Genome-wide Association Studies Studies Research Articles

No causal relationship between glucose and inflammatory bowel disease: a bidirectional two-sample mendelian randomization study

BackgroundAssociation between glucose and inflammatory bowel disease (IBD) was found in previous observational studies and in cohort studies. However, it is not clear whether these associations reflect causality. Thus, this study investigated whether there is such a causal relation between elevated glucose and IBD, Crohn’s disease (CD) and ulcerative colitis (UC).MethodsWe performed a two-sample Mendelian Randomization (MR) with the independent genetic instruments identified from the largest available genome-wide association study (GWAS) for IBD (5,673 cases; 213,119 controls) and its main subtypes, CD and UC. Summarized data for glucose which included 200,622 cases and glycemic traits including HbA1c and type 2 diabetes(T2DM) were obtained from different GWAS studies. Primary and secondary analyses were conducted by preferentially using the radial inverse-variance weighted (IVW) approach. A number of other meta-analysis approach and sensitivity analyses were carried out to assess the robustness of the results.ResultsWe did not find a causal effect of genetically predicted glucose on IBD as a whole (OR 0.858; 95% CI 0.649–1.135; P = 0.286). In subtype analyses glucose was also suggestively not associated with Crohn’s disease (OR 0.22; 95% CI 0.04-1.00; P = 0.05) and ulcerative colitis (OR 0.940; 95% CI 0.628–1.407; P = 0.762). In the other direction, IBD and its subtypes were not related to glucose and glycemic traits.ConclusionsThis MR study is not providing any evidence for a causal relationship between genetically predicted elevated glucose and IBD as well as it’s subtypes UC and CD. Regarding the other direction, no causal associations could be found. Future studies with robust genetic instruments are needed to confirm this conclusion.

Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related risk loci, genes and pathways. We first focused on CIDP, and 516 CIDP cases and 403,545 controls were included in the GWAS analysis. We also investigated genetic risk for inflammatory polyneuropathy (IP), in which we performed a GWAS study using FinnGen data and combined the results with GWAS from UK biobank (UKBB) using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. Stratified analyses by gender were performed. Mendelian randomization (MR), colocalization, and transcriptome-wide association study (TWAS) analyses were performed to identify associated genes. Gene-set analyses were conducted to identify associated pathways. We identified one genome-wide significant locus at 20q13.33 for CIDP risk among women; the top variant located at the intron region of gene CDH4. Sex-combined MR, colocalization and TWAS analyses identified three candidate pathogenic genes for CIDP, five genes for IP. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. Sex-stratified analyses identified three genes for IP among males; and two genes for IP among females. Our study identified suggestive risk genes and pathways for CIDP and IP. Functional analysis should be conducted to further confirm these associations.

Genome wide association studies on seven yield-related traits of 183 rice varieties in Bangladesh.

Rice genetic diversity is regulated by multiple genes and is largely dependent on various environmental factors. Uncovering the genetic variations associated with the diversity in rice populations is the key to breed stable and high yielding rice varieties. We performed genome wide association studies (GWASs) on seven rice yielding traits (grain length, grain width, grain weight, panicle length, leaf length, leaf width, and leaf angle) based on a population of 183 rice landraces of Bangladesh. Our GWASs reveal various chromosomal regions and candidate genes that are associated with different traits in Bangladeshi rice varieties. Noteworthy was the recurrent implication of chromosome 10 in all three grain-shape-related traits (grain length, grain width, and grain weight), indicating its pivotal role in shaping rice grain morphology. Our study also underscores the involvement of transposon gene families across these three traits. For leaf related traits, chromosome 10 was found to harbor regions that are significantly associated with leaf length and leaf width. The results of these association studies support previous findings as well as provide additional insights into the genetic diversity of rice. This is the first known GWAS study on various yield-related traits in the varieties of Oryza sativa available in Bangladesh-the fourth largest rice-producing country. We believe this study will accelerate rice genetics research and breeding stable high-yielding rice in Bangladesh.

