Recent Genome-wide Association Studies Research Articles

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.

Distilling causality between physical activity traits and obesity via Mendelian randomization

BackgroundWhether obesity is a cause or consequence of low physical activity levels and more sedentary time has not yet been fully elucidated. Better instrumental variables and a more thorough consideration of potential confounding variables that may influence the causal inference between physical activity and obesity are needed.MethodsLeveraging results from our recent genome-wide association study for leisure time moderate-to-vigorous intensity (MV) physical activity and screen time, we here disentangle the causal relationships between physical activity, sedentary behavior, education—defined by years of schooling—and body mass index (BMI), using multiple univariable and multivariable Mendelian Randomization (MR) approaches.ResultsUnivariable MR analyses suggest bidirectional causal effects of physical activity and sedentary behavior with BMI. However, multivariable MR analyses that take years of schooling into account suggest that more MV physical activity causes a lower BMI, and a higher BMI causes more screen time, but not vice versa. In addition, more years of schooling causes higher levels of MV physical activity, less screen time, and lower BMI.ConclusionsIn conclusion, our results highlight the beneficial effect of education on improved health and suggest that a more physically active lifestyle leads to lower BMI, while sedentary behavior is a consequence of higher BMI.

Causal effect of systemic lupus erythematosus on psychiatric disorders: A two-sample Mendelian randomization study

BackgroundThis study aims to investigate the association between systemic lupus erythematosus (SLE) and the risk of seven psychiatric disorders through the application of Mendelian randomization (MR) analysis due to previous observational studies that have suggested a potential link between SLE and psychiatric disorders. MethodsWe collected genetic instruments for SLE from a genome-wide association study (GWAS) involving 23,210 individuals. Seven psychiatric traits were enrolled from the recent largest GWAS, including major depression disorder (MDD), generalized anxiety disorder (GAD), schizophrenia (SCZ), bipolar disorder (BID), autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and insomnia. Summary statistics for psychiatric disorders were obtained from different GWAS meta-analysis studies. The inverse variance weighted (IVW) method was used as the main MR analysis. ResultsThe IVW method indicated that SLE is associated with a higher risk of GAD (OR = 1.072, 95 % CI [1.017–1.129], P = 0.008) and SCZ (OR = 3.242, 95 % CI [1.578–6.660], P = 0.007). However, no evidence was found for the causal associations between SLE and other psychiatric disorders. Further analyses found no evidence of pleiotropy and heterogeneity. ConclusionsThis two-sample MR analysis provides evidence that genetically predicted SLE may increase the risk of GAD and SCZ in a European population. Future studies are needed to elucidate and investigate the mechanisms underlying these causal relationships. Considering the existence of racial genomic heterogeneity, our findings must be viewed with caution.

Exploring the association between air pollution and Parkinson's disease or Alzheimer's disease: a Mendelian randomization study.

The correlation between air pollution and neurodegenerative diseases has garnered growing attention. Although observational studies have indicated a potential link between air pollution and neurodegenerative disease, establishing a causal relationship remains uncertain. To address this gap, we performed a two-sample Mendelian randomization analysis utilizing genetic instruments. This analysis aimed to investigate the causal connections between PM2.5, PM10, NO2, and NOX exposure and the occurrence of Parkinson's disease (PD) and Alzheimer's disease (AD). We implemented a series of filtering steps to identify suitable genetic instruments that demonstrated significant associations (P < 5 × 10-8) with PM2.5, PM10, NO2, and NOX. These instruments were derived from a comprehensive genome-wide association study (GWAS) encompassing up to 456,380 participants in the UK Biobank. To obtain summary statistics for PD (N = 482,730) and AD risk (N = 63,926), we utilized the most recent GWAS datasets available. For our primary analysis, we employed the inverse-variance weighted approach for two-sample MR. A multivariable MR (MVMR) was also performed to verify the impact of air pollution exposure on the risk of PD and AD. To ensure the robustness of our findings, sensitivity analyses and heterogeneity assessments were performed. In two-sample MR, by employing the inverse-variance weighted method, our result suggested that genetically NO2 exposure showed a significant association with an elevated risk of PD (OR = 4.07, 95% CI: 1.13 to 19.62, P = 0.034) and genetically PM10 exposure exhibited a significant association with a heightened risk of AD (OR = 1.93, 95% CI: 1.03-3.59, P = 0.040). Further MVMR analysis demonstrated that the causal effect between NO2 and PD disappeared (OR = 3.489, 95% CI: 0.01 to 2.1e + 03, P = 0.703), and only PM10 was associated with an increased risk of AD (OR = 6.500, 95% CI: 1.10 to 38.51, P = 0.039). Sensitivity analysis showed no detectable heterogeneity and pleiotropy (P > 0.05). Our findings demonstrate that NO2 and PM10 exposure may contribute to a risk of PD and AD, respectively. Future research is necessary to elucidate potential physiopathological mechanisms.

