Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.

Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3-8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.

Integrative Multiomics in the Lung Reveals a Protective Role of Asporin in Pulmonary Arterial Hypertension.

BACKGROUND: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare. METHODS: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics. RESULTS: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN, coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-ß/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH. CONCLUSIONS: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH.

Circulating immune complexes and G6PD deficiency predict readmissions for blackwater fever and severe anemia in children with severe malaria in Eastern Uganda.

BACKGROUND: Recently, there has been an unexplained increase in the incidence of blackwater fever (BWF) in Eastern Uganda. In this study, we evaluate the association between immune complexes, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and the occurrence and recurrence of BWF in children with severe malaria (SM). METHODS: Between 2014 and 2017, children aged six months to <4 years hospitalized with SM and community children (CC) were recruited at two hospitals in Central and Eastern Uganda. We measured serum circulating immune complexes (cIC) and their relationship to SM complications and post-discharge outcomes and evaluated effect mediation through G6PD deficiency. RESULTS: 557 children with SM and 101 CC were enrolled. The mean age of children was 2.1 years. Children with SM had higher cIC levels than CC, p<0.001. After controlling for age, sex, and site, cIC were associated with severe anemia, jaundice, and BWF (adjusted odds ratio, 95% confidence interval: 7.33 (3.45, 15.58), p<0.0001; 4.31 (1.68, 11.08), p=0.002; and 5.21 (2.06, 13.18), p<0.0001), respectively. cIC predicted readmissions for SM, severe anemia, and BWF (adjusted incidence rate ratios (95% confidence interval): 2.11 (1.33, 3.34), p=0.001; 8.62 (2.80, 26.59), p<0.0001; and 7.66 (2.62, 22.45), p<0.0001), respectively. The relationship was most evident in males where the frequency of the G6PD African allele (A-) was 16.8%. G6PD deficiency was associated with increases in cIC in males (p=0.01) and mediation analysis suggested G6PD deficiency contributes to recurrent severe anemia and BWF via increased cIC. CONCLUSIONS: Immune complexes are associated with hemolytic complications and predict recurrences in SM survivors.

Clinical and genetic risk factors for progressive fibrosis in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort. METHODS: In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL. RESULTS: FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9). CONCLUSIONS: Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.

Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations.

Genetic risks for substance use disorders (SUDs) are due to both SUD-specific and SUD-shared genes. We performed the largest multivariate analyses to date to search for SUD-shared genes using samples of European (EA), African (AA), and Latino (LA) ancestries. By focusing on variants having cross-SUD and cross-ancestry concordant effects, we identified 45 loci. Through gene-based analyses, gene mapping, and gene prioritization, we identified 250 SUD-shared genes. These genes are highly expressed in amygdala, cortex, hippocampus, hypothalamus, and thalamus, primarily in neuronal cells. Cross-SUD concordant variants explained ~ 50% of the heritability of each SUD in EA. The top 5% individuals having the highest polygenic scores were approximately twice as likely to have SUDs as others in EA and LA. Polygenic scores had higher predictability in females than in males in EA. Using real-world data, we identified five drugs targeting identified SUD-shared genes that may be repurposed to treat SUDs.

Unsupervised representation learning on high-dimensional clinical data improves genomic discovery and prediction.

Although high-dimensional clinical data (HDCD) are increasingly available in biobank-scale datasets, their use for genetic discovery remains challenging. Here we introduce an unsupervised deep learning model, Representation Learning for Genetic Discovery on Low-Dimensional Embeddings (REGLE), for discovering associations between genetic variants and HDCD. REGLE leverages variational autoencoders to compute nonlinear disentangled embeddings of HDCD, which become the inputs to genome-wide association studies (GWAS). REGLE can uncover features not captured by existing expert-defined features and enables the creation of accurate disease-specific polygenic risk scores (PRSs) in datasets with very few labeled data. We apply REGLE to perform GWAS on respiratory and circulatory HDCD-spirograms measuring lung function and photoplethysmograms measuring blood volume changes. REGLE replicates known loci while identifying others not previously detected. REGLE are predictive of overall survival, and PRSs constructed from REGLE loci improve disease prediction across multiple biobanks. Overall, REGLE contain clinically relevant information beyond that captured by existing expert-defined features, leading to improved genetic discovery and disease prediction.

