UK Biobank Genome-wide Association Study Research Articles

Polygenic Risk Scores and Hearing Loss Phenotypes in Children

Monogenic causes of childhood hearing loss are well established, as are polygenic risk contributions to age-related hearing loss. However, an untested possibility is that polygenic risk scores (PRS) also contribute to childhood hearing loss of all severities, alongside environmental and/or monogenic causes. To examine the association between a PRS for adult hearing loss and childhood hearing loss phenotypes. This cross-sectional study used a unique population-based dataset spanning normal hearing to profound loss, combining 2 contemporaneous population cohorts in Australia. This included the Child Health CheckPoint, a national population-based cross-sectional study nested within the Longitudinal Study of Australian Children, and the Victorian Childhood Hearing Longitudinal Databank (VicCHILD), a statewide population-based longitudinal data bank open to every child with congenital hearing loss in Victoria, Australia. The analysis took place from March to August 2023. Genotype data were generated from saliva- or blood-derived DNA using global single-nucleotide variations arrays. Based on genotype data, PRS was computed using published UK Biobank genome-wide association study results for self-reported hearing difficulty in individuals aged 40 to 69 years. Hearing outcomes were classified by laterality (bilateral, unilateral), severity (mild, moderate, severe or worse) and types (sensorineural, conductive, mixed, auditory neuropathy, atresia). Analyses included multinominal logistic regressions of PRS with hearing outcomes. Overall, 1488 CheckPoint study children (49.8% boys, aged 11-12 years) and 527 VicCHILD study children (55.2% boys, aged 0-13 years) with hearing and genotype data were included. A 1-SD increment in PRS was associated with higher odds of mild (odds ratio [OR], 1.3; 95% CI, 1.0-1.6), moderate (OR, 5.1; 95% CI, 3.2-8.1), and severe or worse (OR, 5.3; 95% CI, 3.9-7.3) unilateral hearing loss compared with normal hearing. Similarly, the PRS was associated with increased odds of mild, moderate, and severe or worse bilateral hearing loss (per-SD ORs, 3.9-6.6) and all hearing loss types (per-SD ORs, 8.5-10.6). In this cross-sectional study, a PRS initially developed for adult hearing difficulty was associated with wide-ranging childhood hearing loss phenotypes, partly explaining hearing phenotype variations despite shared genetic and environmental factors (eg, preterm birth). Large-scale studies with objectively defined hearing phenotypes are crucial for refining PRS and predicting high-risk children.

A genome-wide association study of adults with community-acquired pneumonia

BackgroundCommunity-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS).MethodsWe performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted.ResultsSix independent sentinel variants reached the genome-wide significance (p < 5 × 10-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles.ConclusionsWe completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.

Association Between Arterial Stiffness Index and Age-Related Diseases: A Mendelian Randomization Study.

Arterial stiffness is an emerging indicator of cardiovascular risk, but its causal relationship with a variety of age-related diseases is unclear. The objective is to assess the causal relationship between arterial stiffness index (ASI) and age-related diseases by Mendelian randomization (MR) analysis. We obtained instrumental variables associated with age-related diseases from genome-wide association studies (GWAS) of 484,598 European individuals, and data for ASI were obtained from the UK Biobank GWAS of 127,127 participants. We used the inverse variance-weighted as the primary analysis method. In addition, several sensitivity analyses including MR-Egger, weighted-median (WM), Mendelian randomization pleiotropy residual sum and outlier, and Cochran's Q test were performed to test the robustness of the results. Reverse MR analysis was also performed to assess reverse causal relationships between age-related diseases and ASI. We verified the causal relationship between eight age-related diseases and ASI, of which cardiovascular disease (β = 0.19), gallbladder disease (β = 0.85), liver, biliary, or pancreas problem (β = 1.02), hypertension (β = 0.19), joint disorder (β = 0.53), and esophageal disorder (β = 2.10) elevated ASI. In contrast, hyperthyroidism or thyrotoxicosis (β = -2.17) and bowel problems (β = -1.83) may reduce ASI. This MR analysis reveals causal relationships between ASI and several age-related diseases. ASI is expected to be a potential indicator of health conditions for older populations.

Association of Walking Pace and Risk of Stroke: A Two- Sample Mendelian Randomization Study in a European Ancestry Cohort.