Polygenic risk scores for Alzheimer's disease in relation to cognitive change: A representative sample from the general population followed over 16 years.

BackgroundPolygenic risk scores for Alzheimer's disease (AD-PRSs) have been associated with cognition. However, few studies have examined the effect of AD-PRS beyond the APOE gene, and the influence of genetic variants related to level of cognitive ability (COG-PRS) on cognitive performance over time in the general older population. MethodA population-based sample of 965 individuals born in 1930, with genetic and standardized cognitive data on six psychometric tests (Thurstone's picture memory, immediate recall of 10 words, Block design, word fluency, figure identification, delayed recall of 12 items), were examined at age 70, 75, 79, and 85 years. Non-APOE AD-PRSs and COG-PRSs (P < 5e−8, P < 1e−5, P < 1e−3, P < 1e−1) were generated from recent genome-wide association studies. Linear mixed effect models with random intercepts and slope were used to analyze the effect of APOE ε4 allele, AD-PRSs, and COG-PRSs, on cognitive performance and rate of change. Analyses were repeated in samples excluding dementia. ResultsAPOE ε4 and AD-PRS predicted change in cognitive performance (APOE ε4*age: β = −0.03, P < 0.0001 and AD-PRS *age: β = −0.01, P = 0.02). The results remained similar in the sample excluding those with dementia. COG-PRS predicted level of cognitive performance, while APOE ε4 and AD-PRS did not. COG-PRSs did not predict change in cognitive performance. ConclusionWe found that genetic predisposition of AD predicted cognitive decline among 70-year-olds followed over 16 years, regardless of dementia status, while polygenic risk for general cognitive performance did not.

Microbiome and Genetic Factors in the Pathogenesis of Liver Diseases

Our genetic background has not changed over the past century, but chronic diseases are on the rise globally. In addition to the genetic component, among the critical factors for many diseases are inhabitants of our intestines (gut microbiota) as a crucial environmental factor. Dysbiosis has been described in liver diseases with different etiologies like non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), viral hepatitis, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, hepatocellular carcinoma (HCC). On the other hand, new technologies have increased our understanding of liver disease genetics and treatment options. Genome-wide association studies (GWAS) identify unknown genetic risk factors, positional cloning of unknown genes associated with different diseases, gene tests for single nucleotide variations (SNVs), and next-generation sequencing (NGS) of selected genes or the complete genome. NGS also allowed studying the microbiome and its role in various liver diseases has begun. These genes have proven their effect on microbiome composition in host genome–microbiome association studies. We focus on altering the intestinal microbiota, and supplementing some bacterial metabolites could be considered a potential therapeutic strategy. The literature data promote probiotics/synbiotics role in reducing proinflammatory cytokines such as TNF-α and the interleukins (IL-1, IL-6, IL-8), therefore improving transaminase levels, hepatic steatosis, and NAFLD activity score. However, even though microbial therapy appears to be risk-free, evaluating side effects related to probiotics or synbiotics is imperative. In addition, safety profiles for long-term usage should be researched. Thus, this review focuses on the human microbiome and liver diseases, recent GWASs on liver disease, the gut-liver axis, and the associations with the microbiome and microbiome during/after liver disease therapy.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan

Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

A genetic and transcriptomic assessment of the KTN1 gene in Parkinson’s disease risk

Parkinson’s disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson’s Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to unaffected individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

Polygenic risk score for hypertrophic cardiomyopathy predicts population disease risk, penetrance in sarcomeric rare variant carriers and survival in cases

Abstract Background Hypertrophic cardiomyopathy (HCM) is an important cause of mortality, caused by rare pathogenic variants (sarcomere-positive) in around one third of cases. Recent large genome-wide association studies (GWAS) highlight the important contributions of common genetic variation on HCM risk and heritability1-3. Polygenic scores (PGS) quantify the cumulative individual risk from common genetic variation, and may provide important clinical utility. Purpose The aim of this study is to generate PGS for HCM, and evaluate its performance in predicting HCM in the general population, HCM penetrance in sarcomere-positive carriers, and risk of adverse outcomes in individuals with HCM. Methods The PGS was generated using a Bayesian framework (PRS-CS) with individual SNP effect estimates derived from the largest published HCM GWAS (5900 cases and 68359 controls of European ancestry from 7 cohorts) and multi-trait analysis of GWAS (MTAG) (incorporating GWAS of genetically correlated cardiac magnetic resonance imaging (CMR) traits from 36203 White British individuals in the UK Biobank [UKB])1. Genome-wide PGS were calculated using an additive model for participants in two cohorts (UKB and 100,000 Genomes Project [GeL]). To evaluate the effect of PGS on penetrant HCM in sarcomere-positive carriers, we identified individuals with pathogenic or likely pathogenic variants in 8 definitive HCM-causing genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL3, and MYL2) in UKB and GeL. Results In 343,182 unrelated White British ancestry participants from the UK Biobank (UKB), PGS was associated with an increased risk of HCM (OR per PGS SD 2.3, P&amp;lt;2x10-16), with 75% of HCM cases having a PGS above the population mean (Figure 1A). Individuals with PGS in the top centile had a substantially increased risk of HCM compared with those in the median (OR 14.5, P&amp;lt;2x10-16) and bottom centile (OR 36.6, 3x10-25) (Figure 1B). PGS had significant effects on stratifying HCM penetrance in 640 sarcomere-positive carriers in the UKB (top vs. middle quintile HCM OR: 3.7, P 0.009), and risk of being a HCM case in 599 sarcomere-positive carriers in GeL (top vs. middle quintile HCM OR 9.5, P 4x10-5) (Figure 1C), highlighting the important interactive effect of common and rare genetic variants. Finally, PGS predicted risk of all-cause mortality and major adverse cardiovascular events (MACE) after HCM diagnosis in 382 cases in UKB (all-cause mortality: top vs. bottom quintile: HR 3.9, P 0.013; MACE: top vs. bottom quintile: HR 3.5, P 4.x10-4), and all-cause mortality in 683 cases in GeL (top vs. bottom quintile: HR 6.3, P 1x10-6) (Figure 1D). Conclusions We derive a PGS for HCM risk prediction, and demonstrate potential clinical utility in stratifying risk of penetrant HCM in sarcomere-positive carriers, and in predicting risk of adverse outcomes in individuals with HCM.Figure 1