Causal relations between ischemic stroke and epilepsy: A bidirectional Mendelian randomization study

BackgroundAlthough previous studies have reported a bidirectional relationship between ischemic stroke (IS) and epilepsy, the existence of a causal nexus and its directionality remains a topic of controversy. MethodsThe single nucleotide polymorphisms (SNPs) associated with IS were extracted from the Genome-Wide Association Study (GWAS) database. Pooled genetic data encompassing all epilepsy cases, as well as generalized and focal epilepsy subtypes, were acquired from the International League Against Epilepsy's GWAS study. In this study, the primary analysis approach utilized the inverse variance weighting (IVW) method as the main analytical technique. To enhance the robustness of the findings against potential pleiotropy, additional sensitivity analyses were conducted. ResultsIn the forward analysis, the IVW method demonstrated that IS was associated with an increased risk of all epilepsy (odds ratio (OR) = 1.127, 95 % confidence interval (CI) = 1.038–1.224, P = 0.004) and generalized epilepsy (IVW: OR = 1.340, 95 % CI = 1.162–1.546, P = 5.70 × 10–5). There was no substantial causal relationship observed between IS and focal epilepsy (P > 0.05). Furthermore, generalized epilepsy, focal epilepsy, and all epilepsy did not show a causal relationship with IS. ConclusionThis Mendelian randomization (MR) analysis demonstrates that IS increases the risk of developing epilepsy, especially generalized epilepsy. Conversely, no clear causal association was found between epilepsy and the onset of stroke. Therefore, the possible mechanisms of the effect of epilepsy on the pathogenesis of IS still need to be further investigated.

Hearing loss is not associated with risk of Parkinson's disease: A Mendelian randomization study

PurposeA few observational studies have indicated that Parkinson's disease (PD) risk may be higher in those with hearing loss, but the two's causal relationship is yet unknown. Using Mendelian randomization (MR) methods, this study sought to explore the causal link between hearing loss and the risk of PD. MethodsWe identified single nucleotide polymorphisms (SNPs) linked to hearing loss (P-value<5E-08) in a genome-wide association study (GWAS) included 323,978 people from the UK Biobank. The summary data for PD in the discovery group came from a GWAS meta-analysis of 33,647 cases and 449,056 healthy participants of European descent. Using summary data from the aforementioned GWAS of PD (N = 33,647) and hearing loss (N = 323,978), we carried out a two-sample MR study. As validation groups, two separate PD GWAS studies were used. Inverse variance weighting (IVW) was utilized in the principal MR analysis. For our findings to be reliable, further analyses were carried out with the Cochran's Q test, MR-Egger intercept, and leave-one-out analysis. In addition, we assessed the causal link between various forms of hearing loss and PD using the IVW approach. ResultsTwenty-two SNPs with genome-wide significance linked to hearing loss were used as instrumental factors. In the discovery dataset, we failed to detect a causal relationship between hearing loss and PD (OR = 1.297; 95 % CI = 0.420–4.007; P-value = 0.651). The findings of other methods agreed with the IVW method. The results were robust under sensitivity analyses. Furthermore, the above findings were confirmed in two validation PD datasets. Additionally, no causal correlation was found between genetic prediction of four different types of hearing loss and PD (conductive hearing loss, IVW: OR = 1.058, 95%CI = 0.988–1.133, P-value = 0.108; sudden idiopathic hearing loss, IVW: OR = 0.936, 95%CI = 0.863–1.016, P-value = 0.113; mixed conductive and sensorineural hearing loss, IVW: OR = 0.963, 95%CI = 0.878–1.058, P-value = 0.436; sensorineural hearing loss, IVW: OR = 1.050, 95%CI = 0.948–1.161, P-value = 0.354). ConclusionIn those of European heritage, our investigation revealed no causal link between hearing loss and PD risk.