Parkinson's disease variant detection and disclosure: PD GENEration, a North American study.

Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease.

Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.

We report a multi-ancestry genome-wide association study on liver cirrhosis and its associated endophenotypes, alanine aminotransferase (ALT) and γ-glutamyl transferase. Using data from 12 cohorts, including 18,265 cases with cirrhosis, 1,782,047 controls, up to 1 million individuals with liver function tests and a validation cohort of 21,689 cases and 617,729 controls, we identify and validate 14 risk associations for cirrhosis. Many variants are located near genes involved in hepatic lipid metabolism. One of these, PNPLA3 p.Ile148Met, interacts with alcohol intake, obesity and diabetes on the risk of cirrhosis and hepatocellular carcinoma (HCC). We develop a polygenic risk score that associates with the progression from cirrhosis to HCC. By focusing on prioritized genes from common variant analyses, we find that rare coding variants in GPAM associate with lower ALT, supporting GPAM as a potential target for therapeutic inhibition. In conclusion, this study provides insights into the genetic underpinnings of cirrhosis.

Utilizing multimodal AI to improve genetic analyses of cardiovascular traits.

Electronic health records, biobanks, and wearable biosensors contain multiple high-dimensional clinical data (HDCD) modalities (e.g., ECG, Photoplethysmography (PPG), and MRI) for each individual. Access to multimodal HDCD provides a unique opportunity for genetic studies of complex traits because different modalities relevant to a single physiological system (e.g., circulatory system) encode complementary and overlapping information. We propose a novel multimodal deep learning method, M-REGLE, for discovering genetic associations from a joint representation of multiple complementary HDCD modalities. We showcase the effectiveness of this model by applying it to several cardiovascular modalities. M-REGLE jointly learns a lower representation (i.e., latent factors) of multimodal HDCD using a convolutional variational autoencoder, performs genome wide association studies (GWAS) on each latent factor, then combines the results to study the genetics of the underlying system. To validate the advantages of M-REGLE and multimodal learning, we apply it to common cardiovascular modalities (PPG and ECG), and compare its results to unimodal learning methods in which representations are learned from each data modality separately, but the downstream genetic analyses are performed on the combined unimodal representations. M-REGLE identifies 19.3% more loci on the 12-lead ECG dataset, 13.0% more loci on the ECG lead I + PPG dataset, and its genetic risk score significantly outperforms the unimodal risk score at predicting cardiac phenotypes, such as atrial fibrillation (Afib), in multiple biobanks.

Genetic regulation and targeted reversal of lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension.

Vascular inflammation critically regulates endothelial cell (EC) pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulation of lysosomal activity and cholesterol metabolism have known inflammatory roles in disease, but their relevance to PAH is unclear. In human pulmonary arterial ECs and in PAH, we found that inflammatory cytokine induction of the nuclear receptor coactivator 7 (NCOA7) both preserved lysosomal acidification and served as a homeostatic brake to constrain EC immunoactivation. Conversely, NCOA7 deficiency promoted lysosomal dysfunction and proinflammatory oxysterol/bile acid generation that, in turn, contributed to EC pathophenotypes. In vivo, mice deficient for Ncoa7 or exposed to the inflammatory bile acid 7α-hydroxy-3-oxo-4-cholestenoic acid (7HOCA) displayed worsened PAH. Emphasizing this mechanism in human PAH, an unbiased, metabolome-wide association study (N=2,756) identified a plasma signature of the same NCOA7-dependent oxysterols/bile acids associated with PAH mortality (P<1.1x10-6). Supporting a genetic predisposition to NCOA7 deficiency, in genome-edited, stem cell-derived ECs, the common variant intronic SNP rs11154337 in NCOA7 regulated NCOA7 expression, lysosomal activity, oxysterol/bile acid production, and EC immunoactivation. Correspondingly, SNP rs11154337 was associated with PAH severity via six-minute walk distance and mortality in discovery (N=93, P=0.0250; HR=0.44, 95% CI [0.21-0.90]) and validation (N=630, P=2x10-4; HR=0.49, 95% CI [0.34-0.71]) cohorts. Finally, utilizing computational modeling of small molecule binding to NCOA7, we predicted and synthesized a novel activator of NCOA7 that prevented EC immunoactivation and reversed indices of rodent PAH. In summary, we have established a genetic and metabolic paradigm and a novel therapeutic agent that links lysosomal biology as well as oxysterol and bile acid processes to EC inflammation and PAH pathobiology. This paradigm carries broad implications for diagnostic and therapeutic development in PAH and in other conditions dependent upon acquired and innate immune regulation of vascular disease.

Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.

Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.

Polymorphisms in the choline transporter SLC44A1 are associated with reduced cognitive performance in normotypic but not prenatal alcohol-exposed children.

BACKGROUND: Choline is essential for healthy cognitive development. Single nucleotide polymorphisms (SNPs; rs3199966(G), rs2771040(G)) within the choline transporter SLC44A1 increase risk for choline deficiency. In a choline intervention trial of children who experienced prenatal alcohol exposure (PAE), these alleles are associated with improved cognition. OBJECTIVE: This study aimed to determine if SNPs within SLC44A1 are differentially associated with cognition in children with PAE compared with normotypic controls (genotype × exposure). A secondary objective tested for an association of these SNPs and cognition in controls (genotype-only). DESIGN: This is a secondary analysis of data from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Participants (163 normotypic controls, 162 PAE) underwent psychological assessments and were genotyped within SLC44A1. Choline status was not assessed. Association analysis between genotype × exposure was performed using an additive genetic model and linear regression to identify the allelic effect. The primary outcome was the interaction between SLC44A1 genotype × exposure status with respect to cognition. The secondary outcome was the cognitive-genotype association in normotypic controls. RESULTS: Genotype × exposure analysis identified 7 SNPs in SLC44A1, including rs3199966(G) and rs2771040(G), and in strong linkage (D' ≥ 0.87), that were associated (adjusted P ≤ 0.05) with reduced performance in measures of general cognition, nonverbal and quantitative reasoning, memory, and executive function (ß, 1.92-3.91). In controls, carriers of rs3199966(GT or GG) had worsened cognitive performance than rs3199966(TT) carriers (ß, 0.46-0.83; P < 0.0001), whereas cognitive performance did not differ by rs3199966 genotype in those with PAE. CONCLUSIONS: Two functional alleles that increase vulnerability to choline deficiency, rs3199966(G) (Ser644Ala) and rs2771040(G) (3' untranslated region), are associated with worsened cognition in otherwise normotypic children. These alleles were previously associated with greater cognitive improvement in children with PAE who received supplemental choline. The findings endorse that choline benefits cognitive development in normotypic children and those with PAE.

Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank.

BACKGROUND: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. METHODS: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. RESULTS: In COGA EA, PGSAUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, ßs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, ß = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, ß = 0.15). CONCLUSIONS: PGSAUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life.

MicroRNAs Signature Panel Identifies Heavy Drinkers with Alcohol-Associated Cirrhosis from Heavy Drinkers without Liver Injury.