The role of MAPRE2 and microtubules in Brugada syndrome pathogenesis

Abstract Background Brugada syndrome (BrS) is associated with loss-of-function variants in SCN5A (encoding NaV1.5), which are found in only ∼20% of patients. Recent genome-wide association studies identified a novel locus within an intron of MAPRE2 (encoding microtubule end-binding protein 2, EB2), implicating microtubule (MT) involvement in BrS. Purpose To understand the role of MAPRE2 and MT in BrS pathogenesis. Methods A mapre2 knock-out (KO) zebrafish model was generated using CRISPR/Cas9 and validated by western blot. Larval hearts at 5 day-post-fertilization (dpf) were isolated for voltage mapping and immunohistochemistry with confocal imaging. Morpholino targeting mapre2 or ttl (encoding tubulin tyrosine ligase) were injected into zebrafish embryos at the one-cell stage. A transgenic zebrafish line with cdh2 (encoding N-cadherin) tandem fluorescent timer (tFT) was used to study adherens junction. MT plus-end tracking experiments were performed in iPSC-derived cardiomyocytes (CM) with MAPRE2 knockdown (KD) using siRNA. ECG was recorded in adult fish. Results Voltage mapping of larval hearts (14 WTs vs. 19 KOs) showed a significant decrease in ventricular conduction velocity (17.4±1.5 vs. 13.4±0.8 mm/s; p&amp;lt;0.05) and action potential upstroke velocity (Vmax; 86.1±3.6 vs. 73.9±3.2 1/s; p&amp;lt;0.05), suggesting loss of cardiac NaV function. Correspondingly, ECG of adult fish (11 WTs vs. 10 KOs) showed a significant increase in QRS duration (27.8±0.5 vs. 32.3±0.7 ms; p&amp;lt;0.0001). Confocal imaging of KO hearts showed disorganized adherens junction based on N-cadherin staining. Similarly, morpholino KD of mapre2 in the cdh2 tFT line showed ∼40% mislocalization of mature N-cadherin relative to ZO-1 staining in larval ventricles (8 KDs vs 9 control hearts; p&amp;lt;0.05), suggesting disruption of adherens junction. In terms of MT, immunohistochemistry showed a 23% decrease of detyrosinated tubulin relative to total alpha tubulin in KO hearts (16 vs. 8 WT hearts; p&amp;lt;0.01). MAPRE2 KD in iPSC-CM (337 control vs. 285 KD MT in 4 sets of cells) showed an increase in MT velocity (7.9±0.2 vs. 8.8±0.2 µm/min; p&amp;lt;0.001), distance (5.8±0.2 vs. 7.1±0.2 µm; p&amp;lt;0.0001), and duration (46.2±1.4 vs. 52.2±1.6 s; p&amp;lt;0.001), suggesting changes to MT dynamics. Finally, morpholino KD of ttl in mapre2 KO embryos restored the fraction of detyrosinated tubulin (46% increase; 16 controls vs. 16 KDs; p&amp;lt;0.01) as well as Vmax (74.3±3.0 vs. 88.3±2.1 1/s; 13 controls vs. 9 KDs; p&amp;lt;0.01) to WT levels. Conclusion Genetic ablation of mapre2 led to a decrease in cardiac NaV function, a hallmark of BrS. This is associated with disruption of adherens junction, a decrease of detyrosinated tubulin as a marker of MT stability, and changes in MT dynamics. Restoration of detyrosinated tubulin fraction with ttl KD led to a rescue of NaV function in zebrafish larval hearts. Taken together, MAPRE2 loss-of-function may contribute to BrS pathogenesis by disruption of adherens junction via changes in MT dynamics.

