Recent Genome-wide Association Studies Research Articles

Assessing causality between inflammatory bowel diseases with frailty index and sarcopenia: a bidirectional Mendelian randomization study

BackgroundPrevious studies have found that frailty and sarcopenia are commonly diagnosed in inflammatory bowel disease (IBD) patients, indicating an association between these conditions. Nonetheless, the cause‒effect connection between IBD, frailty, and sarcopenia remains unclear.MethodsWe sourced the genetic variants for the exposures and outcomes from publicly accessible, extensive genome-wide association studies (GWAS). Specifically, we obtained IBD data from the International IBD Genetics Consortium, frailty index (FI) data from the United Kingdom Biobank and Swedish TwinGene, and sarcopenia data from a recent GWAS meta-analysis. Five methods, including inverse variance weighted (IVW), simple mode, MR-Egger, weighted mode, and the weighted median, were used to proceed with MR estimates. We also performed heterogeneity and horizontal pleiotropy tests.ResultsOur results indicated a positive causal relationship between ulcerative colitis (UC) (IVW: β = 0.014, 95% CI, 0.006 to 0.021, p = 0.001) and Crohn's disease (CD) (IVW: β = 0.012; 95% CI, 0.006 to 0.018, p = 2e−04) with the FI. However, we uncovered no proof of a cause-and-effect relationship between UC (IVW: β = 0.001, 95% CI, −0.015 to 0.017, p = 0.344) or CD (IVW: β = 0.003, 95% CI, −0.009 to 0.015, p = 0.214) and sarcopenia. Additionally, in the inverse order, we also discovered no cause-and-effect connection between FI or sarcopenia on UC or CD in this study.ConclusionThe MR analysis showed a positive causal association between IBD and FI, indicating that IBD patients may exhibit aging-related characteristics. Therefore, frailty assessments should be conducted as early as possible in IBD patients.

Genetic Associations of Circulating Cardiovascular Proteins With Gestational Hypertension and Preeclampsia

Hypertensive disorders of pregnancy (HDPs), including gestational hypertension and preeclampsia, are important contributors to maternal morbidity and mortality worldwide. In addition, women with HDPs face an elevated long-term risk of cardiovascular disease. To identify proteins in the circulation associated with HDPs. Two-sample mendelian randomization (MR) tested the associations of genetic instruments for cardiovascular disease-related proteins with gestational hypertension and preeclampsia. In downstream analyses, a systematic review of observational data was conducted to evaluate the identified proteins' dynamics across gestation in hypertensive vs normotensive pregnancies, and phenome-wide MR analyses were performed to identify potential non-HDP-related effects associated with the prioritized proteins. Genetic association data for cardiovascular disease-related proteins were obtained from the Systematic and Combined Analysis of Olink Proteins (SCALLOP) consortium. Genetic association data for the HDPs were obtained from recent European-ancestry genome-wide association study meta-analyses for gestational hypertension and preeclampsia. Study data were analyzed October 2022 to October 2023. Genetic instruments for 90 candidate proteins implicated in cardiovascular diseases, constructed using cis-protein quantitative trait loci (cis-pQTLs). Gestational hypertension and preeclampsia. Genetic association data for cardiovascular disease-related proteins were obtained from 21 758 participants from the SCALLOP consortium. Genetic association data for the HDPs were obtained from 393 238 female individuals (8636 cases and 384 602 controls) for gestational hypertension and 606 903 female individuals (16 032 cases and 590 871 controls) for preeclampsia. Seventy-five of 90 proteins (83.3%) had at least 1 valid cis-pQTL. Of those, 10 proteins (13.3%) were significantly associated with HDPs. Four were robust to sensitivity analyses for gestational hypertension (cluster of differentiation 40, eosinophil cationic protein [ECP], galectin 3, N-terminal pro-brain natriuretic peptide [NT-proBNP]), and 2 were robust for preeclampsia (cystatin B, heat shock protein 27 [HSP27]). Consistent with the MR findings, observational data revealed that lower NT-proBNP (0.76- to 0.88-fold difference vs no HDPs) and higher HSP27 (2.40-fold difference vs no HDPs) levels during the first trimester of pregnancy were associated with increased risk of HDPs, as were higher levels of ECP (1.60-fold difference vs no HDPs). Phenome-wide MR analyses identified 37 unique non-HDP-related protein-disease associations, suggesting potential on-target effects associated with interventions lowering HDP risk through the identified proteins. Study findings suggest genetic associations of 4 cardiovascular disease-related proteins with gestational hypertension and 2 associated with preeclampsia. Future studies are required to test the efficacy of targeting the corresponding pathways to reduce HDP risk.