A novel locus in CSMD1 gene is associated with increased susceptibility to severe malaria in Malian children

BackgroundPlasmodium falciparum malaria is still a leading cause of child mortality in sub-Saharan Africa. The clinical manifestations of malaria range from asymptomatic infection to severe disease. The variation in clinical presentation is partly attributed to host genetic factors with estimated narrow-sense heritability of 23%. Here, we investigate the associations between candidate gene polymorphisms and the likelihood of severe malaria (SM) in a cohort of Malian children.MethodsBased on our previous genome-wide association studies (GWAS) analysis, candidate genes were selected for in-depth analysis using several criteria including gene-level GWAS scores, functional overlap with malaria pathogenesis, and evidence of association with protection or susceptibility to other infectious or inflammatory diseases. Single Nucleotide Polymorphisms (SNPs) residing within these genes were selected mainly based on p-values from previous severe malaria susceptibility GWAS studies and minor allele frequency (MAF) in West African populations.ResultsOf 182 candidate genes reported in our previous study, 11 genes and 22 SNPs residing in these genes were selected. The selected SNPs were genotyped using KASP technology in 477 DNA samples (87 SM and 390 controls). Logistic regression analysis revealed that a common intron variant, rs13340578 in CUB and Sushi Multi Domain (CSMD1) gene, is associated with increased odds of SM in recessive mode of inheritance (MAF = 0.42, OR = 1.8, 95% CI = [1.78, 1.84], p = 0.029). The SNP is in linkage disequilibrium (LD) with multiple variants with regulatory features.ConclusionTaken together, the current study showed that an intron variant rs13340578, residing in CSMD1 gene, is associated with increased susceptibility to malaria. This finding suggests that modified regulation of complement may contribute to malaria disease severity. Further studies are needed to identify the causal variants and the underlying molecular mechanisms.

Genetic predisposition to bone mineral density and their health conditions in East Asians.

Osteoporosis, a condition defined by low BMD (typically < -2.5 SD), causes a higher fracture risk and leads to significant economic, social, and clinical impacts. Genome-wide studies mainly in Caucasians have found many genetic links to osteoporosis, fractures, and BMD, with limited research in East Asians (EAS). We investigated the genetic aspects of BMD in 86 716 individuals from the Taiwan Biobank and their causal links to health conditions within EAS. A genome-wide association study (GWAS) was conducted, followed by observational studies, polygenic risk score assessments, and genetic correlation analyses to identify associated health conditions linked to BMD. GWAS and gene-based GWAS studies identified 78 significant SNPs and 75 genes related to BMD, highlighting pathways like Hedgehog, WNT-mediated, and TGF-β. Our cross-trait linkage disequilibrium score regression analyses for BMD and osteoporosis consistently validated their genetic correlations with BMI and type 2 diabetes (T2D) in EAS. Higher BMD was linked to lower osteoporosis risk but increased BMI and T2D, whereas osteoporosis linked to lower BMI, waist circumference, hemoglobinA1c, and reduced T2D risk. Bidirectional Mendelian randomization analyses revealed that a higher BMI causally increases BMD in EAS. However, no direct causal relationships were found between BMD and T2D, or between osteoporosis and either BMI or T2D. This study identified key genetic factors for bone health in Taiwan, and revealed significant health conditions in EAS, particularly highlighting the genetic interplay between bone health and metabolic traits like T2D and BMI.

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer's disease in the Framingham Heart Study.

Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer's disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.

Risk relationship between inflammatory bowel disease and urolithiasis: A two-sample Mendelian randomization study.

The causal genetic relationship between common parenteral manifestations of inflammatory bowel disease (IBD) and urolithiasis remains unclear because their timing is difficult to determine. This study investigated the causal genetic association between IBD and urolithiasis using Mendelian randomization (MR) based on data from large population-based genome-wide association studies (GWASs). A two-sample MR analysis was performed to assess the potential relationship between IBD and urolithiasis. Specific single nucleotide polymorphism data were obtained from GWASs, including IBD (n = 59957) and its main subtypes, Crohn's disease (CD) (n = 40266) and ulcerative colitis (UC) (n = 45975). Summarized data on urolithiasis (n = 218792) were obtained from different GWAS studies. A random-effects model was analyzed using inverse-variance weighting, MR-Egger, and weighted medians. Genetic predisposition to IBD and the risk of urolithiasis were significantly associated [odds ratio (OR), 1.04 (95% confidence interval [CI], 1.00-.08), P = 0.01]. Consistently, the weighted median method yielded similar results [OR, 1.06 (95% CI, 1.00-1.12), P = 0.02]. The MR-Egger method also demonstrated comparable findings [OR, 1.02 (95% CI, 0.96-1.08), P = 0.45]. Both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between IBD and urolithiasis. CD was strongly associated with it in its subtype analysis [OR, 1.04 (95% CI, 1.01-1.07), P = 0.01], and UC was also causally associated with urolithiasis, although the association was not significant [OR, 0.99 (95% CI, 0.95-1.03), P = 0.71]. A unidirectional positive causal correlation was identified between IBD and urolithiasis, with varying degrees of association observed among the different subtypes of IBD. Recognizing the increased incidence of urolithiasis in patients with IBD is crucial in clinical practice. Early detection and surveillance of IBD, improved patient awareness, adoption of preventive strategies, and promotion of collaborative efforts among healthcare providers regarding treatment methodologies are vital for improving patient outcomes.