Large-scale genetic and multi-omics analyses identify molecular pathways underlying dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) is a heart muscle disease that represents a major public health burden. While both common and rare genetic variants are known to affect DCM risk, previous genome-wide association studies (GWAS) have yielded only few loci and the molecular pathways underlying DCM remain largely unknown. Purpose We aimed to discover novel genetic loci for DCM by combining data from biobank and case-control studies, and by combining GWAS with multi-trait analyses. We also pursued multi-omics Mendelian randomization to nominate novel molecular pathways underlying DCM. Methods and results We first performed a GWAS of ICD-code defined DCM (N=1472 cases) from two large biobank datasets (UK Biobank and Mass General Brigham Biobank), and found good genetic correlation (rg=0.82, SE=0.22) and similar heritability estimates (h2=0.12, SE=0.03 vs. h2=0.14, SE=0.03) when compared with a previously published GWAS of recruited DCM cases. In a large meta-analysis across case-control and biobank datasets (N=4191 cases), we identified 10 loci significantly associated with DCM. We then integrated this novel meta-analysis into a multi-trait GWAS (MTAG) with MRI-derived left ventricular traits from the UK Biobank (LVEF and LVESV; N=36083), which yielded 44 lead variants at 36 significant loci. Novel loci overlap reported Mendelian cardiomyopathy genes (ACTN2, OBSCN, MYH7B), support previous mechanistic findings (HSPB8; heat shock protein family), and include genomic regions also arising from a recent GWAS of hypertrophic cardiomyopathy (notably, SVIL). We then performed Mendelian randomization analyses on the MTAG GWAS, using genetic instruments from published multi-omics datasets. Mendelian randomisation of the blood metabolome suggests potential causal roles for metabolites, notably those involved in the pentose phosphate pathway (ribitol; β=0.25, SE=0.04) and glycemic excursion (1,5-anhydroglucitol; β=0.08, SE=0.02). Analyses of the blood proteome suggest potential causal roles for several serum proteins, including proteins involved in redox balance (glutathione synthetase; β=-0.34, SE=0.05), mTORC1 signalling (LAMTOR3; β=0.08, SE=0.01), and the pentose phosphate pathway (G6PE; β=0.09, SE=0.02). Conclusion Our analyses link several new genomic regions with DCM, and implicate redox disbalance and alternative usage of (gluco)metabolic pathways as putative causal mechanisms of disease. Future functional studies could determine whether these represent actionable findings.

Correlates of Risk for Disinhibited Behaviors in the Million Veteran Program Cohort

Many psychiatric outcomes share a common etiologic pathway reflecting behavioral disinhibition, generally referred to as externalizing (EXT) disorders. Recent genome-wide association studies (GWASs) have demonstrated the overlap between EXT disorders and important aspects of veterans' health, such as suicide-related behaviors and substance use disorders (SUDs). To explore correlates of risk for EXT disorders within the Veterans Health Administration (VA) Million Veteran Program (MVP). A series of phenome-wide association studies (PheWASs) of polygenic risk scores (PGSs) for EXT disorders was conducted using electronic health records. First, ancestry-specific PheWASs of EXT PGSs were conducted in the African, European, and Hispanic or Latin American ancestries. Next, a conditional PheWAS, covarying for PGSs of comorbid psychiatric problems (depression, schizophrenia, and suicide attempt; European ancestries only), was performed. Lastly, to adjust for unmeasured confounders, a within-family analysis of significant associations from the main PheWAS was performed in full siblings (European ancestries only). This study included the electronic health record data from US veterans from VA health care centers enrolled in MVP. Analyses took place from February 2022 to August 2023 covering a period from October 1999 to January 2020. PGSs for EXT, depression, schizophrenia, and suicide attempt. Phecodes for diagnoses derived from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification, codes from electronic health records. Within the MVP (560 824 patients; mean [SD] age, 67.9 [14.3] years; 512 593 male [91.4%]), the EXT PGS was associated with 619 outcomes, of which 188 were independent of risk for comorbid problems or PGSs (from odds ratio [OR], 1.02; 95% CI, 1.01-1.03 for overweight/obesity to OR, 1.44; 95% CI, 1.42-1.47 for viral hepatitis C). Of the significant outcomes, 73 (11.9%) were significant in the African results and 26 (4.5%) were significant in the Hispanic or Latin American results. Within-family analyses uncovered robust associations between EXT PGS and consequences of SUDs, including liver disease, chronic airway obstruction, and viral hepatitis C. Results of this cohort study suggest a shared polygenic basis of EXT disorders, independent of risk for other psychiatric problems. In addition, this study found associations between EXT PGS and diagnoses related to SUDs and their sequelae. Overall, this study highlighted the potential negative consequences of EXT disorders for health and functioning in the US veteran population.

