability of our findings without significant bias. Pathway enrichment analysis of gene expression associated with these 14 plasma proteins, using GO and KEGG pathways, revealed that CHST15, L1CAM, FTMT, and PMM2 may serve as protective factors against gastric cancer, while ABO, FAM3D, FAM3B, ADH7, MAP1LC3A, PGLYRP1, PDE5A, GLUL, NFE2L1, and MAFG may contribute to gastric cancer pathogenesis. These results highlight the complex biological interactions between plasma proteins and tumorigenesis, providing valuable insights for preventive and therapeutic strategies in gastric malignancy management.

Genetics of sorghum: grain quality, molecular aspects, and drought responses.

Sorghum kernel composition is a crucial characteristic that determines its functional qualities. The total protein content of sorghum grain increases under drought stress, but starch, protein digestibility, and micronutrient contents decrease. Sorghum (Sorghum bicolor L.) is a staple source of starch, protein, and micronutrients in Ethiopia, where it is a key ingredient in local foods like injera and traditional beverages such as tela and areke. It has adapted remarkably to the diverse climatic conditions and soils of both highland and lowland regions. However, grain quality is influenced by climate change, drought stress, and genotype-environment interactions. Under drought conditions, sorghum shows reduced starch content, protein digestibility, and micronutrient levels, as well as increased kernel hardness and total protein content. The genetic and geographic diversity of sorghum makes it an adaptable crop, essential for breeding and diversity studies. Genome-wide association studies (GWAS) have emerged as essential tools for identifying candidate genes linked to key traits, thereby advancing genetic improvement initiatives, particularly for Ethiopian sorghum landraces. Advances in genotyping techniques, particularly genotyping-by-sequencing (GBS) and association mapping, have facilitated the identification of quantitative trait loci (QTL) associated with grain quality, enhancing breeding efficiency and the development of resilient, high-quality sorghum varieties. This review explored the genetic and phenotypic diversity of sorghum, focusing on grain quality traits, molecular mechanisms, and responses to drought stress.

Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.

Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses. We integrated the published sCJD genome-wide association study (GWAS) summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies (TWAS & PWAS) and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline on the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner. Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk gene GAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on the level of evidence and confidence for further studies. This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself and beyond the previously highlighted sCJD risk loci through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis.

MiR-423 Coding Region Genetic Polymorphism rs8067576 May Associate With the Risk of Developing Recurrent Spontaneous Abortion: A Case-Control Study in a Chinese Han Population.

Our previous study has identified an association of a single nucleotide polymorphism (SNP) in the miR-423 gene with recurrent spontaneous abortion (RSA). The presence of additional RSA-linked SNPs in the miR-423 gene remains unclear. We evaluated polymorphisms in the coding region of miR-423 in Han Chinese women with unexplained RSA (URSA). Significant differences were observed in the genotype and allele distribution of miR-423 rs8067576 between patients with RSA and control subjects. A robust association was found between an elevated RSA incidence and the presence of A/T heterozygosity in miR-423 rs8067576, with an odds ratio (OR) of 1.76 (95% confidence interval [CI]: 1.26 to 2.47, p = 0.000292). The rare allele T in the pre-miR-423 sequence was shown to cause a discernible structural change and a reduced ΔG value. Compared with the A allele, the rare T allele promoted cell proliferation. Furthermore, compared with the T allele, the A allele in the rs8067576 polymorphism exhibited a greater ability to inhibit the translation of proliferation-associated 2 group 4 (Pa2g4), which is the functional target of miR-423. The T allele in the rs8067576 polymorphism was also found to be more susceptible to the inhibition of cell proliferation induced by mifepristone. The rs8067576 A > T polymorphism in the miR-423 gene may serve as a genetic susceptibility locus for RSA. This polymorphism appears to contribute to an increased risk of acquiring URSA in humans by destroying mature miR-423.

Strength of Genetic Associations with Thyrotropin Values Differs Between Populations with Similarity to African and European Reference Populations.

Background: Epidemiological data suggest the population distribution of thyrotropin (TSH) values is shifted toward lower values in self-identified Black non-Hispanic individuals compared with self-identified White non-Hispanic individuals. It is unknown whether genetic differences between individuals with genetic similarities to African reference populations (GSA) and those with similarities to European reference populations (GSE) contribute to these observed differences. We aimed to compare genome-wide associations with TSH and putative causal TSH-associated variants between GSA and GSE groups. Methods: We performed genome-wide association studies (GWAS) in 9827 GSA individuals and 9827 GSE individuals with TSH values between 0.45 and 4.5 mU/L. We compared effect sizes and allele frequencies of previously reported putative causal TSH-associated variants and our power to detect associations with these variants between the two groups. We additionally focused on variants in PDE8B and PDE10A, loci that have been most strongly associated with TSH in previous GWAS in GSE populations. Results: Four loci attained genome-wide significance in the GSA group compared with seven in the GSE group. PDE8B was not significantly associated with TSH in the GSA group, despite its strong association in the GSE group. Eight putative causal variants had significantly different effect sizes between groups. There was ≥80% power in the GSA group to detect significant associations with variants in PDE8B, PDE10A, NFIA, and LOC105377480, with higher expected power than in the GSE group for variants in PDE8B, NFIA, and LOC105377480 and similar power for other variants in PDE8B and PDE10A. No additional putative causal variants in PDE8B and PDE10A had effect sizes that differed significantly between the groups; power to identify associations with additional putative causal variants in PDE8B and PDE10A was similar between the groups. Conclusions: Patterns of genetic associations with TSH differed between identically sized GSA and GSE groups. Failure to replicate the strongest associations previously reported in GSE individuals in our GSA population was not fully explained by differences in allele frequencies or power, assuming similar effect sizes. Larger GSA population GWAS are necessary to confirm our findings and further investigate the contribution of genetic factors to population differences in the distribution of TSH values.