Walking pace (WP), a simple physiological indicator, has been found to be strongly associated with a variety of health outcomes in recent years. Among them, the relationship between walking pace and stroke is of particular interest. Given the high morbidity, disability and mortality associated with stroke, identifying modifiable indicators of health, such as walking pace, could help in stroke prevention strategies. However, the causal relationship between WP and stroke risk remains unclear. This study aims to determine the causal relationship between walking pace and risk of stroke using a two-sample Mendelian randomization approach in a European-ancestry population. In order to evaluate the potential for a causal relationship between WP and stroke in people of European heritage, a two-sample Mendelian randomization (MR) study was carried out. Statistics about the association of single nucleotide polymorphisms (SNPs) with stroke were taken from FinnGen (R8) (n = 284,040), while the UK Biobank genome-wide association studies (GWAS) provided the summary data on the association of SNPs with WP (n = 459,915). The inverse-variance weighted (IVW) method was utilised as the primary strategy to examine the causal connection between WP and stroke. Additionally, complementary analyses were conducted using the MR-Egger and weighted median. In order to identify the potential directional pleiotropy and heterogeneity, the MR-Egger intercept test, the MR-PRESSO test, and Cochran's Q statistic were all carried out. This connection was evaluated using OR with 95% confidence intervals (CIs). A total of 48 SNPs were identified as valid instrumental variables in our two-sample MR analysis. The result showed that a slower walking pace is associated with a higher risk of stroke (OR = 0.573; 95% CI, 0.383-0.858, P = 0.007). The "leave-one-out" analysis demonstrated that the absence of a single SNP did not affect the robustness of our results. The MR-Egger intercept test indicated that genetic pleiotropy did not introduce bias into the results [intercept = -2.9E-03, SE = 0.008, P = 0.719] and Cochran's Q test revealed no heterogeneity. Therefore, the sensitivity analyses yielded comparable results. Consequently, the results of the sensitivity analyses were consistent. Our MR study revealed that WP is inversely associated with risk of stroke. These results provided evidence that slower WP causally increased the risk of stroke, recommending that patients with lower WP should have a prompt physical examination and targeted interventions to reduce their risk of stroke and enhance their quality of life.

Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study.

Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes. As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively. In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes. Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions.

Abstract P322: Assessing the causal associations of obstructive sleep apnea syndrome and hypertension: a bidirectional two-sample Mendelian randomization study

Background: Obstructive sleep apnea syndrome (OSA) frequently coexists with hypertension, with 30% to 70% of OSA patients also having hypertension. Conversely, the incidence of OSA in hypertensive patients ranges from 30% to 50%. This study designs a bidirectional Mendelian randomization trial to explore the causal relationship between OSA and hypertension. Methods: The summary data for OSA were sourced from a recent large-scale genome-wide association study (GWAS) meta-analysis, which included 16,761 OSA patients and 201,194 European-ancestry controls from the Finnish biobank. Five SNPs were selected as instrumental variables (IVs) for OSA. The summary data for hypertension were obtained from the UK Biobank GWAS, which included 124,227 hypertension patients and 337,653 European-ancestry controls, making it the largest hypertension dataset in GWAS. From this dataset, 214 SNPs were selected as IVs for hypertension. Multiple MR methods, primarily the inverse variance weighted (IVW) method, were used for analysis. Sensitivity analyses of the MR results were performed using methods such as MR-Egger, and the F-statistic was used to evaluate the IVs. Results: OSA was associated with an increased risk of hypertension (OR=1.053, 95%CI 1.019-1.089, P&lt;0.01), and hypertension was significantly associated with an increased risk of OSA (OR=1.812, 95%CI 1.354-2.425, P&lt;0.001). There was heterogeneity in the bidirectional results (OSA → hypertension, P&lt;0.001; hypertension → OSA, P&lt;0.001), but no horizontal pleiotropy (OSA → hypertension, P=0.666; hypertension → OSA, P=0.556). The selected IVs for OSA and hypertension were strong (OSA-IVs F=14.695; hypertension-IVs F=39.624). Conclusion: This bidirectional MR analysis confirms the causal relationship between OSA and hypertension, with hypertension having a more pronounced effect on the incidence of OSA. OSA patients should regularly monitor their blood pressure and undergo routine physical examinations to detect hypertension early.

Effects of genetically proxied statins on diabetic nephropathy and retinopathy: a Mendelian randomization study

There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = − 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative.

Single nucleus RNA-sequencing integrated into risk variant colocalization discovers 17 cell-type-specific abdominal obesity genes for metabolic dysfunction-associated steatotic liver disease

Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD). To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants. We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue. Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis. NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki.

Physical activity and the osteoarthritis of the knee: A Mendelian randomization study.

