Combining Transdiagnostic and Disorder-Level GWAS Enhances Precision of Psychiatric Genetic Risk Profiles in a Multi-Ancestry Sample.

The etiology of substance use disorders (SUDs) and psychiatric disorders reflects a combination of both transdiagnostic (i.e., common) and disorder-level (i.e., independent) genetic risk factors. We applied genomic structural equation modeling to examine these genetic factors across SUDs, psychotic, mood, and anxiety disorders using genome-wide association studies (GWAS) of European-(EUR) and African-ancestry (AFR) individuals. In EUR individuals, transdiagnostic genetic factors represented SUDs (143 lead single nucleotide polymorphisms [SNPs]), psychotic (162 lead SNPs), and mood/anxiety disorders (112 lead SNPs). We identified two novel SNPs for mood/anxiety disorders that have probable regulatory roles on FOXP1 , NECTIN3 , and BTLA genes. In AFR individuals, genetic factors represented SUDs (1 lead SNP) and psychiatric disorders (no significant SNPs). The SUD factor lead SNP, although previously significant in EUR- and cross-ancestry GWAS, is a novel finding in AFR individuals. Shared genetic variance accounted for overlap between SUDs and their psychiatric comorbidities, with second-order GWAS identifying up to 12 SNPs not significantly associated with either first-order factor in EUR individuals. Finally, common and independent genetic effects showed different associations with psychiatric, sociodemographic, and medical phenotypes. For example, the independent components of schizophrenia and bipolar disorder had distinct associations with affective and risk-taking behaviors, and phenome-wide association studies identified medical conditions associated with tobacco use disorder independent of the broader SUDs factor. Thus, combining transdiagnostic and disorder-level genetic approaches can improve our understanding of co-occurring conditions and increase the specificity of genetic discovery, which is critical for psychiatric disorders that demonstrate considerable symptom and etiological overlap.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Cost-Effective and Scalable Clonal Hematopoiesis Assay Provides Insight into Clonal Dynamics.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon in which hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or to serial sequencing. In this study, an affordable (approximately US $8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated. The efficacy of the assay was demonstrated by identifying CHIP mutations in a cohort of 456 individuals with DNA collected at multiple time points in Vanderbilt University's biobank and quantifying clonal expansion rates over time. A total of 101 individuals with CHIP/clonal cytopenia of undetermined significance were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction at both time points. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. Additionally, the study explores mutation co-occurrence and clonal competition between multiple driver mutations.

Genomic evolution shapes prostate cancer disease type.

The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types. We therefore propose the evotype model for prostate cancer evolution wherein Alternative-evotype tumors diverge from those of the Canonical-evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding. Our model unifies many previous molecular observations, providing a powerful new framework to investigate prostate cancer disease progression.

The complex polyploid genome architecture of sugarcane.

Sugarcane, the world's most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide1. While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued2. The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species (Saccharum officinarum) and the wild species (Saccharum spontaneum). In contrast to the existing single haplotype ('monoploid') representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.

Previous Extensor Mechanism Repair Is Associated With Increased Rates of Surgical Complications Following Total Knee Arthroplasty: A Propensity-matched Analysis.

Background: Although extensor mechanism failure following total knee arthroplasty (TKA) is a devastating complication and has been heavily studied in the literature, the impact of extensor mechanism rupture and concomitant repair prior to TKA has not previously been evaluated. The purpose of this investigation was to evaluate how quadriceps and/or patellar tendon repairs prior to TKA would impact medical and surgery-related complications following TKA. Methods: The PearlDiver database was retrospectively reviewed to identify all primary TKA patients from 2010 to 2019. Patients who underwent quadriceps or patellar tendon repair prior to TKA were matched using a propensity score algorithm to a control cohort. We compared medical and surgical complication rates, emergency room visits, readmissions, and 90-day cost of care between the groups. Results: A total of 1197 patients underwent extensor mechanism repair prior to TKA and were matched to 11,970 patients who did not undergo repair prior to TKA. Patients who underwent extensor mechanism repair had higher rates of 90-day medical complications, as well as 1-year surgery-related complications including revision TKA (odds ratio [OR] 6.06; P < .001), lysis of adhesions (OR 2.18; P = .026), aseptic loosening (OR 2.21; P = .018), infection (OR 7.58; P < .001), and fracture (OR 8.53; P < .001). Patients with prior extensor mechanism repair were more likely to return to the emergency department (OR 1.66; P < .001) and become readmitted (OR 4.15; P < .001) within 90 days. Conclusions: Patients with previous extensor mechanism repair exhibited higher medical and surgery-related complications, including lysis of adhesions, following TKA than a control cohort. These findings may suggest that patients may require additional surveillance in the early postoperative period to avoid these disastrous complications following primary TKA.