Causal relationship of gut microbiota with diabetic nephropathy: a Mendelian randomization analysis.

Patients with DN (diabetic nephropathy) show remarkable variations in their gut microbiota composition. However, to date, no study has shown whether a causal relationship exists between gut microbiota composition and DN. Here, we performed a two-sample Mendelian randomization (MR) investigation for identifying causal associations of gut microbiota with DN. Gut microbiota genetic data were gathered from the recent genome-wide association study pooled data of the MiBioGen consortium, which included 24 cohorts and 18,340 individuals. IVW(Inverse variance weighting) revealed that Verrucomicrobia [odds ratio (OR) = 1.390; 95% confidence interval (CI) = 1.10-1.75; p = 0.005], Peptostreptococcaceae (OR = 1.284; 95% CI = 1.03-1.59; p = 0.012), Verrucomicrobiaceae (OR = 1.390; 95% CI = 1.10-1.75; p = 0.005), Akkermansia (OR = 1.390; 95% CI = 1.10-1.75; p = 0.005), Butyricimonas (OR = 1.261; 95% CI = 1.02-1.55; p = 0.031), Catenibacterium (OR = 1.278; 95% CI = 1.02-1.59; p = 0.030). Two-sample MR analysis identified 12 microbial taxa in gut microbiota (one of which is yet to be officially named) that showed significant causal associations with DN; 8 of these taxa significantly increased the risk of DN, while the remaining 4 taxa (including the one without an official name) reduced the risk of DN. The precise mechanisms influencing the interactions of gut microbiota with DN occurrence remain unclear; hence, additional investigations should be conducted to clarify these mechanisms.

Elucidating the Mechanisms Underlying Interindividual Differences in the Onset of Adverse Drug Reactions.

Idiosyncratic drug toxicities (IDTs) pose a significant challenge; they are marked by life-threatening adverse reactions that emerge aftermarket release and are influenced by intricate genetic and environmental variations. Recent genome-wide association studies have highlighted a strong correlation between specific human leukocyte antigen (HLA) polymorphisms and IDT onset. This review provides an overview of current research on HLA-mediated drug toxicities. In the last six years, HLA-transgenic (Tg) mice have been instrumental in advancing our understanding of these underlying mechanisms, uncovering systemic immune reactions that replicate human drug-induced immune stimulation. Additionally, the potential role of immune tolerance in shaping individual differences in adverse effects highlights its relevance to the interplay between HLA polymorphisms and IDTs. Although HLA-Tg mice offer valuable insights into systemic immune reactions, further exploration is essential to decipher the intricate interactions that lead to organ-specific adverse effects, especially in organs such as the skin or liver. Navigating the intricate interplay of HLA, which may potentially trigger intracellular immune responses, this review emphasizes the need for a holistic approach that integrates findings from both animal models and molecular/cellular investigations. The overarching goal is to enhance our comprehensive understanding of HLA-mediated IDTs and identify factors shaping individual variations in drug reactions. This review aims to facilitate the development of strategies to prevent severe adverse effects, address existing knowledge gaps, and provide guidance for future research initiatives in the field of HLA-mediated IDTs.

Genetically predicted HLA-DR+ natural killer cells as potential mediators in the lipid-coronary artery disease/ calcification (CAD/CAC) causal pathway.

