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Abstract Background: Autozygosity, the proportion of the genome that is homozygous by descent, has been associated with variation in multiple health-related traits impacting evolutionary fitness. Autozygosity (FROH) is typically measured from runs of homozygosity (ROHs) that arise when identical-by-descent (IBD) haplotypes are inherited from each parent. Population isolates with a small set of common founders have elevated autozygosity relative to outbred populations. Methods: In this study, we examined whether degree of autozygosity was associated with variation in 96 cardiometabolic traits among 7221 Old Order Amish individuals residing in Lancaster County, PA. We estimated the average length of an ROH segment to be 6350 KB, with each individual having on average 17.2 segments 1.5 KB or larger. Measurements of genome-wide and regional FROH were used as the primary predictors of trait variation in association analysis. Results: In genome-wide FROH analysis, we did not identify any associations that withstood Bonferroni-correction (p = 0.0005). However, on regional FROH analysis, we identified associations exceeding genome-wide thresholds for two traits: serum bilirubin levels, which were significantly associated with a region on chromosome 2 localized to a region surrounding UGT1A10 (p = 1 × 10− 43), and HbA1c levels, which were significantly associated with a region on chromosome 8 localized near CHRNB3 (p = 8 × 10− 10). Conclusions: These analyses highlight the potential value of autozygosity mapping in founder populations.

This study of 23,000 non-diabetic individuals highlights loci associated with fasting glucose and fasting insulin in diverse cohorts with whole genome sequence data.

Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary vasculature which results in elevations of pulmonary arterial pressures. Here, we conducted a genome-wide association study (GWAS) using the UK Biobank, analyzing the genomes of 493 individuals diagnosed with primary pulmonary hypertension, based on ICD-10 coding, compared to 24,650 age, sex, and ancestry-matched controls in a 1:50 case-control design. Genetic variants were analyzed by Plink’s firth logistic regression and assessed for association with primary pulmonary hypertension. We identified three linked variants in the PIM1 gene, which encodes a protooncogene that has been garnering interest as a potential therapeutic target for PAH, that were associated with PAH with genome wide significance, one (rs192449585) of which lies in the promoter region of the gene. We also identified 15 linked variants in the LINC01491 gene. These results provide genetic evidence supporting the role of PIM1 inhibitors as a potential therapeutic option for PAH.

Abstract Background Limited information currently exists regarding the clinical progression and outcomes of cats that undergo choledochal stenting as a treatment for extrahepatic biliary obstruction (EHBO). Hypothesis/Objectives Describe clinical characteristics, indications for choledochal stent placement, procedure, and outcomes in a cohort of cats undergoing choledochal stenting and evaluate risk factors associated with survival as well as recurrence of EHBO in affected cats. Animals Twenty‐three client‐owned cats undergoing choledochal stent placement. Methods Retrospective study. Medical records from 6 academic institutions were reviewed, and data were extracted and analyzed statistically. Results Median age of cats was 10.1 years (range, 2‐16), and all cats had at least 2 clinical signs. Most common clinical signs were vomiting in 20/22 (90.9%), inappetence in 19/22 (86.4%), and lethargy in 19/23 (82.6%). Procedural complications were uncommon and rarely related to the stenting procedure. Clinical signs improved postoperatively in 15/20 (75.0%) cats and serum total bilirubin concentration decreased postoperatively in 13/19 (68.4%) cats. Eighteen (78.3%) cats survived to discharge. Recurrence of EHBO was documented in 7/18 (38.9%) cats that survived to discharge. Cholelithiasis was associated with recurrence of EHBO. Median survival time for cats that survived to discharge was 931 days (range, 19‐3034). Absence of peritoneal effusion was associated with survival to discharge. Conclusions and Clinical Importance Choledochal stenting was an effective treatment modality in cats with EHBO with few procedural complications and potential for prolonged survival, but substantial risk for recurrence of EHBO was identified.

The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.

Objectives: To identify previously unrecognized genetic variants and clinical variables associated with the ICD-10 (International Classification of Diseases 10)-based diagnosis of hypertrophic cardiomyopathy in the UK Biobank cohort.Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder with more than 2000 known mutations in one of eight genes encoding sarcomeric proteins. However, there is considerable variation in disease manifestation, suggesting the role of additional unrecognized contributors, genetic and otherwise. There is substantial interest in the use of real-world data, such as electronic health records to better understand disease mechanisms and discover new treatment strategies, but whether ICD-10-based diagnosis can be used to study HCM genetics is unknown.Methods: In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 363 individuals diagnosed with HCM based on ICD-10 coding compared to 7,260 age, ancestry, and sex-matched controls in a 1:20 case:control design. Genetic variants were analyzed by Plink’s firth logistic regression and assessed for association with HCM. We also examined 61 biomarkers and other diagnoses in the 363 HCM cases and matched controls.Results: The prevalence of ICD-10-based diagnosis of HCM in the UK Biobank cohort was 1 in 1,342, suggesting disease assignment based on the two ICD-10 codes underestimates HCM prevalence. In addition, common cardiovascular comorbidities were more prevalent in ICD-10-based HCM cases in comparison to controls. We identified two novel, non-sarcomeric genetic variants in KMT2C rs78630626, and PARD3B rs188937806 that were associated with ICD-10 codes for HCM with genome-wide significance (p < 5 x 10−8). These are associated with an increased odds ratio (OR) of ∼3.8 for being diagnosed with HCM. Minor allele frequency (MAF) of each variant was >1%.Discussion: Disease assignment based strictly on ICD-10 codes may underestimate HCM prevalence. Individuals with HCM were more frequently diagnosed with several comorbid conditions, such as hypertension, atherosclerotic heart disease, diabetes, and kidney failure, suggesting they may contribute to disease manifestation. This UK Biobank database-based GWAS identified common variants in KMT2C and PARD3B that are associated with HCM diagnosis, which may represent novel modifier genes. Our study demonstrates the feasibility and limitations of conducting phenotypic and genotypic characterization of HCM based on ICD-10 diagnosis in a large population-based cohort.

