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Importance: Leveraging real-world clinical biobanks to investigate the associations between genetic and environmental risk factors for mental illness may help direct clinical screening efforts and evaluate the portability of polygenic scores across environmental contexts., Objective: To examine the associations between sexual trauma, polygenic liability to mental health outcomes, and clinical diagnoses of schizophrenia, bipolar disorder, and major depressive disorder in a clinical biobank setting., Design, Setting, and Participants: This genetic association study was conducted using clinical and genotyping data from 96 002 participants across hospital-linked biobanks located at Vanderbilt University Medical Center (VUMC), Nashville, Tennessee (including 58 262 individuals with high genetic similarity to the 1000 Genomes Project [1KG] Northern European from Utah reference population [1KG-EU-clustered] and 11 047 with high genetic similarity to the 1KG African-ancestry reference population of Yoruba in Ibadan, Nigeria [1KG-YRI-clustered]), and Mass General Brigham (MGB), Boston, Massachusetts (26 693 individuals with high genetic similarity to the combined European-ancestry superpopulation [1KG-EU-clustered]). Clinical data analyzed included diagnostic billing codes and clinical notes spanning from 1976 to 2023. Data analysis was performed from 2022 to 2024., Exposures: Clinically documented sexual trauma disclosures and polygenic scores for schizophrenia, bipolar disorder, and major depressive disorder., Main Outcomes and Measures: Diagnoses of schizophrenia, bipolar disorder, and major depressive disorder, determined by aggregating related diagnostic billing codes, were the dependent variables in logistic regression models including sexual trauma disclosure status, polygenic scores, and their interactions as the independent variables., Results: Across the VUMC and MGB biobanks, 96 002 individuals were included in analyses (VUMC 1KG-EU-clustered: 33 011 [56.7%] female; median [range] age, 56.8 [10.0 to >89] years; MGB 1KG-EU-clustered: 14 647 [54.9%] female; median [range] age, 58.0 [10.0 to >89] years; VUMC 1KG-YRI-clustered: 6961 [63.0%] female; median [range] age, 44.6 [10.1 to >89] years). Sexual trauma history was associated with all mental health conditions across institutions (ORs ranged from 8.83 [95% CI, 5.50-14.18] for schizophrenia in the VUMC 1KG-YRI-clustered cohort to 17.65 [95% CI, 12.77-24.40] for schizophrenia in the VUMC 1KG-EU-clustered cohort). Sexual trauma history and polygenic scores jointly explained 3.8% to 8.8% of mental health phenotypic variance. Schizophrenia and bipolar disorder polygenic scores had greater associations with mental health outcomes in individuals with no documented disclosures of sexual trauma (schizophrenia interaction: OR, 0.70 [95% CI, 0.56-0.88]; bipolar disorder interaction: OR, 0.83 [95% CI, 0.74-0.94])., Conclusions and Relevance: Sexual trauma and mental health polygenic scores, while correlated with one another, were independent and joint risk factors for severe mental illness in a large, diverse hospital biobank population. Furthermore, associations of schizophrenia and bipolar disorder polygenic scores with respective diagnoses were greater in those without disclosures, suggesting that genetic predisposition to mental illness as measured by polygenic scores may be less impactful in the presence of this severe environmental risk factor.

Background: A subset of children with short stature do not have an identified clinical explanation and are assigned a diagnosis of idiopathic short stature (ISS). We hypothesized that a polygenic score for height (PGS height ) could identify children with ISS who have an unrecognized heritable predisposition to shorter height., Methods: We examined 534 pediatric participants in an EHR-linked DNA biobank (BioVU) who had undergone an evaluation for short stature by an endocrinologist. We used a previously validated PGS height and standardized it to a standard deviation (SDS) of 1. PGS height differences between short stature subtypes was estimated using Tukey's HSD. The PGS height and mid-parental height (MPH) were then used to predict adult heights for each participant and these predictions were compared using Cohen's d stratifying by short stature subtype. The ability of the PGS height to discriminate between ISS and short stature due to underlying disease was evaluated using logistic regression models with area under the ROC curve (AUC) analyses and testing the incremental benefit (ΔAUC) of adding the PGS height to prediction models., Results: Among the 534 participants, 22.1% had ISS (median [IQR] PGS height SDS = -1.31 [-2.15 to -0.47]), 6.6% had familial (genetic) short stature (FSS) (-1.62 [-2.13 to -0.54]), and 45.1% had short stature due to underlying pathology (-0.74 [-1.23 to -0.19]). Children with ISS had similar PGS height values as those with FSS (ΔPGS height [95% CI] = 0.19 [-0.31 to 0.70], p = 0.75), but predicted heights generated by the PGS height were lower than the MPH estimate for children with ISS ( d = -0.64; p = 4.0×10 -18 ) but not FSS ( d = 0.05; p = 0.46), suggesting that MPH underestimates height in the ISS group. Children with ISS had lower PGS height values than children with pathology (ΔPGS height = -0.60 SDS [-0.89 to -0.31], p < 0.001), suggesting children with ISS have a larger predisposition to shorter height. In addition, the PGS height improved model discrimination between ISS and pathologic short stature (ΔAUC, + 0.07 [95% CI, 0.01 to 0.11])., Conclusions: Some children with ISS have a clinically unrecognized polygenic predisposition to shorter height that is comparable to children with FSS and larger than those with underlying pathology. A PGS height could help clinicians identify children who have a benign predisposition to shorter height., Competing Interests: Competing Interests No competing interest or conflicts to declare.