Coronary artery disease (CAD) imposes a significant global health burden, necessitating a deeper comprehension of its genetic foundations to uncover innovative therapeutic targets. Employing a comprehensive Mendelian randomization (MR) approach, we aimed to explore the genetic associations between lipid profiles, immune cell phenotypes, and CAD risk. Utilizing data from recent large-scale genome-wide association studies (GWAS), we scrutinized 179 lipid and 731 immune cell phenotypes to delineate their genetic contributions to CAD pathogenesis, including coronary artery calcification (CAC). Moreover, specific immune cell phenotypes were examined as potential mediators of the lipid-CAD/CAC causal pathway. Among the 162 lipid species with qualified instrumental variables (IVs) included in the analysis, we identified 36 lipids that exhibit a genetic causal relationship with CAD, with 29 being risk factors and 7 serving as protective factors. Phosphatidylethanolamine (18:0_20:4) with 8 IVs (OR, 95% CI, P-value: 1.04, 1.02-1.06, 1.50E-04) met the Bonferroni-corrected significance threshold (0.05/162=3.09E-04). Notably, all 18 shared lipids were determined to be risk factors for both CAD and CAC, including 16 triacylglycerol traits (15 of which had ≥ 3 IVs), with (50:1) exhibiting the highest risk [OR (95% CI) in CAC: 1.428 (1.129-1.807); OR (95% CI) in CAD: 1.119 (1.046-1.198)], and 2 diacylglycerol traits. Furthermore, we identified HLA DR+ natural killer cells (IVs = 3) as nominally significant with lipids and as potential mediators in the causal pathway between diacylglycerol (16:1_18:1) or various triacylglycerols and CAD (mediated effect: 0.007 to 0.013). This study provides preliminary insights into the genetic correlations between lipid metabolism, immune cell dynamics, and CAD susceptibility, highlighting the potential involvement of natural killer cells in the lipid-CAD/CAC causal pathway and suggesting new targets for therapy. Further evidence is necessary to substantiate our findings.

Genetic analyses of the bidirectional associations between common mental disorders and asthma.

Although extensive research has explored the link between mental disorders and asthma, the characteristics and patterns of this association are still unclear. Our study aims to examine the genetic causal links between common mental disorders (specifically, anxiety and depression) and asthma. We conducted genetic analyses including linkage disequilibrium score regression (LDSC) and bidirectional two-sample Mendelian randomization (MR) analyses, and utilized summary statistics from recent large-scale Genome-Wide Association Studies (GWASs) in European populations, covering sensation of anxiety or depression, anxiety sensation, depression sensation, anxiety disorders, major depression disorder (MDD), and asthma. LDSC revealed significant genetic correlations among sensation of anxiety or depression, MDD and asthma (P < 0.017), highlighting potential genetic correlation between anxiety disorders and asthma (P < 0.05 yet > 0.017). In bidirectional two-sample MR, inverse-variance weighted (IVW) analyses suggested that genetic liability to asthma was significantly associated with an increased risk of sensation of anxiety or depression (OR = 4.760, 95%CI: 1.645-13.777), and MDD (OR = 1.658, 95%CI: 1.477-1.860). Conversely, IVW analyses indicated that genetic liability to anxiety disorders was not associated with an increased risk of asthma (P > 0.01), nor was genetic liability to asthma associated with an increased risk of anxiety disorders (P > 0.01). Furthermore, no significant genetic causal relationships were observed for other studied traits. Multivariate MR, after adjusting for body mass index and alcohol consumption, further corroborated the independent causal effect of genetic predisposition to MDD on the risk of asthma (OR = 1.460, 95% CI: 1.285-1.660). Our study establishes MDD as a predisposing factor for asthma. Meanwhile, anxiety disorders are not causal risk factors for asthma, nor is the reverse true. It is recommended to closely monitor asthma symptoms in patients with MDD.

Causal association of type 2 diabetes with central retinal artery occlusion: a Mendelian randomization study.