Abstract 17672: Implications of Pcsk9 on Abdominal Aortic Aneurysm

Objective: Recent genome-wide association studies revealed a potential role of proprotein convertase subtilisin/kexin type9(Pcsk9) in the human abdominal aortic aneurysm(AAA) disease.Altered Pcsk9 gene expression and smaller AAA diameter were observed in murine AAA using the porcine pancreatic elastase(PPE) model in our lab. Pcsk9 increases plasma LDL-cholesterol,enhances tissue inflammation and induces vascular smooth muscle cell (VSMC) senescence, hallmarks in AAA.However, the exact cellular mechanisms of Pcsk9 in AAA disease remain unclear.Despite the absence of a pharmacological treatment for AAA, monoclonal Pcsk9 antibody therapies have proven effective against statin-resistant hypercholesterolemia.This study aimed to explore the impacts of Pcsk9 on aortic vascular inflammation and VSMC dedifferentiation with a view to better understanding AAA pathophysiology and providing a basis for future investigations into Pcsk9 inhibitors. Hypothesis: We hypothesized that local vascular injury escalates Pcsk9 expression,amplifying vascular inflammation and driving VSMC towards dedifferentiation that further advances AAA. Conversely,Pcsk9 inhibition will mitigate these processes. Methods: AAA was induced by PPE model in wildtype C57Bl/6 mice and Pcsk9 knock-out (KO)mice.Sonography was used to evaluate the aneurysm growth. Single-cell RNA sequencing was employed to examine local changes in the aortic wall. Local vascular Pcsk9,pro-inflammatory and VSMC marker gene/protein expression were quantified using qPCR and immunohistochemistry.VSMCs were treated with exogenous Pcsk9 in vitro to assess metabolism via Seahorse. Results: Reduced AAA diameters were observed in Pcsk9 KO mice compared to wildtype controls. Significant upregulation of local Pcsk9 expression accompanied AAA induction. Single-cell RNA sequencing revealed altered gene expression profiles across vascular cell populations. In vitro,VSMCs displayed changes in marker gene/protein expression after treatment with exogenous Pcsk9, alongside metabolic changes (Mann-Whitney Test). Conclusions: The findings suggest a significant role of Pcsk9 in AAA pathogenesis. Its inhibition appears to mitigate AAA growth,indicating a promising treatment target for AAA.

Abstract 16539: Endometriosis Does Not Have a Causal Role in Determining Cardiovascular Disease and Cardiac Structure and Function: Evidence From Mendelian Randomization

Introduction: Previous observational studies have suggested an association between endometriosis and higher risk of cardiovascular disease. However, in the observational setting residual confounding could drive the association. Hypothesis: In this study, we hypothesize that endometriosis might be causally related to cardiac disease, structure and function, and investigate this using Mendelian randomization (MR), a method that is not liable to influence by observational confounding. Methods: Genome-wide significant (p&lt;5x10-8) uncorrelated (r2&lt;0.001) variants associated with endometriosis in a recent genome-wide association study of 60,674 cases and 701,926 controls were extracted as instrumental variants. Gene-outcome association data was extracted from GWAS of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 15 different indexed cardiac magnetic resonance markers of structure and function. Inverse-variance weighted MR was used for primary analysis. A further exploratory analysis was performed for the outcome of atrial fibrillation, extracting data from a different GWAS study, to further explore to a borderline result on primary analysis. Results: A higher genetically-predicted risk of endometriosis was not associated with risk of atrial fibrillation (OR 1.06, 95%CI 1.00 to 1.12, p=0.059), coronary artery disease (OR 1.00, 95%CI 0.93 to 1.07, p=0.933), heart failure (OR 1.00, 95%CI 0.94 to 1.05, p=0.920), or ischaemic stroke (OR 0.97, 95%CI 0.91 to 1.03, p=0.342). Replication analysis using a different data source for atrial fibrillation corroborated a lack of association (OR 1.02, 95%CI 0.96 to 1.09, p=0.488). There were no associations with any of measures of cardiac structure and function, as displayed in Figure 1. Conclusions: The results do not support a causal role of endometriosis in determining the risk of cardiovascular diseases, and in promoting an adverse cardiac structure and function.