Investigation of Genomic and Transcriptomic Risk Factors of Clopidogrel Response in African Americans.

Clopidogrel, an anti-platelet drug, is used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic events, with African Americans (AA) suffering disproportionately. The aim of this study was to discover novel biomarkers of clopidogrel resistance in African Americans using genome and transcriptome data. We conducted a genome-wide association study (GWAS), including local ancestry adjustment, in 141 AA on clopidogrel to identify genetic associations with high on-treatment platelet reactivity (HTPR), with validation of genome-wide significant and suggestive loci in an independent cohort of AA clopidogrel patients (N = 823) from the Million Veteran's Program (MVP) along with in vitro functional analysis. We performed differential gene expression (DGE) analysis in whole blood to identify transcriptomic predictors of response, followed by functional validation in MEG-01 cells. GWAS identified one signal on Chromosome 7 as significantly associated with increasing risk of HTPR. The lead single-nucleotide polymorphism (SNP), rs7807369, within thrombospondin 7A (THSD7A) was associated with an increased risk of HTPR (odds ratio (OR) = 4.02, P = 4.56 × 10-9). Higher THSD7A gene expression was associated with HTPR in an independent cohort of clopidogrel-treated patients (P = 0.004) and carrying a risk allele showed increased gene expression in primary human endothelial cells. Notably, the CYP2C19*2 variants showed no association with clopidogrel response in the discovery or MVP cohorts. DGE analysis identified an association with decreased LAIR1 and AP3B2 expression to HTPR. LAIR1 knockdown in MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. In summary, these findings suggest that other variants and genes outside of CYP2C19 star alleles play an important role in clopidogrel response in AA.

The Causal Relationships and Therapeutic Targets of Plasma Proteins in Ankylosing Spondylitis

Objective: The purpose of this study was to assess the causal effects of circulating plasma proteins on ankylosing spondylitis (AS) and to explore potential therapeutic targets. Methods: The study used protein quantitative trait loci (pQTLs) for thousands of plasma proteins from nine genome-wide association studies (GWAS) as instrumental variables. The relationship between genetically predicted plasma proteins and AS was assessed through Mendelian randomization (MR) analysis. Further analyses, including colocalization analysis, Steiger filtering analysis, protein-altering variant assessment, protein–protein interaction (PPI), and pathway enrichment analysis, were conducted to validate the robustness and causal direction of the results, as well as to investigate the protein functions and potential drug targets. Results: Nine unique proteins were found to have strong causal associations with AS. Steiger filtering analysis confirmed that all associations identified by MR analysis have a direct causal link from the proteins to AS. Colocalization analysis identified four unique proteins—Interleukin-6 receptor alpha (IL-6Rα), Interleukin-23 receptor (IL-23R), Thrombospondin-2 (THBS2), and Interleukin-1 receptor type 2 (IL-1R2)—that share the same causal variants with AS. PPI and pathway enrichment analysis revealed the potential roles of these proteins in inflammatory responses and immune regulation. Moreover, these proteins were valuable drug targets or considered druggable. Conclusions: This study has identified multiple plasma proteins associated with AS, revealing the important roles of these proteins in the pathogenesis of AS and providing potential therapeutic targets for AS.

Genome-wide association study identifies QTL and candidate genes for grain size and weight in a Triticum turgidum collection.

Wheat breeders are constantly looking for genes and alleles that increase grain yield. One key strategy is finding new genetic resources in the wild and domesticated gene pools of related species with genes affecting grain size. This study explored a natural population of Triticum turgidum (L.) phenotyped for grain weight and size-related traits in three field trials and genotyped with single nucleotide polymorphism markers spread across the entire genome. The genome-wide association study analysis identified 39 quantitative trait loci (QTL) for 1000-kernel weight, grain length, grain width, grain area, and grain aspect consistent in at least two and across environments. Interestingly, 23 QTL for grain-related traits were grouped in nine QTL clusters located on chromosomes 1A, 1B, 2B, 3B, 4B, 5A, and 6B, respectively. Moreover, most of these QTL support findings from previous QTL analyses and are further strengthened by the known functions of the genes (such as BG2, GS5, and SRS3) and their similarity to genes in other cereal species. QTL clusters harbored genes that participate in various metabolic processes potentially involved in seed development, phytohormone signaling, sugar transport, mitogen-activated protein kinases signaling, and transcriptional factors (such as MADS-box and WRKY). Identifying loci controlling grain-related traits will provide information on the genetic resources available to breeders to improve grain yield, as well as the opportunity to develop close gene markers to be used in marker-assisted selection programs.