Central retinal artery occlusion (CRAO) is a medical condition characterized by sudden blockage of the central retinal artery, which leads to a significant and often irreversible loss of vision. Observational studies have indicated that diabetes mellitus is a risk factor for CRAO; however, there is no research on the causal relationship between diabetes mellitus, particularly type 2 diabetes, and CRAO. This study aimed to perform Mendelian randomization (MR) analysis to clarify the causal relationship between type 2 diabetes and CRAO. Genetic variants associated with type 2 diabetes were selected from two different datasets. A recent genome-wide association study of CRAO conducted using the FinnGen database was used as the outcome data. A two-sample MR was performed to evaluate the causal relationship between type 2 diabetes and CRAO. Inverse variance weighting was the primary method, and MR-Egger, maximum likelihood, and median weighting were used as complementary methods. A multivariate MR (MVMR) analysis was performed to further evaluate the robustness of the results. Cochran's Q test, MR-Egger intercept test, and MR-PRESSO global test were used for the sensitivity analyses. Genetically predicted type 2 diabetes was causally associated with CRAO(odds ratio [OR] =2.108, 95% confidence interval [CI]: 1.221-3.638, P=7.423×10-3), which was consistent with the results from the validation dataset (OR=1.398, 95%CI: 1.015-1.925, P=0.040). The MVMR analysis suggested that type 2 diabetes may be an independent risk factor for CRAO (adjusted OR=1.696; 95%CI=1.150-2.500; P=7.655×10-3), which was assumed by the validation dataset (adjusted OR=1.356; 95%CI=1.015-1.812; P=0.039). Our results show that genetically predicted type 2 diabetes may be causally associated with CRAO in European populations. This suggests that preventing and controlling type 2 diabetes may reduce the risk of CRAO.

Unveiling facial kinship: The BioKinVis dataset for facial kinship verification and genetic association studies.

Facial image-based kinship verification represents a burgeoning frontier within the realms of computer vision and biomedicine. Recent genome-wide association studies have underscored the heritability of human facial morphology, revealing its predictability based on genetic information. These revelations form a robust foundation for advancing facial image-based kinship verification. Despite strides in computer vision, there remains a discernible gap between the biomedical and computer vision domains. Notably, the absence of family photo datasets established through biological paternity testing methods poses a significant challenge. This study addresses this gap by introducing the biological kinship visualization dataset, encompassing 5773 individuals from 2412 families with biologically confirmed kinship. Our analysis delves into the distribution and influencing factors of facial similarity among parent-child pairs, probing the potential association between forensic short tandem repeat polymorphisms and facial similarity. Additionally, we have developed a machine learning model for facial image-based kinship verification, achieving an accuracy of 0.80 in the dataset. To facilitate further exploration, we have established an online tool and database, accessible at http://120.55.161.230:88/.

Leisure time television watching, computer use and risks of breast, colorectal and prostate cancer: A Mendelian randomisation analysis.

Sedentary behaviours have been associated with increased risks of some common cancers in epidemiological studies; however, it is unclear if these associations are causal. We used univariable and multivariable two-sample Mendelian randomisation (MR) to examine potential causal relationships between sedentary behaviours and risks of breast, colorectal and prostate cancer. Genetic variants associated with self-reported leisure television watching and computer use were identified from a recent genome-wide association study (GWAS). Data related to cancer risk were obtained from cancer GWAS consortia. A series of sensitivity analyses were applied to examine the robustness of the results to the presence of confounding. A 1-standard deviation (SD: 1.5 h/day) increment in hours of television watching increased risk of breast cancer (OR per 1-SD: 1.15, 95% confidence interval [CI]: 1.05-1.26) and colorectal cancer (OR per 1-SD: 1.32, 95% CI: 1.16-1.49) while there was little evidence of an association for prostate cancer risk (OR per 1-SD: 0.94, 95% CI: 0.84-1.06). After adjusting for years of education, the effect estimates for television watching were attenuated (breast cancer, OR per 1-SD: 1.08, 95% CI: 0.92-1.27; colorectal cancer, OR per 1-SD: 1.08, 95% CI: 0.90-1.31). Post hoc analyses showed that years of education might have a possible confounding and mediating role in the association between television watching with breast and colorectal cancer. Consistent results were observed for each cancer site according to sex (colorectal cancer), anatomical subsites and cancer subtypes. There was little evidence of associations between genetically predicted computer use and cancer risk. Our univariable analysis identified some positive associations between hours of television watching and risks of breast and colorectal cancer. However, further adjustment for additional lifestyle factors especially years of education attenuated these results. Future studies using objective measures of exposure can provide new insights into the possible role of sedentary behaviour in cancer development.