Heritability of complex traits in sub-populations experiencing bottlenecks and growth

Populations that have experienced a bottleneck are regularly used in Genome Wide Association Studies (GWAS) to investigate variants associated with complex traits. It is generally understood that these isolated sub-populations may experience high frequency of otherwise rare variants with large effect size, and therefore provide a unique opportunity to study said trait. However, the demographic history of the population under investigation affects all SNPs that determine the complex trait genome-wide, changing its heritability and genetic architecture. We use a simulation based approach to identify the impact of the demographic processes of drift, expansion, and migration on the heritability of complex trait. We show that demography has considerable impact on complex traits. We then investigate the power to resolve heritability of complex traits in GWAS studies subjected to demographic effects. We find that demography is an important component for interpreting inference of complex traits and has a nuanced impact on the power of GWAS. We conclude that demographic histories need to be explicitly modelled to properly quantify the history of selection on a complex trait.

Menarche-a journey into womanhood: age at menarche and health-related outcomes in East Asians.

Are there associations of age at menarche (AAM) with health-related outcomes in East Asians? AAM is associated with osteoporosis, Type 2 diabetes (T2D), glaucoma, and uterine fibroids, as demonstrated through observational studies, polygenic risk scores, genetic correlations, and Mendelian randomization (MR), with additional findings indicating a causal effect of BMI and T2D on earlier AAM. Puberty timing is linked to adult disease risk, but research predominantly focuses on European populations, with limited studies in other groups. We performed an AAM genome-wide association study (GWAS) with 57890 Han Taiwanese females and examined the association between AAM and 154 disease outcomes using the Taiwanese database. Additionally, we examined genetic correlations between AAM and 113 diseases and 67 phenotypes using Japanese GWAS summary statistics. We performed AAM GWAS and gene-based GWAS studies to obtain summary statistics and identify potential AAM-related genes. We applied phenotype, polygenic risk scores, and genetic correlation analyses of AAM to explore health-related outcomes, using multivariate regression and linkage disequilibrium score regression analyses. We also explored potential bidirectional causal relationships between AAM and related outcomes through univariable and multivariable MR analyses. Fifteen lead single-nucleotide polymorphisms and 24 distinct genes were associated with AAM in Taiwan. AAM was genetically associated with later menarche and menopause, greater height, increased osteoporosis risk, but lower BMI, and reduced risks of T2D, glaucoma, and uterine fibroids in East Asians. Bidirectional MR analyses indicated that higher BMI/T2D causally leads to earlier AAM. Our findings were specific to Han Taiwanese individuals, with genetic correlation analyses conducted in East Asians. Further research in other ethnic groups is necessary. Our study provides insights into the genetic architecture of AAM and its health-related outcomes in East Asians, highlighting causal links between BMI/T2D and earlier AAM, which may suggest potential prevention strategies for early puberty. The work was supported by China Medical University, Taiwan (CMU110-S-17, CMU110-S-24, CMU110-MF-49, CMU111-SR-158, CMU111-MF-105, CMU111-MF-21, CMU111-S-35, CMU112-SR-30, and CMU112-MF-101), the China Medical University Hospital, Taiwan (DMR-111-062, DMR-111-153, DMR-112-042, DMR-113-038, and DMR-113-103), and the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-039-063-MY3, MOST 111-2314-B-039-064-MY3, MOST 111-2410-H-039-002-MY3, and NSTC 112-2813-C-039-036-B). The funders had no influence on the data collection, analyses, or conclusions of the study. No conflict of interests to declare. N/A.

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis.

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

Prediction of antipsychotics efficacy based on a polygenic risk score: a real-world cohort study.