Objective: Polygenic risk scores (PRS) for diverticular disease must be evaluated in diverse cohorts. We sought to explore shared genetic predisposition across the phenome and to assess risk stratification in individuals genetically similar to European, African and Admixed-American reference samples., Methods: A 44-variant PRS was applied to the All of Us Research Program. Phenome-wide association studies (PheWAS) identified conditions linked with heightened genetic susceptibility to diverticular disease. To evaluate the PRS in risk stratification, logistic regression models for symptomatic and for severe diverticulitis were compared with base models with covariates of age, sex, body mass index, smoking and principal components. Performance was assessed using area under the receiver operating characteristic curves (AUROC) and Nagelkerke's R 2 ., Results: The cohort comprised 181 719 individuals for PheWAS and 50 037 for risk modelling. PheWAS identified associations with diverticular disease, connective tissue disease and hernias. Across ancestry groups, one SD PRS increase was consistently associated with greater odds of severe (range of ORs (95% CI) 1.60 (1.27 to 2.02) to 1.86 (1.42 to 2.42)) and of symptomatic diverticulitis ((95% CI) 1.27 (1.10 to 1.46) to 1.66 (1.55 to 1.79)) relative to controls. European models achieved the highest AUROC and Nagelkerke's R 2 (AUROC (95% CI) 0.78 (0.75 to 0.81); R 2 0.25). The PRS provided a maximum R 2 increase of 0.034 and modest AUROC improvement., Conclusion: Associations between a diverticular disease PRS and severe presentations persisted in diverse cohorts when controlling for known risk factors. Relative improvements in model performance were observed, but absolute change magnitudes were modest., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6%-16.6% in European ancestry, 5.5%-9.5% in African ancestry, 13.5%-18.2% in Hispanic/Latino, and 8.6%-15.3% in Asian ancestry, and decreased with increasing age. Mid-life genetically-adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10 -6 ) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10 -6 ) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10 -6 ) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels., Competing Interests: Declaration of interests J.S.W. is a non-employee and cofounder of Avail Bio. H.L. is named on a patent for assays to measure intact PSA and a patent for a statistical method to detect prostate cancer commercialized by OPKO Health (4KScore). H.L. receives royalties from sales of the assay and has stock in OPKO Health. H.L. serves on the Scientific Advisory Board for Fujirebio Diagnostics Inc and owns stock in Diaprost AB and Acousort AB. R.E.G. consults for Hunton Andrews Kurth LLC on subject matter unrelated to this study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGS WBC ) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGS WBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10 -5 ) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit., (© 2024. The Author(s).)