Blood lipids, lipid-regulatory medications, and risk of bladder cancer: a Mendelian randomization study.

The influences of blood lipids and lipid-regulatory medications on the risk of bladder cancer have long been suspected, and previous findings remain controversial. We aimed to assess the causality between blood lipids or lipid-regulatory medications and bladder cancer susceptibility by means of a comprehensive Mendelian Randomization (MR) study. Genetic proxies from genome-wide association studies (GWAS) of four blood lipid traits and lipid-lowering variants in genes encoding the targets of lipid-regulatory medications were employed. The largest ever GWAS data of blood lipids and bladder cancer involving up to 440,546 and 205,771 individuals of European ancestry were extracted from UK Biobank and FinnGen Project Round 6, respectively. A two-sample bidirectional MR study was performed using the inverse variance weighted as the main method. The heterogeneity, horizontal pleiotropy, MR Steiger, and leave-one-out analyses were also conducted as sensitivity tests. There was indicative evidence that genetically predicted low-density lipoprotein cholesterol (LDL-C) affected bladder cancer susceptibility based on 146 single nucleotide polymorphisms (SNPs) with an odds ratio (OR) of 0.776 (95% confidence interval [CI] = 0.625-0.965, p = 0.022). However, this result became non-significant after two SNPs that possibly drove the effect were removed as demonstrated by leave-one-out analysis. The reversed MR analysis suggested that bladder cancer could not affect serum lipid levels. No causal relationship was found between the lipid-lowering effect of lipid-regulatory medications (fibrates, probucol, statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, and evinacumab) and the risk of bladder cancer. No heterogeneity or pleiotropy was found (all p > 0.05). This MR study revealed for the first time, using the most recent and comprehensive GWAS data to date, that genetically predicted total cholesterol (TC) and the lipid-lowering effect of lipid-regulatory medications had no causal association with bladder cancer susceptibility. We also verified claims from early studies that low-density lipoprotein cholesterol (HDL-C), LDL-C, and triglyceride (TG) are not related to bladder cancer susceptibility either. The current study indicated that lipid metabolism may not be as important in the tumorigenesis of bladder cancer as previously believed.

DIGITAL CLOCK DRAWING PERFORMANCE ASSOCIATIONS WITH ALZHEIMER’S DISEASE GENETIC RISK SCORE AND APOE IN OLDER ADULTS

Abstract Alzheimer’s disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until clinical signs and symptoms are present. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker. We used two primary independent variables, Apolipoprotein E (APOE) ɛ4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures. We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White). PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed and Drawing Efficiency were significantly associated with higher PRS levels and more copies of APOE ε4. Associations displayed similar effect sizes in men and women. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

The genetics of Graves' disease.

Graves' disease (GD) is the commonest cause of hyperthyroidism and has a strong female preponderance. Everyday clinical practice suggests strong aggregation within families and twin studies demonstrate that genetic factors account for 60-80% of risk of developing GD. In this review, we collate numerous genetic studies and outline the discoveries over the years, starting with historic candidate gene studies and then exploring more recent genome-wide linkage and association studies, which have involved substantial cohorts of East Asian patients as well as those of European descent. Variants in genes including HLA, CTLA4, and PTPN22 have been shown to have substantial individual effects on disease susceptibility. In addition, we examine emerging evidence concerning the possibility that genetic variants may correlate with relevant clinical phenotypes including age of onset of GD, severity of thyrotoxicosis, goitre size and relapse of hyperthyroidism following antithyroid drug therapy, as well as thyroid eye disease. This review supports the inheritance of GD as a complex genetic trait, with a growing number of more than 80 susceptibility loci identified so far. Future implementation of more targeted clinical therapies requires larger studies investigating the influence of these genetic variants on the various phenotypes and different outcomes of conventional treatments.