The Cs a and Cs b Red Cell Antigens of the Cost Blood Group Collection Correspond to the HNA-3a and HNA-3b Neutrophil Antigens: Unexpected Twins with Implications for Sickle Cell Anemia

Recent genome-wide association and murine studies identified the human neutrophil antigen 3a/b polymorphism (HNA-3a/b) in SLC44A2 (rs2288904-G/A) as a risk factor in venous thromboembolism (VTE). We tested whether this polymorphism associates with clinical features in SCA patients in whose VTE and stroke are frequently encountered complications. Incidentally, we discovered that rare subjects with the homozygous HNA-3b/b genotype (genotype frequency &amp;lt; 2%) also carry the uncommon Cs(a-) red cell phenotype. Despite its discovery more than 50 years ago, the molecular basis of this red cell phenotype and the presumptive protein carrier for the antigens of the COST blood group collection (Cs a and Cs b) has remained unknown. Inspired by this fortuitous discovery, we hypothesized that rs2288904 and COST antigens are closely associated. Thus, we genotyped this SNP in a cohort of 35 Cs(a-) subjects and found that all of them showed a HNA-3b/b genotype, indicating that the high-frequency allele of rs2288904 (HNA-3a; 461G) encoding Arg154 might encode the Cs a antigen (COST1). Interestingly, anti-Cs a does not react with SLC44A2 null RBCs (exceptional VER- blood type) and SLC44A2 knockout K562 cell line, confirming that the COST antigens are carried on this protein. In addition, using a panel of K562 cells expressing HNA-3a or 3b antigens developed by CRISPR/Cas9 genome editing, we confirmed that anti-Cs a recognizes the HNA-3a antigen. Overall, our results confirmed that HNA-3 and COST antigens have the same molecular basis. As a result, the Cs a and Cs b red cell antigens can now be included in the CTL2 blood group system, encoded by the SLC44A2 gene. This new finding could be of medical and biological value because anti-HNA-3a may be responsible for severe cases of neonatal neutropenia and transfusion-related acute lung injury (TRALI). Current testing for HNA-3a antibodies includes the granulocyte agglutination test and granulocyteindirect immunofluorescence test, as recommended by the ISBT Working Party on Granulocyte Immunobiology. These classical methods, however, are cumbersome because they require fresh granulocytes that have to be prepared daily and used immediately. Consequently, screening for HNA-3a antibodies is restricted to a few expert laboratories. Therefore, we propose to use the simple indirect antiglobulin red cell agglutination test (IAT) and Cs(a-) RBCs to screen for this antibody in the plasma of donors and patients. Finally, given that the starting point for this project was the study of a potential association of the HNA-3 polymorphism with clinical and biological features in SCA patients, we found that the HNA-3b allele was significantly associated with a higher monocyte and platelet count (p&amp;lt;0.02) and the occurrence of leg ulcer (p=0.01), suggesting an important role of the SLC44A2 protein in the SCD physiopathology.

Host genetic variation at a locus near CHD1L impacts HIV sequence diversity in a South African population.

It has been previously shown that genetic variants near CHD1L on chromosome 1 are associated with reduced HIV VL in African populations. However, the impact of these variants on viral diversity and how they restrict viral replication are unknown. We report on a regional association analysis in a South African population and show evidence of selective pressure by variants near CHD1L on HIV RT and gag. Our findings provide further insight into how genetic variability at this locus contributes to host control of HIV in a South African population.