Background: Response to antipsychotics is subject to a wide interindividual variability, due to genetic and non-genetic factors. Several single nucleotide polymorphisms (SNPs) have been associated with response to antipsychotics in genome-wide association studies (GWAS). Polygenic risk scores (PRS) are a powerful tool to aggregate into a single measure the small effects of multiple risk alleles. Materials and methods: We studied the association between a PRS composed of SNPs associated with response to antipsychotics in GWAS studies (PRSresponse) in a real-world sample of patients (N = 460) with different diagnoses (schizophrenia spectrum, bipolar, depressive, neurocognitive, substance use disorders and miscellaneous). Two other PRSs composed of SNPs previously associated with risk of schizophrenia (PRSschizophrenia1 and PRSschizophrenia2) were also tested for their association with response to treatment. Results: PRSresponse was significantly associated with response to antipsychotics considering the whole cohort (OR = 1.14, CI = 1.03-1.26, p = 0.010), the subgroup of patients with schizophrenia, schizoaffective disorder or bipolar disorder (OR = 1.18, CI = 1.02-1.37, p = 0.022, N = 235), with schizophrenia or schizoaffective disorder (OR = 1.24, CI = 1.04-1.47, p = 0.01, N = 176) and with schizophrenia (OR = 1.27, CI = 1.04-1.55, p = 0.01, N = 149). Sensitivity and specificity were sub-optimal (schizophrenia 62%, 61%; schizophrenia spectrum 56%, 55%; schizophrenia spectrum plus bipolar disorder 60%, 56%; all patients 63%, 58%, respectively). PRSschizophrenia1 and PRSschizophrenia2 were not significantly associated with response to treatment. Conclusion: PRSresponse defined from GWAS studies is significantly associated with response to antipsychotics in a real-world cohort; however, the results of the sensitivity-specificity analysis preclude its use as a predictive tool in clinical practice.

Causal relationship between atrial fibrillation/warfarin and cutaneous melanoma: a two-sample Mendelian randomization study.

In recent years, the relationship between malignant tumors and atrial fibrillation has attracted more and more attention. Atrial fibrillation can also cause a series of adverse events, such as the risk of thromboembolism. Also, Warfarin is often used here. But, the relationship between cutaneous melanoma and atrial fibrillation, and between cutaneous melanoma and warfarin is still unclear. Therefore, we used a two-sample Mendelian randomization to assess the causal relationship between atrial fibrillation/warfarin and cutaneous melanoma (cM). Firstly, atrial fibrillation (ukb-b-11550; nCase = 3,518, nControl = 459,415) and warfarin (ukb-b-13248; nCase = 4,623, nControl = 458,310) as exposures, with genome-wide association studies (GWAS) data from the United Kingdom Biobank. And cM (ieu-b-4969; nCase = 3,751, nControl = 372,016) as outcome, with GWAS data from the IEU Open GWAS project. Subsequently, single-nucleotide polymorphisms (SNPs) were filtered from GWAS studies using quality control measures. In addition, two-sample Mendelian randomization (MR) analysis was performed to explore the causal relationship between atrial fibrillation or warfarin and cM and used inverse variance weighting (IVW) as the primary analytical method. Finally, relevant heterogeneity and sensitivity analysis were performed to ensure the accuracy of the results. A causal relationship between atrial fibrillation and cutaneous melanoma was observed, and between warfarin and cutaneous melanoma. The atrial fibrillation may play a causal role in the development of cutaneous melanoma, but the mechanism and the causal relationship between warfarin and cutaneous melanoma needs to be further elucidated.

Genome-wide association study (GWAS) identified PCOS susceptibility variants and replicates reported risk variants.