Association between human blood metabolome and the risk of hypertension

Hypertension, commonly referred to as high blood pressure, is a chronic medical condition characterized by persistently elevated blood pressure levels. It is a prevalent global health issue, affecting a significant portion of the population worldwide. Hypertension is often asymptomatic, making it a silent but potentially dangerous condition if left untreated. Genetic instruments for 1,091 were from a recent comprehensive metabolome genome-wide association study (GWAS). Summary statistics of diastolic blood pressure (DBP) and systolic blood pressure (SBP) involving 757,601 sample size were analyzed. Two-sample Mendelian Randomization (MR) was conducted to assess causal effect of metabolites on DBP and SBP risk, and reverse MR analysis was performed to identify the DBP/SBP causal effect on blood metabolites. Twelve and twenty-two metabolites were identified to be associated with DBP and SBP, respectively. Sensitive analysis showed four metabolites had robustness association on BP. Reverse MR demonstrated DBP and SBP could decrease the tricosanoyl sphingomyelin (d18:1/23:0)* level and increase the 2-hydroxyhippurate (salicylurate) level in blood, respectively. Our findings reveal an association between blood metabolites and blood pressure (DBP and SBP), suggesting potential therapeutic targets for hypertension intervention.

The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction.

Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2, which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome. A mapre2 knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with MAPRE2 knockdown and knockout, respectively. Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential. Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel-related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.

Association between HNF4A rs1800961 polymorphisms and gallstones in a Taiwanese population.

A large genetic effect of a novel gallstone-associated genetic variant, the hepatocyte nuclear factor 4α (HNF4A) rs1800961 polymorphism, has been identified through recent genome-wide association studies. However, this effect has not been validated in Asian populations. We investigated the association between the rs1800961 variant and gallstones among a Taiwanese population. A total of 20405 participants aged between 30 and 70years voluntarily enrolled in the Taiwan Biobank. Self-report questionnaires, physical examinations, biochemical tests, and genotyping were used for analysis. The association of the HNF4A rs1800961 variant and other metabolic risks with gallstone disease was analyzed using multiple logistic regression models. The minor T allele of HNF4A rs1800961 was associated with an increased risk of gallstone, and the association remained significant even after adjustment for other risk factors including age, body mass index (BMI), diabetes, hyperlipidemia, hypertension, and cigarette smoking (adjusted odds ratio [OR]=1.90, 95% confidence interval [CI]=1.31 to 2.75) in male participants. When further stratified by BMI and age, the lithogenic effect was the most significant in male participants with obesity (adjusted OR=3.55, 95% CI=1.92 to 6.56) and who were younger (adjusted OR=2.45, 95% CI=1.49 to 4.04). The novel gallstone-associated HNF4A rs1800961 variant was associated with the risk of gallstone in the Taiwanese men. Screening for the rs1800961 polymorphism may be particularly useful in assessing the risk of gallstone formation in younger or obese men.

Identifying Genes Associated with Alzheimer's Disease Using Gene-Based Polygenic Risk Score.

Except APOE, Alzheimer's disease (AD) associated genes identified in recent large-scale genome-wide association studies (GWAS) had small effects and explained a small portion of heritability. Many AD-associated genes have even smaller effects thereby sub-threshold p-values in large-scale GWAS and remain to be identified. For some AD-associated genes, drug targeting them may have limited efficacies due to their small effect sizes. The purpose of this study is to identify AD-associated genes with sub-threshold p-values and prioritize drugs targeting AD-associated genes that have large efficacies. We developed a gene-based polygenic risk score (PRS) to identify AD genes. It was calculated using SNPs located within genes and having the same directions of effects in different study cohorts to exclude cohort-specific findings and false positives. Gene co-expression modules and protein-protein interaction networks were used to identify AD-associated genes that interact with multiple other genes, as drugs targeting them have large efficacies via co-regulation or interactions. Gene-based PRS identified 389 genes with 164 of them not previously reported as AD-associated. These 389 genes explained 56.12% -97.46% SNP heritability; and they were enriched in brain tissues and 164 biological processes, most of which are related to AD and other neurodegenerative diseases. We prioritized 688 drugs targeting 64 genes that were in the same co-expression modules and/or PPI networks. Gene-based PRS is a cost-effective way to identify AD-associated genes without substantially increasing the sample size. Co-expression modules and PPI networks can be used to identify drugs having large efficacies.