Previous studies have reported an association between physical activity and the occurrence and progression of knee osteoarthritis (KOA). However, the existing evidence remains limited and of low-quality. This study aimed to examine the causal relationship between different levels of physical activity and KOA. Instrumental variables, represented by single nucleotide polymorphisms (SNPs), were utilized to capture sedentary behavior, appropriate physical exercise, and excessive physical activity. Aggregated statistics from the UK Biobank genome-wide association study dataset were used to assess the impact of these SNPs on KOA. Causality was estimated using inverse variance weighting (IVW), MR Egger, simple model, weighted median, and weighted model approaches. The stability of the results was assessed through heterogeneity and sensitivity analyses. Mendelian randomization (MR) analysis revealed a strong association between sedentary behavior and KOA, with an odds ratio (OR) of 2.096 (95% CI: 1.506-2.917) and a P value of 1.14 × 10-5. Appropriate physical exercise behavior exhibited a strong negative association with KOA, with an OR of 0.147 (95% CI: 0.037-0.582) and a P value of 0.006. Conversely, excessive physical activity behavior showed a significant positive association with KOA, with an OR of 2.162 (95% CI: 1.327-3.521) and a P value of .002. Our findings indicate that sedentary behavior and excessive physical activity are identified as risk factors for KOA, whereas engaging in appropriate physical exercise emerges as a protective factor against the development of KOA.

Unsupervised deep representation learning enables phenotype discovery for genetic association studies of brain imaging

Understanding the genetic architecture of brain structure is challenging, partly due to difficulties in designing robust, non-biased descriptors of brain morphology. Until recently, brain measures for genome-wide association studies (GWAS) consisted of traditionally expert-defined or software-derived image-derived phenotypes (IDPs) that are often based on theoretical preconceptions or computed from limited amounts of data. Here, we present an approach to derive brain imaging phenotypes using unsupervised deep representation learning. We train a 3-D convolutional autoencoder model with reconstruction loss on 6130 UK Biobank (UKBB) participants’ T1 or T2-FLAIR (T2) brain MRIs to create a 128-dimensional representation known as Unsupervised Deep learning derived Imaging Phenotypes (UDIPs). GWAS of these UDIPs in held-out UKBB subjects (n = 22,880 discovery and n = 12,359/11,265 replication cohorts for T1/T2) identified 9457 significant SNPs organized into 97 independent genetic loci of which 60 loci were replicated. Twenty-six loci were not reported in earlier T1 and T2 IDP-based UK Biobank GWAS. We developed a perturbation-based decoder interpretation approach to show that these loci are associated with UDIPs mapped to multiple relevant brain regions. Our results established unsupervised deep learning can derive robust, unbiased, heritable, and interpretable brain imaging phenotypes.

Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment.

Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Loci in/near discs large homolog 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P < 5 × 10-8) for BF% and/or BMI. To further evaluate the functional role of postsynaptic density protein-95 (PSD-95; gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PSD-95/disc large/ZO-1 (PDZ) domain-targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising therapeutic avenue for sustained weight loss.

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.

Anxiety disorder and cardiovascular disease: a two-sample Mendelian randomization study.

Cardiovascular disease is the leading cause of death worldwide. Anxiety disorders are common psychiatric conditions associated with cardiovascular outcomes. This two-sample Mendelian randomization (MR) study investigated the causal relationship between anxiety disorders and coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). Single nucleotide polymorphisms (SNPs) associated with anxiety disorders (16730 cases; 101021 controls) were obtained from the UK Biobank genome-wide association study (GWAS). Cardiovascular outcome data were derived from the FinnGen study (CHD: 21012 cases and 197780 controls; MI: 12801 cases and 187840 controls; HF: 23397 cases and 194811 controls; and AF: 22068 cases and 116926 controls). Inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode analyses examined causality. IVW analysis demonstrated significant causal relationships between anxiety disorders and increased risk of CHD [odds ratio (OR): 4.496; 95% confidence interval (CI): 1.777-11.378; P=0.002], MI (OR: 5.042; 95% CI: 1.451-17.518; P=0.011), and HF (OR: 3.255; 95% CI: 1.461-7.252; P=0.004). No relationship was observed with AF (OR: 1.775; 95% CI: 0.612-5.146; P=0.29). Other methods showed non-significant associations. Two-way analysis indicated no reverse causality. Anxiety disorders were causally associated with greater risk of CHD, MI, and HF but not AF among individuals of European descent. Further research on mediating mechanisms and in diverse populations is warranted.

Principal and independent genomic components of brain structure and function.