Genetic predisposition and environmental factors are considered risk factors for polycystic ovary syndrome (PCOS). Genome-wide association studies (GWAS) have been reported from various subpopulations to evaluate SNPs associated with PCOS risk. No PCOS-associated GWAS study has been reported from India so far. The current study was conducted to identify the PCOS-susceptible loci among the North Indian population and to validate the significant loci reported by previous GWAS studies. A total of 272 participants with 134 PCOS patients and 138 age-matchedhealthy controls were recruited. Genomic DNA was isolated and genotyped by using Infinium Global Screening Array v3.0 microchip considering HWE 10e-5 statistically significant. A total of fifteen markers have been identified as candidate PCOS risk factors. Only two SNPs, namely rs17186366 and rs11171739 have been identified through replication analysis while comparing the previously reported PCOS GWAS data. In-silico analysis was performed to study the functional impact of identified significant genes for gene ontology, pathways related to gene set, and cluster analysis to determine protein-protein interaction among genes or gene products. The study suggests that multiple variants play an important role in PCOS pathogenesis and emphasizes the importance of further genetic studies among Indian subpopulations.The study also validates two previously reported SNPs in the Indian population. What this study adds to clinical work Study summarizes the importance of candidate gene markers validated by replication and in-silico functional study, significantly involved in PCOS pathogenesis in the studied population. These markers can be used in the future as diagnostic markers for clinical phenotype identification.

Causal associations of refractive error and early age-related macular degeneration: A Mendelian randomization study

This study aims to determine the risk associated with early age-related macular degeneration (AMD) due to refractive errors (RE) using an analysis of genome-wide association study (GWAS) data through the two-sample Mendelian randomization approach. Single-nucleotide polymorphisms (SNPs) linked to refractive errors (RE) were obtained from numerous GWAS studies involving individuals of European descent. The data for early AMD was obtained from a diverse, multiethnic GWAS meta-analysis that included 105,248 participants (14,034 cases and 91,214 controls). The primary outcome measure focused on the rise in early AMD risk corresponding to a 1-diopter alteration in spherical power and cylindrical power. In the main Mendelian randomization analysis, inverse-variance weighting (IVW) methods were applied for the evaluation. Mendelian Randomization (MR) study revealed a substantial impact of refractive error (RE) on early AMD risk, with a 1-diopter increase in hypermetropia being related to a 1.16 odds ratio (OR) for a greater risk of early AMD (95% CI, 1.10–1.23; P < 0.01). This conclusion was further supported by four supplementary approaches, namely, Weighted mode, Weighted-median, Simple mode, and MR-Egger. The results suggest a heightened risk of early AMD correlated with hyperopia, necessitating further research to thoroughly elucidate this potential causal relationship.

Relationship Between Sleep Duration and Cognitive Function in Older Adults: Analysis of NHANES and UK Biobank GWAS Data.

To explore the relationship between sleep duration and cognitive functions in older adults using NHANES, a national US population study dataset, and to explore the causal association with Mendelian randomization (MR) using the UK Biobank. First, an observational study was conducted with the NHANES database with participants ≥60 years. Sleep duration was measured with accelerometers for 7 consecutive days. Participants were divided into habitual short sleep (<7h) and long sleep (>9h) groups. Cognitive functions were measured with the CERAD Word Learning sub-set, Animal Fluency, and Digit Symbol Substitution test (DSST). Multivariate regression models were used to explore relationships between sleep duration and cognitive functions. Second, bidirectional MR was conducted with data for self-reported sleep duration, which came from a genome-wide association study (GWAS) comprising 446,118 adults from the UK Biobank, and general cognitive performance, which was obtained from a recent GWAS study (N = 257,841). Inverse-variance weighted (IVW) was used as the primary estimation of the outcome. In the observational study, 2687 participants were included. Sleep duration was associated with cognitive functions in a non-linear way. Habitual long sleep (>9°h) was associated with lower scores on DSST (OR = 0.01, p = .003) in the fully-adjusted model. The association between habitual short sleep and cognitive functions was insignificant. For the MR, genetically predicted lower general cognitive performance was causally associated with a higher prevalence of habitual short sleep (OR = 0.97, p = 5.1 × 10-7) and long sleep (OR = 0.97, p = 8.87 × 10-16). Short and long sleep duration might be both causally associated with worse outcomes of cognitive functions in older adults, highlighting the importance of maintaining sleep health.

Assessing the impact of novel risk loci on Alzheimer's and Parkinson's diseases in a Chinese Han cohort.