Scoliosis Without Fusion and Increased Risk of Early Medical and Surgery-Related Complications After Total Hip Arthroplasty: A Propensity-score Analysis.

INTRODUCTION: There is a paucity of literature that examines how the abnormal spinopelvic alignment of scoliosis affects outcomes after total hip arthroplasty (THA) in the absence of a lumbar fusion. METHODS: Patients with a history of scoliosis (idiopathic, adolescent, degenerative, or juvenile) without fusion and those without a history of scoliosis who underwent primary THA were identified using a large national database. Ninety-day incidence of various medical complications, emergency department (ED) visit, and readmission and 1-year incidence of surgery-related complications and cost of care were evaluated in both the scoliosis and control cohorts. Propensity score matching was used to control for patient demographic factors and comorbidities as covariates. RESULTS: After propensity matching, 21,992 and 219,920 patients were identified in the scoliosis and control cohorts, respectively. Patients with scoliosis were at increased risk of several 90-day medical complications, including pulmonary embolism (odds ratio [OR] 1.96; P < 0.001), deep vein thrombosis (1.49; P < 0.001), transfusion (OR, 1.13; P < 0.001), pneumonia (OR, 1.37; P < 0.001), myocardial infarction (OR, 1.38; P = 0.008), sepsis (OR, 1.59; P < 0.001), acute anemia (OR, 1.21; P < 0.001), and urinary tract infection (OR, 1.1; P = 0.001). Patients with a history of scoliosis were at increased 1-year risk of revision (OR, 1.31; P < 0.001), periprosthetic joint infection (OR, 1.16; P = 0.0089), dislocation (OR, 1.581; P < 0.001), and aseptic loosening (OR, 1.39; P < 0.001) after THA. Patients with scoliosis without a history of fusion were more likely to return to the emergency department (OR, 1.26; P < 0.001) and be readmitted (OR, 1.78; P < 0.001) within 90 days of THA. DISCUSSION: Patients with even a remote history of scoliosis without fusion are at increased risk of 90-day medical and surgery-related complications after hip arthroplasty. Hip and spine surgeons should collaborate in future studies to best understand how to optimize these patients for their adult reconstructive procedures.

Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders.

Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10-18), CanUD (rg = 0.37, p = 8.21 × 10-37), OUD (rg = 0.20, p = 1.50 × 10-3), and PTU (rg = 0.29, p = 8.53 × 10-12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10-4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10-6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10-8; pain-outcome: beta = 0.09, p = 3.05 × 10-6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10-8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10-5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.

Genetic contribution to the comorbidity between attention-deficit/hyperactivity disorder and substance use disorders.

We characterized the genetic architecture of the attention-deficit hyperactivity disorder-substance use disorder (ADHD-SUD) relationship by investigating genetic correlation, causality, pleiotropy, and common polygenic risk. Summary statistics from genome-wide association studies (GWAS) were used to investigate ADHD (Neff = 51,568), cannabis use disorder (CanUD, Neff = 161,053), opioid use disorder (OUD, Neff = 57,120), problematic alcohol use (PAU, Neff = 502,272), and problematic tobacco use (PTU, Neff = 97,836). ADHD, CanUD, and OUD GWAS meta-analyses included cohorts with case definitions based on different diagnostic criteria. PAU GWAS combined information related to alcohol use disorder, alcohol dependence, and the items related to alcohol problematic consequences assessed by the alcohol use disorders identification test. PTU GWAS was generated a multi-trait analysis including information regarding Fagerström Test for Nicotine Dependence and cigarettes per day. Linkage disequilibrium score regression analyses indicated positive genetic correlation with CanUD, OUD, PAU, and PTU. Genomic structural equation modeling showed that these genetic correlations were related to two latent factors: one including ADHD, CanUD, and PTU and the other with OUD and PAU. The evidence of a causal effect of PAU and PTU on ADHD was stronger than the reverse in the two-sample Mendelian randomization analysis. Conversely, similar strength of evidence was found between ADHD and CanUD. CADM2 rs62250713 was a pleiotropic SNP between ADHD and all SUDs. We found seven, one, and twenty-eight pleiotropic variants between ADHD and CanUD, PAU, and PTU, respectively. Finally, OUD, CanUD, and PAU PRS were associated with increased odds of ADHD. Our findings demonstrated the contribution of multiple pleiotropic mechanisms to the comorbidity between ADHD and SUDs.