Objective: Columnaris disease is a leading cause of disease-related losses in the catfish industry of the southeastern United States. The term "columnaris-causing bacteria" (CCB) has been coined in reference to the four described species that cause columnaris disease: Flavobacterium columnare, F. covae, F. davisii, and F. oreochromis. Historically, F. columnare, F. covae, and F. davisii have been isolated from columnaris disease cases in the catfish industry; however, there is a lack of knowledge of which CCB species are most prevalent in farm-raised catfish. The current research objectives were to (1) sample columnaris disease cases from the U.S. catfish industry and identify the species of CCB involved and (2) determine the virulence of the four CCB species in Channel Catfish Ictalurus punctatus in controlled laboratory challenges., Methods: Bacterial isolates or swabs of external lesions from catfish were collected from 259 columnaris disease cases in Mississippi and Alabama during 2015-2019. The DNA extracted from the samples was analyzed using a CCB-specific multiplex polymerase chain reaction to identify the CCB present in each diagnostic case. Channel Catfish were challenged by immersion with isolates belonging to each CCB species to determine virulence at ~28°C and 20°C., Result: Flavobacterium covae was identified as the predominant CCB species impacting the U.S. catfish industry, as it was present in 94.2% (n = 244) of diagnostic case submissions. Challenge experiments demonstrated that F. covae and F. oreochromis were highly virulent to Channel Catfish, with most isolates resulting in near 100% mortality. In contrast, F. columnare and F. davisii were less virulent, with most isolates resulting in less than 40% mortality., Conclusion: Collectively, these results demonstrate that F. covae is the predominant CCB in the U.S. catfish industry, and research aimed at developing new control and prevention strategies should target this bacterial species. The methods described herein can be used to continue monitoring the prevalence of CCB in the catfish industry and can be easily applied to other industries to identify which Flavobacterium species have the greatest impact., (© 2023 American Fisheries Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Prostate-specific antigen (PSA) levels are influenced by genetic variation unrelated to prostate cancer risk. Whether a genetic predisposition to a higher PSA level predisposes to a diagnostic work-up for prostate cancer is not known., Methods: Participants were 3110 men of African and European ancestries ages 45-70, without prostate cancer and with a baseline PSA < 4 ng/mL, undergoing routine clinical PSA screening. The exposure was a polygenic score (PGS) comprising 111 single nucleotide polymorphisms associated with PSA level, but not prostate cancer. We tested whether the PGS was associated with a: 1) PSA value > 4 ng/mL, 2) International Classification of Diseases (ICD) code for an elevated PSA, 3) encounter with a urologist, or 4) prostate biopsy. Multivariable Cox proportional hazards models were adjusted for age and genetic principal components. Analyses were stratified by age (45-59 years, and 60-70 years old). Association estimates are per standard deviation change in the PGS., Findings: The median age was 56.6 years, and 2118 (68%) participants were 45-59 years. The median (IQR) baseline PSA level was 1.0 (0.6-1.7) ng/mL. Among men ages 45-59, the PGS was associated with a PSA > 4 (hazard ratio [HR] = 1.35 [95% CI, 1.17-1.57], p = 4.5 × 10 -5 ), an ICD code for elevated PSA (HR = 1.30 [1.12-1.52], p = 8.0 × 10 -4 ), a urological evaluation (HR = 1.34 [1.14-1.57], p = 4.8 × 10 -4 ), and undergoing a prostate biopsy (HR = 1.35 [1.11-1.64], p = 0.002). Among men ages 60-70, association effect sizes were smaller and not significant., Interpretation: A predisposition toward higher PSA levels was associated with clinical evaluations of an elevated PSA among men ages 45-59 years., Funding: National Institutes of Health (NIH)., Competing Interests: Declaration of interests JJT holds minor equity in and has received consulting fees from LynxDx. JSW receives additional funding from the National Institutes of Health (U01CA261339). The remaining authors have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10 -8 ) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGS PSA ) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10 -14 , area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10 -12 , AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10 -4 ). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening., (© 2023. The Author(s).)

Purpose: To describe patterns of care use for Alabama Medicaid adult beneficiaries with diabetes and the association between primary care utilization and ambulatory care sensitive (ACS) diabetes hospitalizations., Methods: This retrospective cohort study analyzes Alabama Medicaid claims data from January 2010 to April 2018 for 52,549 covered adults ages 19-64 with diabetes. Individuals were characterized by demographics, comorbidities, and health care use including primary, specialty, mental health and hospital care. Characteristics of those with and without any ACS diabetes hospitalization are reported. A set of 118,758 observations was created, pairing information on primary care use in one year with ACS hospitalizations in the following year. Logistic regression analysis was used to assess the impact of primary care use on the occurrence of an ACS hospitalization., Results: One third of the cohort had at least one ACS diabetes hospitalization over their observed periods; hospital users tended to have multiple ACS hospitalizations. Hospital users had more comorbidities and pharmaceutical and other types of care use than those with no ACS hospitalizations. Controlling for other types of care use, comorbidities and demographics, having a primary care visit in one year was significantly associated with a reduced likelihood of ACS hospitalization in the following year (odds ratio comparing 1-2 visits versus none 0.79, 95% confidence interval 0.73-0.85)., Conclusions: Program and population health interventions that increase access to primary care can have a beneficial effect of reducing excess inpatient hospital use for Medicaid covered adults with diabetes., (Copyright © 2021 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