Causal association between subtypes of osteoarthritis and common comorbidities: A Mendelian randomisation study

ObjectiveTo investigate the causal association between Osteoarthritis (OA) and five comorbidities: depression, tiredness, multisite chronic pain, irritable bowel syndrome (IBS) and gout. DesignThis study used two-sample Mendelian Randomisation (MR). To select the OA genetic instruments, we used data from the largest recent genome-wide association study (GWAS) of OA (GO Consortium), with a focus on OA of the knee (62,497 cases, 333,557 controls), hip (35,445 cases, 316,943 controls) and hand (20,901 cases, 282,881 controls). Genetic associations for comorbidities were selected from GWAS for depression (246,363 cases, 561,190 controls), tiredness (449,019 participants), multisite chronic pain (387,649 participants), IBS (53,400 cases, 433,201 controls) and gout (6543 cases, 456,390 controls). We performed a bidirectional MR analysis using the inverse variance weighted method, for both joint specific and overall OA. ResultsHip OA had a causal effect on multisite chronic pain (per unit change 0.02, 95% CI 0.01 to 0.04). Multisite chronic pain had a causal effect on knee (odd ratio (OR) 2.74, 95% CI 2.20 to 3.41), hip (OR 2.12, 95% CI 1.54 to 2.92), hand (OR 2.24, 95% CI 1.59 to 3.16) and overall OA (OR 2.44, 95% CI, 2.06 to 2.86). In addition, depression and tiredness had causal effects on knee and hand, but not hip, OA. ConclusionsApart from Hip OA to multisite chronic pain, other joint OA did not have causal effects on these comorbidities. In contrast, multisite chronic pain had a causal effect on any painful OA.

Causal relationships between blood lipids and major psychiatric disorders: Univariable and multivariable mendelian randomization analysis

BackgroundWhether the positive associations of blood lipids with psychiatric disorders are causal is uncertain. We conducted this two-sample Mendelian randomization (MR) analysis to comprehensively investigate associations of blood lipids with psychiatric disorders.MethodsUnivariable and multivariable models were established for MR analyses. Inverse variance-weighted (IVW) MR was employed as the main approach; weighted median and MR-Egger were used as sensitivity analysis methods. The possibility of violating MR assumptions was evaluated utilizing several sensitivity analyses, including heterogeneity statistics, horizontal pleiotropy statistics, single SNP analysis, leave-one-out analysis and MR-PRESSO analysis. As instrumental variables, we screened 362 independent single-nucleotide polymorphisms (SNP) related to blood lipids from a recent genome-wide association study involving 76,627 individuals of European ancestry, with a genome-wide significance level of p < 5 × 10− 8. Summary-level information for the six psychiatric disorders was extracted from Psychiatric Genomics Consortium and Alzheimer Disease Genetics Consortium.ResultsWe observed eight significant associations in univariable MR analysis, four of which were corroborated by multivariable MR (MVMR) analysis modified for the other three lipid traits: high-density lipoprotein cholesterol (HDL-C) level with the risk of PTSD (OR = 0.91, 95% CI = 0.85–0.97, p = 0.002) and AD (OR = 0.79, 95% CI = 0.71–0.88, p < 0.001) and triglycerides (TG) level with the risk of MDD (OR = 1.02, 95% CI = 1.003–1.03, p = 0.01) and panic disorder (OR = 0.83, 95% CI = 0.74–0.92, p < 0.001). In addition, four associations were not significant in MVMR analysis after adjustment for three lipid traits: total cholesterol (TC) level with the risk of PTSD, low-density lipoprotein cholesterol (LDL-C) level with the risk of MDD and AD and TG level with the risk of AD.ConclusionsOur results show that blood lipids and psychiatric disorders may be related in a causal manner. This shows that abnormal blood lipid levels may act as reliable biomarker of psychiatric disorders and as suitable targets for their prevention and treatment.