Cemented Versus Cementless Femoral Fixation for Total Hip Arthroplasty Following Femoral Neck Fracture in Patients Aged 65 and Older.

BACKGROUND: Femoral neck fractures are common in individuals over 65, necessitating quick mobilization for the best outcomes. There's ongoing debate about the optimal femoral component fixation method in total hip arthroplasty (THA) for these fractures. Recent U.S. data shows a preference for cementless techniques in over 93% of primary THAs. Nonetheless, cemented fixation might offer advantages like fewer revisions, reduced periprosthetic fractures, lesser thigh pain, and enhanced long-term implant survival for those above 65. This study compares cementless and cemented fixation methods in THA, focusing on postoperative complications in patients aged 65 and older. METHODS: We analyzed a national database to identify patients aged 65+ who underwent primary THA for femoral neck fractures between 2016 and 2021, using either cementless (n = 2,842) or cemented (n = 1,124) techniques. A 1:1 propensity-matched analysis was conducted to balance variables such as age, sex, and comorbidities, resulting in two equally sized groups (n = 1,124 each). We evaluated outcomes like infection, venous thromboembolism (VTE), wound issues, dislocation, periprosthetic fracture, etc., at 90 days, 1 year, and 2 years post-surgery. A P-value < 05 indicated statistical significance. RESULTS: The cemented group initially consisted of older individuals, more females, and higher comorbidity rates. Both groups had similar infection and wound complication rates, and aseptic loosening. The cemented group, however, had lower periprosthetic fracture rates (2.5 versus 4.4%, P = .02) and higher VTE rates (2.9 versus 1.2%, P = .01) at 90 days. After 1 and 2 years, the cementless group experienced more aseptic revision surgeries. CONCLUSIONS: This study, using a large, national database and propensity-matched cohorts, indicates that cemented femoral component fixation in THA leads to fewer periprosthetic fractures and aseptic revisions, but a higher VTE risk. Fixation type choice should consider various factors, including age, sex, comorbidities, bone quality, and surgical expertise. This data can inform surgeons in their decision-making process.

Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress.

Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell-specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca2+ handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. Panx3 deficiency was associated with increased expression of the gene encoding the H2O2-producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H2O2-induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and in blood pressure seen in mice with endothelial Panx3 deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.

Machine Learning of Functional Connectivity to Biotype Alcohol and Nicotine Use Disorders.

BACKGROUND: Magnetic resonance imaging provides noninvasive tools to investigate alcohol use disorder (AUD) and nicotine use disorder (NUD) and neural phenotypes for genetic studies. A data-driven transdiagnostic approach could provide a new perspective on the neurobiology of AUD and NUD. METHODS: Using samples of individuals with AUD (n = 140), individuals with NUD (n = 249), and healthy control participants (n = 461) from the UK Biobank, we integrated clinical, neuroimaging, and genetic markers to identify biotypes of AUD and NUD. We partitioned participants with AUD and NUD based on resting-state functional connectivity (FC) features associated with clinical metrics. A multitask artificial neural network was trained to evaluate the cluster-defined biotypes and jointly infer AUD and NUD diagnoses. RESULTS: Three biotypes-primary NUD, mixed NUD/AUD with depression and anxiety, and mixed AUD/NUD-were identified. Multitask classifiers incorporating biotype knowledge achieved higher area under the curve (AUD: 0.76, NUD: 0.74) than single-task classifiers without biotype differentiation (AUD: 0.61, NUD: 0.64). Cerebellar FC features were important in distinguishing the 3 biotypes. The biotype of mixed NUD/AUD with depression and anxiety demonstrated the largest number of FC features (n = 5), all related to the visual cortex, that significantly differed from healthy control participants and were validated in a replication sample (p < .05). A polymorphism in TNRC6A was associated with the mixed AUD/NUD biotype in both the discovery (p = 7.3 × 10-5) and replication (p = 4.2 × 10-2) sets. CONCLUSIONS: Biotyping and multitask learning using FC features can characterize the clinical and genetic profiles of AUD and NUD and help identify cerebellar and visual circuit markers to differentiate the AUD/NUD group from the healthy control group. These markers support a new growing body of literature.