Overwhelming evidence points to that genetic factors contributing to the development of Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-Wide Association Study (GWAS) has come a long way in the last decade. So far, a large number of GWAS studies have been published on neurological diseases and many other diseases, providing us with a wealth of genetic information and unique biological insights. Genomic DNA was extracted from both patients' and controls' peripheral blood samples utilizing the Blood Genome Extraction Kit. Single nucleotide polymorphisms (SNPs) were genotyped employing the enhanced multiple ligase detection reaction (iMLDR) technology. A case-control study was conducted, involving 211 AD patients, 508 PD patients (including 117 with dementia), and 412 healthy individuals. Age and sex stratification analysis revealed that rs871269/TNIP1 was associated with LOAD (p = 0.035), and rs5011436/TMEM106B was associated with AD in males (p = 0.044) in the genotype model. In the allele model, rs871269/TNIP1 was found to be associated with PD in the Chinese Han population (p = 0.0035, OR 0.741, 95% CI 0.559-0.983), and rs708382/GRN was identified as a risk factor for Parkinson's disease dementia (PDD) in the Chinese Han population (p = 0.004, odds ratio (OR) 0.354, 95% confidence interval (CI) 0.171-0.733). However, no significant associations with AD or PD were observed for the remaining four loci (rs113020870/AGRN, rs6891966/HAVCR2, rs2452170/NTN5, rs1761461/LILRB2) in terms of allele or genotype frequencies. This study identifies rs871269/TNIP1 as a potential risk factor for both LOAD and PD, rs708382/GRN as a risk factor for PDD, and rs5011436/TMEM106B as associated with AD in males when stratified by age.

A Genome-Wide Association Study of Respiratory Syncytial Virus Infection Severity in Infants.

Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide. Most children experience at least one 1 RSV infection by the age of two 2 years, but not all develop severe disease. However, the understanding of genetic risk factors for severe RSV is incomplete. Consequently, we conducted a genome-wide association study of RSV severity. Disease severity was assessed by the ReSVinet scale, in a cohort of 251 infants aged 1 week to 1 year. Genotyping data were collected from multiple European study sites as part of the RESCEU Consortium. Linear regression models were used to assess the impact of genotype on RSV severity and gene expression as measured by microarray. While no SNPs reached the genome-wide statistical significance threshold (P < 5 × 10-8), we identified 816 candidate SNPs with a P-value of <1 × 10-4. Functional annotation of candidate SNPs highlighted genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Moreover, SNPs within the RAB27A locus significantly altered gene expression (false discovery rate, FDR P < .05). These findings may provide insights into genetic mechanisms driving severe RSV infection, offering biologically relevant information for future investigations.

Genetic Association Studies in Restless Legs Syndrome: Risk Variants & Ethnic Differences.

Genetic association studies have not produced consistent results in restless legs syndrome (RLS). To conduct a systematic review on genetic association studies in RLS to highlight the common gene variants and ethnic differences. We conducted Pubmed, Embase, and Cochrane search using terms "Genetic association studies" and "restless legs syndrome" for candidate gene-based studies. Out of the initial 43 studies, 18 case control studies (from 2012 to 2022) were included. Thirteen studies including 10794 Caucasian subjects (4984 RLS cases and 5810 controls) and five studies involving 2009 Asian subjects (796 RLS cases and 1213 controls) were tabulated and analyzed. In addition, three Genome-Wide Association Studies (GWAS) in Asians and Europeans/Caucasians were included for comparisons. In the Asian population, gene variants in BST1, SNCA Rep1, IL1B, BTBD9, and MAP2K5/SKOR1 increased the risk of RLS (odds ratio range 1.2-2.8). In Caucasian populations, examples of variants that were associated with an increased risk of RLS (odds ratio range 1.1-1.9) include those in GABRR3 TOX3, ADH1B, HMOX1, GLO1, DCDC2C, BTBD9, SKOR1, and SETBP1. Based on the meta-analysis of GWAS studies, the rs9390170 variant in UTRN gene was identified to be a novel genetic marker for RLS in Asian cohorts, whereas rs113851554 in MEIS1 gene was a strong genetic factor among the >20 identified gene variants for RLS in Caucasian populations. Our systemic review demonstrates that multiple genetic variants modulate risk of RLS in Caucasians (such as MEIS1 BTBD9, MAP2K5) and in Asians (such as BTBD9, MAP2K5, and UTRN).