Causal relationships between susceptibility and severity of COVID-19 and neuromyelitis optica spectrum disorder (NMOSD) in European population: a bidirectional Mendelian randomized study.

Neurological disorders can be caused by viral infections. The association between viral infections and neuromyelitis optica spectrum disorder (NMOSD) has been well-documented for a long time, and this connection has recently come to attention with the occurrence of SARS-CoV-2 infection. However, the precise nature of the causal connection between NMOSD and COVID-19 infection remains uncertain. To investigate the causal relationship between COVID-19 and NMOSD, we utilized a two-sample Mendelian randomization (MR) approach. This analysis was based on the most extensive and recent genome-wide association study (GWAS) that included SARS-CoV-2 infection data (122616 cases and 2475240 controls), hospitalized COVID-19 data (32519 cases and 2062805 controls), and data on severe respiratory confirmed COVID-19 cases (13769 cases and 1072442 controls). Additionally, we incorporated a GWAS meta-analysis comprising 132 cases of AQP4-IgG-seropositive NMOSD (NMO-IgG+), 83 cases of AQP4-IgG-seronegative NMOSD (NMO-IgG-), and 1244 controls. The findings of our study indicate that the risk of developing NMO-IgG+ is elevated when there is a genetic predisposition to SARS-CoV-2 infection (OR = 5.512, 95% CI = 1.403-21.657, P = 0.014). Furthermore, patients with genetically predicted NMOSD did not exhibit any heightened susceptibility to SARS-CoV2 infection, COVID-19 hospitalization, or severity. our study using Mendelian randomization (MR) revealed, for the first time, that the presence of genetically predicted SARS-CoV2 infection was identified as a contributing factor for NMO-IgG+ relapses.

Genetic associations with neuropathological outcomes revealed a novel role in neuritic plaque formation

AbstractBackgroundNumerous genome‐wide association studies (GWASs) have been performed for the determination of genes and variants contributing to Alzheimer’s disease (AD). We hypothesized that it is important to explore whether the previously‐reported AD‐associated genes in GWASs can have neuropathological effects in the brain and can be employed as potential biomarkers for neuropathological outcomes such as neuritic plaque development. Neuritic plaques (also known as amyloid plaques) are extracellular deposits of the amyloid beta protein primarily found in the grey matter of the brain and are the most discernible neuropathological alterations observed in individuals with dementia.MethodHere, we report the genetic association study of neuropathology data such as neuritic plaque measurements in an AD cohort at the National Alzheimer’s Coordinating Center (NACC) using a sample of 1,283 individuals. We acquired the genetic data from the Alzheimer’s Disease Sequencing Project (ADSP) which generated whole genome sequencing data through the ADSP Quality Control pipeline. We employed 18 loci where the associations of these loci with AD risk were validated by the recent GWASs. Analysis was obtained using a linear mixed model after adjustment for covariates including age at death, gender, the number of the APOE e4 allele (i.e., 0, 1, and 2), ancestry representative principle components (i.e., population structure), and a genetic relatedness matrix (i.e., a polygenic effect due to genetic relatedness among individuals).ResultFrom our analysis, we generalized to the NACC cohort significant associations after Bonferroni correction with neuritic plaque measurements and one previously identified locus such as BIN1 on chromosome 2 (p = 4.65×10−5). Furthermore, we detected, at the significance level after Bonferroni correction, a novel locus for neuritic plaque formation that has not previously been reported: PICALM (or nearby LINC02695 or nearby RNU6‐560P) on chromosome 11 (p = 1.02×10−3). PICALM is a strong candidate for playing a role in neuritic plaque formation because deficiency in PICALM results in diminished amyloid‐β clearance.ConclusionThe results from our genetic association study of neuritic plaque formation in the AD cohort underline the potential of utilizing neuropathology data to discover additional support for relevant loci being associated with AD across diverse populations.