Background: Alcohol-associated liver disease (ALD) is the most common disorder of prolonged drinking. Mechanisms underlying cirrhosis in such patients remain unclear. MicroRNAs play regulatory role in several diseases, are affected by alcohol and may be important players in alcohol use disorders, such as cirrhosis. Methods: We investigated serum samples from heavy chronic alcohol users (80 g/day (male) and 50 g/day (female) for ≥10 years) that were available from our previously reported GenomALC study. A subset of GenomALC drinkers with liver cirrhosis (cases, n = 24) and those without significant liver disease (drinking controls, n = 23) were included. Global microRNA profiling was performed using high-throughput real-time quantitative PCR to identify the microRNA signatures associated with cirrhosis. Ingenuity Pathway Analysis (IPA) software was utilized to identify target mRNAs of significantly altered microRNAs, and molecular pathways were analysed. Identified microRNAs were analysed for correlation with traditional liver disease biomarkers and risk gene variants previously reported from GenomALC genome-wide association study. Results: The expression of 21 microRNAs was significantly downregulated in cases compared to drinking controls (p < 0.05, ∆∆Ct > 1.5-fold). Seven microRNAs (miR-16, miR-19a, miR-27a, miR-29b, miR-101, miR-130a, and miR-191) had a highly significant correlation (p < 0.001) with INR, bilirubin and MELD score. Three microRNAs (miR-27a, miR-130a and miR-191) significantly predicted cases with AUC-ROC 0.8, 0.78 and 0.85, respectively (p < 0.020); however, INR performed best (0.97, p < 0.001). A different set of six microRNAs (miR-19a, miR-26a, miR-101, miR-151-3p, miR-221, and miR-301) showed positive correlation (ranging from 0.32 to 0.51, p < 0.05) with rs10433937:HSD17B13 gene variant, associated with the risk of cirrhosis. IPA analysis revealed mRNA targets of the significantly altered microRNAs associated with cell death/necrosis, fibrosis and increased steatosis, particularly triglyceride metabolism. Conclusions: MicroRNA signatures in drinkers distinguished those with liver cirrhosis from drinkers without liver disease. We identified mRNA targets in liver functions that were enriched for disease pathogenesis pathways.

Genomic approaches to explore susceptibility and pathogenesis of alcohol use disorder and alcohol-associated liver disease.

Excessive alcohol use is a major risk factor for the development of an alcohol use disorder (AUD) and contributes to a wide variety of other medical illnesses, including alcohol-associated liver disease (ALD). Both AUD and ALD are complex and causally interrelated diseases, and multiple factors other than alcohol consumption are implicated in the disease pathogenesis. While the underlying pathophysiology of AUD and ALD is complex, there is substantial evidence for a genetic susceptibility of both diseases. Current genome-wide association studies indicate that the genes associated with clinical AUD only poorly overlap with the genes identified for heavy drinking and, in turn, neither overlap with the genes identified for ALD. Uncovering the main genetic factors will enable us to identify molecular drivers underlying the pathogenesis, discover potential targets for therapy, and implement patient care early in disease progression. In this review, we described multiple genomic approaches and their implications to investigate the susceptibility and pathogenesis of both AUD and ALD. We concluded our review with a discussion of the knowledge gaps and future research on genomic studies in these 2 diseases.

Mutation in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations.

Fetal Alcohol Spectrum Disorders (FASD) describe ethanol-induced developmental defects including craniofacial malformations. While ethanol-sensitive genetic mutations contribute to facial malformations, the impacted cellular mechanisms remain unknown. Bmp signaling is a key regulator of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. Integrating FASD patient data, we provide the first evidence that variants in the human Bmp receptor gene BMPR1B associate with ethanol-related differences in jaw volume. Our results show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, facial epithelia that mirror overall viscerocranial shape changes and are predictive for Bmp-ethanol associations in human jaw development. Our data provide a mechanistic paradigm linking ethanol to disrupted epithelial cell behaviors that underlie facial defects in FASD.

Providing genetic testing and genetic counseling for Parkinson's disease to the community.

PURPOSE: To evaluate the feasibility and impact of offering genetic testing and counseling to patients with Parkinson's disease (PD), with the potential to enroll in gene-targeted clinical trials and improve clinical care. METHODS: A multicenter, exploratory pilot study at 7 academic hospital sites in the United States tracked enrollment and randomized participants to receive results and genetic counseling at local sites or by genetic counselors, remotely. Follow-up surveys measured participant/provider satisfaction, knowledge, and psychological impact. RESULTS: From September 5, 2019 to January 4, 2021, 620 participants were enrolled and 387 completed outcome surveys. There were no significant differences in outcomes between local and remote sites, with both arms reporting high knowledge and satisfaction scores (>80%). Notably, 16% of those tested had reportable PD gene variants (pathogenic/likely pathogenic/risk allele). CONCLUSION: Local clinicians, as well as genetic counselors, with educational support as needed, can effectively return genetic results for PD as we observed favorable outcome measures in both groups. Increasing access to PD genetic testing and counseling is urgent; this can inform future efforts to integrate genetic testing and counseling into clinical care for all those with PD.