The highly polygenic and pleiotropic nature of behavioural traits, psychiatric disorders and structural and functional brain phenotypes complicate mechanistic interpretation of related genome-wide association study (GWAS) signals, thereby obscuring underlying causal biological processes. We propose genomic principal and independent component analysis (PCA, ICA) to decompose a large set of univariate GWAS statistics of multimodal brain traits into more interpretable latent genomic components. Here we introduce and evaluate this novel methods various analytic parameters and reproducibility across independent samples. Two UK Biobank GWAS summary statistic releases of 2240 imaging-derived phenotypes (IDPs) were retrieved. Genome-wide beta-values and their corresponding standard-error scaled z-values were decomposed using genomic PCA/ICA. We evaluated variance explained at multiple dimensions up to 200. We tested the inter-sample reproducibility of output of dimensions 5, 10, 25 and 50. Reproducibility statistics of the respective univariate GWAS served as benchmarks. Reproducibility of 10-dimensional PCs and ICs showed the best trade-off between model complexity and robustness and variance explained (PCs: |rz - max| = 0.33, |rraw - max| = 0.30; ICs: |rz - max| = 0.23, |rraw - max| = 0.19). Genomic PC and IC reproducibility improved substantially relative to mean univariate GWAS reproducibility up to dimension 10. Genomic components clustered along neuroimaging modalities. Our results indicate that genomic PCA and ICA decompose genetic effects on IDPs from GWAS statistics with high reproducibility by taking advantage of the inherent pleiotropic patterns. These findings encourage further applications of genomic PCA and ICA as fully data-driven methods to effectively reduce the dimensionality, enhance the signal to noise ratio and improve interpretability of high-dimensional multitrait genome-wide analyses.

Gut microbiota as a residual risk factor causally influencing cardiac structure and function: Mendelian randomization analysis and biological annotation.

The gut microbiota (GM) is widely acknowledged to have a significant impact on cardiovascular health and may act as a residual risk factor affecting cardiac structure and function. However, the causal relationship between GM and cardiac structure and function remains unclear. This study aims to employ a two-sample Mendelian randomization (MR) approach to investigate the causal association between GM and cardiac structure and function. Data on 119 GM genera were sourced from a genome-wide association study (GWAS) meta-analysis (13,266 European participants) conducted by the MiBioGen consortium, while data on 16 parameters of cardiac structure and function were obtained from the UK Biobank's GWAS of cardiac magnetic resonance imaging (up to 41,135 European participants). Inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods were utilized for causal association assessments, with sensitivity analyses conducted to reinforce the findings. Finally, biological annotation was performed on the GWAS data of GM and cardiac phenotypes with causal associations to explore potential mechanisms. The MR analysis, predominantly based on the IVW model, revealed 93 causal associations between the genetically predicted abundance of 44 GM genera and 16 cardiac structure and function parameters. These associations maintained consistent directions in MR-Egger and WM models, with no evidence of pleiotropy detected. Biological annotations suggest that GM may influence cardiac structure and function through pathways involved in myocardial cell development, cardiac contractility, and apoptosis. The MR analysis supports a causal association between certain abundances of genetically predicted GM and cardiac structure and function, suggesting that GM could be a residual risk factor impacting cardiac phenotypes.

Uncovering myocardial infarction genetic signatures using GWAS exploration in Saudi and European cohorts

Genome-wide association studies (GWAS) have yielded significant insights into the genetic architecture of myocardial infarction (MI), although studies in non-European populations are still lacking. Saudi Arabian cohorts offer an opportunity to discover novel genetic variants impacting disease risk due to a high rate of consanguinity. Genome-wide genotyping (GWG), imputation and GWAS followed by meta-analysis were performed based on two independent Saudi Arabian studies comprising 3950 MI patients and 2324 non-MI controls. Meta-analyses were then performed with these two Saudi MI studies and the CardioGRAMplusC4D and UK BioBank GWAS as controls. Meta-analyses of the two Saudi MI studies resulted in 17 SNPs with genome-wide significance. Meta-analyses of all 4 studies revealed 66 loci with genome-wide significance levels of p < 5 × 10–8. All of these variants, except rs2764203, have previously been reported as MI-associated loci or to have high linkage disequilibrium with known loci. One SNP association in Shisa family member 5 (SHISA5) (rs11707229) was evident at a much higher frequency in the Saudi MI populations (> 12% MAF). In conclusion, our results replicated many MI associations, whereas in Saudi-only GWAS (meta-analyses), several new loci were implicated that require future validation and functional analyses.

Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system

The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.