Abstract Background Lower urinary tract transitional cell carcinoma (TCC) is an important but rarely described disease of cats. Objectives To report the clinical characteristics, treatments, and outcomes in a cohort of cats with lower urinary tract TCC and to test identified variables for prognostic relevance. Animals One‐hundred eighteen client‐owned cats with lower urinary tract carcinoma. Methods Medical records were retrospectively reviewed to obtain information regarding clinical characteristics, treatments, and outcomes. Recorded variables were analyzed statistically. Results Median age of affected cats was 15 years (range, 5.0‐20.8 years) and median duration of clinical signs was 30 days (range, 0‐730 days). The trigone was the most common tumor location (32/118; 27.1%) as assessed by ultrasound examination, cystoscopy, or both. Treatment was carried out in 73 of 118 (61.9%) cats. Metastatic disease was documented in 25 of 118 (21.2%) cats. Median progression‐free survival and survival time for all cats were 113 days (95% confidence interval [CI], 69‐153) and 155 days (95% CI, 110‐222), respectively. Survival increased significantly (P

Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.

Objectives To utilize the UK Biobank to identify genetic variants associated with the ICD10 (International Classification of Diseases10)-based diagnosis of cerebrovascular disease (CeVD). Background Cerebrovascular disease occurs because of a complex interplay between vascular, environmental, and genetic factors. It is the second leading cause of disability worldwide. Understanding who may be genetically predisposed to cerebrovascular disease can help guide preventative efforts. Moreover, there is considerable interest in the use of real-world data, such as EHR (electronic health records) to better understand disease mechanisms and to discover new treatment strategies, but whether ICD10-based diagnosis can be used to study CeVD genetics is unknown. Methods Using the UK Biobank, we conducted a genome-wide association study (GWAS) where we analyzed the genomes of 11,155 cases and 122,705 controls who were sex, age and ancestry-matched in a 1:11 case: control design. Genetic variants were identified by Plink’s firth logistic regression and assessed for association with the ICD10 codes corresponding to CeVD. Results We identified two groups of SNPs closely linked to PITX2 and LRRTM4 that were significantly associated with CeVD in this study (p < 5 x 10−8) and had a minor allele frequency of > 0.5%. Discussion Disease assignment based on ICD10 codes may underestimate prevalence; however, for CeVD, this does not appear to be the case. Compared to the age- and sex-matched control population, individuals with CeVD were more frequently diagnosed with comorbid conditions, such as hypertension, hyperlipidemia & atrial fibrillation or flutter, confirming their contribution to CeVD. The UK Biobank based ICD10 study identified 2 groups of variants that were associated with CeVD. The association between PITX2 and CeVD is likely explained by the increased rates of atrial fibrillation and flutter. While the mechanism explaining the relationship between LRRTM4 and CeVD is unclear, this has been documented in previous studies.

Common genetic variants associated with plasma lipids have been extensively studied for a better understanding of common diseases. Here, the authors use whole-genome sequencing of 16,324 individuals to analyze rare variant associations and to determine their monogenic and polygenic contribution to lipid traits.

Context: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10−20). Objective: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis. Design: Retrospective cohort study. Setting: Academic research. Patients: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study. Main outcome measures: DHEA, DHEA-S, and DHEA-S/DHEA ratio. Results: Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10−13), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03). Conclusions: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