A novel microsporidial disease was documented in two ornamental fish species, black tetra Gymnocorymbus ternetzi Boulenger 1895 and cardinal tetra Paracheirodon axelrodi Schultz 1956. The non-xenoma-forming microsporidium occurred diffusely in most internal organs and the gill, thus referring to the condition as tetra disseminated microsporidiosis (TDM). The occurrence of TDM in black tetra was associated with chronic mortality in a domestic farmed population, while the case in cardinal tetra occurred in moribund fish while in quarantine at a public aquarium. Histology showed that coelomic visceral organs were frequently necrotic and severely disrupted by extensive infiltrates of macrophages. Infected macrophages were presumed responsible for the dissemination of spores throughout the body. Ultrastructural characteristics of the parasite developmental cycle included uninucleate meronts directly in the host cell cytoplasm. Sporonts were bi-nucleated as a result of karyokinesis and a parasite-produced sporophorous vesicle (SPV) became apparent at this stage. Cytokinesis resulted in two spores forming within each SPV. Spores were uniform in size, measuring about 3.9 ± 0.33 long by 2.0 ± 0.2 μm wide. Ultrastructure demonstrated two spore types, one with 9-12 polar filament coils and a double-layered exospore and a second type with 4-7 polar filament coils and a homogenously electron-dense exospore, with differences perhaps related to parasite transmission mechanisms. The 16S rDNA sequences showed closest identity to the genus Glugea (≈ 92%), though the developmental cycle, specifically being a non-xenoma-forming species and having two spores forming within a SPV, did not fit within the genus. Based on combined phylogenetic and ultrastructural characteristics, a new genus (Fusasporis) is proposed, with F. stethaprioni n. gen. n. sp. as the type species.

Recent research has identified four distinct genetic groups among isolates of Flavobacterium columnare through multilocus phylogenetic analyses; however, there are no quick methods to determine the genotype of an isolate. The objective of this research was to develop a multiplex PCR to rapidly genotype F. columnare to genetic group. Comparative bacterial genomics was used to identify regions in the genomes unique to each genetic group, and primers were designed to specifically amplify different sized amplicons for each genetic group. The optimized assay was demonstrated to be specific for each genetic group and F. columnare, and no specific amplicons were generated using gDNA from a panel of other Flavobacterium spp. and bacterial fish pathogens. The analytical sensitivity of the assay ranged from 209 to 883 genome equivalents depending on the genetic group. The multiplex PCR was evaluated by genotyping a panel of 22 unknown F. columnare isolates and performing DNA sequencing of the dnaK gene in parallel. The results demonstrated 100% accordance between multiplex PCR results and assignment to genetic group via phylogenetic analysis. The multiplex PCR provides a useful tool for assigning an unknown isolate to genetic group and may be used to determine which genetic groups of F. columnare are circulating and most predominant in different aquaculture industries., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Among nonelderly adults with diabetes, we compared hospitalizations for ambulatory care-sensitive conditions from 2013 (pre-Medicaid expansion) and 2014 (post-Medicaid expansion) for 13 expansion and 4 nonexpansion states using State Inpatient Databases. Medicaid expansion was associated with decreases in proportions of hospitalizations for chronic conditions (difference between 2014 and 2013 -0.17 percentage points in expansion and 0.37 in nonexpansion states, P = .04), specifically diabetes short-term complications (difference between 2014 and 2013 -0.05 percentage points in expansion and 0.21 in nonexpansion states, P = .04). Increased access to care through Medicaid expansion may improve disease management in nonelderly adults with diabetes.

Aim: Undiagnosed diabetes is more prevalent among racial/ethnic minorities in the United States (U.S.). Despite the proliferation of risk scores, few have been validated in Hispanics populations. The aim of this study is to systematically review published studies that developed risk scores to identify undiagnosed Type 2 Diabetes Mellitus based on self-reported information that were validated for Hispanics in the U.S., Methods: The search included PubMed, EMBASE, Cochrane and CINAHL from inception to 2016 without language restrictions. Risk scores whose main outcome was undiagnosed Type 2 diabetes reporting performance measures for Hispanics were included., Results: We identified three studies that developed and validated risk scores for undiagnosed diabetes based on questionnaire data. Two studies were conducted in Latin America and one in the U.S. All three studies reported adequate performance (area under the receiving curve (AUC) range between0.68and 0.78). The study conducted in the U.S. reported a higher sensitivity of their risk score for Hispanics than whites. The limited number of studies, small size and heterogeneity of the combined cohorts provide limited evidence of the validity of risk scores for Hispanics., Conclusions: Efforts to develop and validate risk prediction models in Hispanic populations in the U.S are needed, particularly given the diversity of thisfast growing population. Healthcare professionals should be aware of the limitations of applying risk scores developed for the general population on Hispanics., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)