Investigating the Impact of Sun/UV Protection and Ease of Skin Tanning on the Risk of Pseudoexfoliation Glaucoma: A Mendelian Randomization Study.

To investigate the potential causal associations between the use of sun/ultraviolet (UV) protection and ease of skin tanning and the risk of pseudoexfoliation glaucoma (PXG) in European populations. Single nucleotide polymorphisms (SNPs) associated with the use of sun/UV protection and ease of skin tanning were selected from the UK Biobank genome-wide association study database consisting of 498,751 European participants. SNPs of PXG were obtained from the FinnGen study including 3424 PXG cases and 326,434 controls. Two-sample Mendelian randomization (MR) analyses were performed to assess the association between the use of sun/UV protection and ease of skin tanning and risk of PXG. Inverse variance weighted regression of genetic susceptibility predicted that both use of sun/UV protection and ease of skin tanning were potentially positively associated with the decreased risk of PXG in the European ancestry (use of sun/UV protection: odds ratio [OR] = 0.47; 95% confidence interval [CI], 0.24-0.92; P = 0.028; ease of skin tanning: OR = 0.81; 95% CI, 0.67-0.97; P = 0.025). We found genetic evidence supporting a potential causal association between UV protection and a decreased risk of PXG in European population. Further research will help elucidate the underlying mechanisms and promote UV protection for eyes, especially in people with a high risk of PXG.

THE ASSOCIATION BETWEEN BLOOD PRESSURE VARIABILITY AND DEMENTIA: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY

Objective: This study aims to investigate the causal inference by applying a mendelian randomization (MR) study using single-nucleotide polymorphisms (SNPs) from the genome-wide association study (GWAS) based on the UK biobank. Design and method: The genetic instruments were chosen from BPV GWAS based on UK Biobank data. Four GWA studies were used for the genetic evaluation of dementia, including (1) The International Genomic of Alzheimer's Project (IGAP) GWAS for dementia; (2) and (3) UK Biobank GWAS for proxy phenotypes of Alzheimer's dementia: the maternal and paternal family history (MFH and PFH-UKBB); (4) A combined GWAS meta-analysis from the abovementioned three GWAS results. The following exclusion criteria were applied for SNPs: (1) confounding SNPs by searching hypertension and artery stiffness GWAS; (2) significant SNPs that are associated with dementia in the datasets; (3) palindromic SNPs with an effect allele frequency between 0.4 and 0.7. Proxy SNPs were manually selected for some SNPs. (4) only SNPs with linkage disequilibrium r2 &lt; 0.01 were selected as genetic instruments, also known as independent SNPs. The effect/reference alleles were checked to ensure the consistency of the base pair between BPV and dementia GWAS, which is also known as data harmonization. After data harmonization, four MR methods were employed to measure the causal effect: IVW-MR with random effect, IVW-MR with fixed effect, MR-Egger, and weighted median MR. Results: Finally, six independent SNPs were chosen as instrument variants for SBPV, and five for DBPV. Significant causal effects of SBPV on dementia were found in the PFH-UKBB dataset, and the odds ratio of dementia per 10-unit increase in SBPV was 1.028, 1.015, and 1.015 for MR-Egger, weighted median, and IVW-MR, respectively (Table 1). In contrast, only one significant result was found for DBPV in MFH-UKBB. No significant results were found on other datasets. Conclusions: Along with the evidence from different observational studies, this GWAS study demonstrates that systolic blood pressure variability is a potential causal risk factor for Alzheimer's dementia, while the evidence from diastolic blood pressure variability is still uncertain.

Genetic basis of STEM occupational choice and regional economic performance: a UK biobank genome-wide association study

BackgroundScience, technology, engineering, and mathematics (STEM) professionals are regarded as the highly skilled labor force that fosters economic productivity, enterprise innovation, and international competitiveness of a country. This study aims to understand the genetic predisposition to STEM occupations and investigate its associations with regional economic performance. We conducted a genome-wide association study on the occupational choice of STEM jobs based on a sample of 178,976 participants from the UK Biobank database.ResultsWe identified two genetic loci significantly associated with participants’ STEM job choices: rs10048736 on chromosome 2 and rs12903858 on chromosome 15. The SNP heritability of STEM occupations was estimated to be 4.2%. We also found phenotypic and genetic evidence of assortative mating in STEM occupations. At the local authority level, we found that the average polygenic score of STEM is significantly and robustly associated with several metrics of regional economic performance.ConclusionsThe current study expands our knowledge of the genetic basis of occupational choice and potential regional disparities in socioeconomic developments.