Abstract Background Electrocardiograms (ECGs) in athletes commonly reveal findings related to physiologic adaptations to exercise, that may be difficult to discern from true underlying cardiovascular abnormalities. North American and European societies have published consensus statements for normal, borderline, and abnormal ECG findings for athletes, but these criteria are not based on established correlation with disease states. Additionally, data comparing ECG findings in athletes to non-athlete control subjects are lacking. Our objective was to compare the ECGs of collegiate athletes and non-athlete controls using Z-scores for digital ECG variables to better identify significant differences between the groups and to evaluate the ECG variables in athletes falling outside the normal range. Methods Values for 102 digital ECG variables on 7206 subjects aged 17–22 years, including 672 athletes, from Hawaii Pacific Health, University of Hawaii, and Rady Children’s Hospital San Diego were obtained through retrospective review. Age and sex-specific Z-scores for ECG variables were derived from normal subjects and used to assess the range of values for specific ECG variables in young athletes. Athletes with abnormal ECGs were referred to cardiology consultation and/or echocardiogram. Results Athletes had slower heart rate, longer PR interval, more rightward QRS axis, longer QRS duration but shorter QTc duration, larger amplitude and area of T waves, prevalent R’ waves in V1, and higher values of variables traditionally associated with left ventricular hypertrophy (LVH): amplitudes of S waves (leads V1-V2), Q waves (V6, III) and R waves (II, V5, V6). Z-scores of these ECG variables in 558 (83%) of the athletes fell within − 2.5 and 2.5 range derived from the normal population dataset, and 60 (8.9%) athletes had a Z-score outside the − 3 to 3 range. While 191 (28.4%) athletes met traditional voltage criteria for diagnosis of LVH on ECG, only 53 athletes (7.9%) had Z-scores outside the range of -2.5 to 2.5 for both S amplitude in leads V1-V2 and R amplitude in leads V5-6. Only one athlete was diagnosed with hypertrophic cardiomyopathy with a Z-score of R wave in V6 of 2.34 and T wave in V6 of -5.94. Conclusion The use of Z-scores derived from a normal population may provide more precise screening to define cardiac abnormalities in young athletes and reduce unnecessary secondary testing, restrictions and concern.

Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10−8) and 27.3% (P = 6.9 × 10−14) decrease in serum sulfate, respectively (P = 8.8 × 10-20 for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10−12). Consistent with sulfate’s role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1. This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.

BackgroundPlatelet activation can lead to enhanced oxidative stress, inflammatory response, and endothelial dysfunction. To quantify the effects of platelet inhibition on endothelial function, we assessed platelet activity of healthy persons before and after clopidogrel administration and evaluated its effects on endothelial function. We hypothesized that clopidogrel, by attenuating platelet activity, would result in enhanced endothelial function. Methods and ResultsMicrocirculatory endothelial function was quantified by laser Doppler flowmetry (LDF) mediated by thermal hyperemia (TH) and postocclusive reactive hyperemia, respectively, in 287 and 241 relatively healthy and homogenous Old Order Amish persons. LDF and platelet aggregation measures were obtained at baseline and after 7 days of clopidogrel administration. Our primary outcome was percentage change in post‐ versus preclopidogrel LDF measures. Preclopidogrel TH‐LDF and platelet aggregation were higher in women than in men (P

Abstract mGluR2 receptors are widely expressed in limbic brain regions associated with memory, including the hippocampal formation, retrosplenial and frontal cortices, as well as subcortical regions including the mammillary bodies. mGluR2/3 agonists have been proposed as potential therapeutics for neurological and psychiatric disorders, however, there is still little known about the role of these receptors in cognitive processes, including memory consolidation. To address this, we assessed the effect of the mGluR2/3 agonist, eglumetad, on spatial memory consolidation in both mice and rats. Using the novel place preference paradigm, we found that post-sample injections of eglumetad impaired subsequent spatial discrimination when tested 6 h later. Using the immediate early gene c-fos as a marker of neural activity, we showed that eglumetad injections reduced activity in a network of limbic brain regions including the hippocampus and mammillary bodies. To determine whether the systemic effects could be replicated with more targeted manipulations, we performed post-sample infusions of the mGluR2/3 agonist 2R,4R-APDC into the mammillary bodies. This impaired novelty discrimination on a place preference task and an object-in-place task, again highlighting the role of mGluR2/3 transmission in memory consolidation and demonstrating the crucial involvement of the mammillary bodies in post-encoding processing of spatial information.

Objectives: We tested the feasibility and efficacy of a brief mindfulness-based intervention (bMBI) for adult brain tumor (BT) survivors experiencing elevated depressive symptoms. Specifically, we examined whether there are improvements in mental health symptoms (i.e. depressive symptoms, quality of life (QOL), mental wellbeing, perceived stress) among participants at post-intervention.Methods: Nineteen BT survivors participated in a five-session, in-person, group-based bMBI intervention. Data on attendance, depressive symptoms, QOL, mental well-being, and perceived stress were collected at three timepoints. Findings: The preliminary analysis supports that this bMBI: (a) was efficacious in decreasing depressive symptoms and perceived stress, as well as increasing mental well-being and QOL, and (b) was feasible, with a retention rate greater than 70% and an attendance rate greater than 80% for adult BT survivors.Conclusions: These findings lend support for a feasible and efficacious intervention for adult BT survivors experiencing elevated depressive symptomsImplications: With the paucity of psychosocial interventions targeting adult BT survivorship, future empirically rigorous studies for this population are warranted. The uptake/adoption of this bMBI by psychosocial providers may play an important role in improving the mental health and QOL of adult BT survivors.