Age-dependent genetic regulation of osteoarthritis: independent effects of immune system genes

ObjectivesOsteoarthritis (OA) is a joint disease with a heritable component. Genetic loci identified via genome-wide association studies (GWAS) account for an estimated 26.3% of the disease trait variance in humans. Currently, there is no method for predicting the onset or progression of OA. We describe the first use of the Collaborative Cross (CC), a powerful genetic resource, to investigate knee OA in mice, with follow-up targeted multi-omics analysis of homologous regions of the human genome.MethodsWe histologically screened 275 mice for knee OA and conducted quantitative trait locus (QTL) mapping in the complete cohort (> 8 months) and the younger onset sub-cohort (8–12 months). Multi-omic analysis of human genetic datasets was conducted to investigate significant loci.ResultsWe observed a range of OA phenotypes. QTL mapping identified a genome-wide significant locus on mouse chromosome 19 containing Glis3, the human equivalent of which has been identified as associated with OA in recent GWAS. Mapping the younger onset sub-cohort identified a genome-wide significant locus on chromosome 17. Multi-omic analysis of the homologous region of the human genome (6p21.32) indicated the presence of pleiotropic effects on the expression of the HLA − DPB2 gene and knee OA development risk, potentially mediated through the effects on DNA methylation.ConclusionsThe significant associations at the 6p21.32 locus in human datasets highlight the value of the CC model of spontaneous OA that we have developed and lend support for an immune role in the disease. Our results in mice also add to the accumulating evidence of a role for Glis3 in OA.

Linking Prenatal Environmental Exposures to Lifetime Health with Epigenome-Wide Association Studies: State-of-the-Science Review and Future Recommendations.

The prenatal environment influences lifetime health; epigenetic mechanisms likely predominate. In 2016, the first international consortium paper on cigarette smoking during pregnancy and offspring DNA methylation identified extensive, reproducible exposure signals. This finding raised expectations for epigenome-wide association studies (EWAS) of other exposures. We review the current state-of-the-science for DNA methylation associations across prenatal exposures in humans and provide future recommendations. We reviewed 134 prenatal environmental EWAS of DNA methylation in newborns, focusing on 51 epidemiological studies with meta-analysis or replication testing. Exposures spanned cigarette smoking, alcohol consumption, air pollution, dietary factors, psychosocial stress, metals, other chemicals, and other exogenous factors. Of the reproducible DNA methylation signatures, we examined implementation as exposure biomarkers. Only 19 (14%) of these prenatal EWAS were conducted in cohorts of 1,000 or more individuals, reflecting the still early stage of the field. To date, the largest perinatal EWAS sample size was 6,685 participants. For comparison, the most recent genome-wide association study for birth weight included more than 300,000 individuals. Replication, at some level, was successful with exposures to cigarette smoking, folate, dietary glycemic index, particulate matter with aerodynamic diameter and , nitrogen dioxide, mercury, cadmium, arsenic, electronic waste, PFAS, and DDT. Reproducible effects of a more limited set of prenatal exposures (smoking, folate) enabled robust methylation biomarker creation. Current evidence demonstrates the scientific premise for reproducible DNA methylation exposure signatures. Better powered EWAS could identify signatures across many exposures and enable comprehensive biomarker development. Whether methylation biomarkers of exposures themselves cause health effects remains unclear. We expect that larger EWAS with enhanced coverage of epigenome and exposome, along with improved single-cell technologies and evolving methods for integrative multi-omics analyses and causal inference, will expand mechanistic understanding of causal links between environmental exposures, the epigenome, and health outcomes throughout the life course. https://doi.org/10.1289/EHP12956.