Decreased Risk of Periprosthetic Joint Infection with Concurrent Hardware Removal During Conversion Total Hip Arthroplasty Compared to Staged Removal: A Matched Cohort Analysis.

INTRODUCTION: Hardware removal before conversion total hip arthroplasty (cTHA) is a challenging task for the orthopaedic surgeon, although there is little consensus on the timing of hardware removal to mitigate risk of surgery-related complication following cTHA. METHODS: Using a national insurance database, we evaluated patients who underwent hardware removal either on the same day or within 1 year before cTHA, resulting in a total of 7,756 patients. After matching based on demographic factors and comorbidities, both staged and concurrent groups consisted of 2,752 patients. The 90-day and 1-year risk of revision surgery, periprosthetic joint infection (PJI), periprosthetic fracture, and aseptic loosening were calculated and compared. Demographic factors and comorbidities were further evaluated as risk factors for PJI. RESULTS: The rates of infection were 1.85% and 3.05% at 90 days postoperatively and 2.94% and 4.14% at 1 year postoperatively for concurrent versus staged cohorts, respectively (P = 0.004 and P = 0.02). No difference was observed at 90 days or 1 year between the two cohorts in risk of fracture, revision surgery, or aseptic loosening. Diabetes (P = 0.002 and P < 0.001), tobacco use (P < 0.001 and P < 0.001), and obesity (P = 0.026 and P = 0.025) were identified as risk factors for PJI at both 90 days and 1 year postoperatively. DISCUSSION: The timing of hardware removal is associated with an increased risk of PJI, although no difference was observed in revision surgery, fracture, or loosening among staged versus concurrent cohorts. These findings are important to consider when surgeons are evaluating patients with periarticular implants surrounding their hip.

Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications.

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Genome-wide association study of antisocial personality disorder diagnostic criteria provides evidence for shared risk factors across disorders.

INTRODUCTION: While progress has been made in determining the genetic basis of antisocial behaviour, little progress has been made for antisocial personality disorder (ASPD), a condition that often co-occurs with other psychiatric conditions including substance use disorders, attention deficit hyperactivity disorder (ADHD), and anxiety disorders. This study aims to improve the understanding of the genetic risk for ASPD and its relationship with other disorders and traits. METHODS: We conducted a genome-wide association study (GWAS) of the number of ASPD diagnostic criteria data from 3217 alcohol-dependent participants recruited in the UK (UCL, N = 644) and the USA (Yale-Penn, N = 2573). RESULTS: We identified rs9806493, a chromosome 15 variant, that showed a genome-wide significant association ( Z -score = -5.501, P = 3.77 × 10 -8 ) with ASPD criteria. rs9806493 is an eQTL for SLCO3A1 (Solute Carrier Organic Anion Transporter Family Member 3A1), a ubiquitously expressed gene with strong expression in brain regions that include the anterior cingulate and frontal cortices. Polygenic risk score analysis identified positive correlations between ASPD and smoking, ADHD, depression traits, and posttraumatic stress disorder. Negative correlations were observed between ASPD PRS and alcohol intake frequency, reproductive traits, and level of educational attainment. CONCLUSION: This study provides evidence for an association between ASPD risk and SLCO3A1 and provides insight into the genetic architecture and pleiotropic associations of ASPD.

Association Patterns of Antisocial Personality Disorder across Substance Use Disorders.

There is a high prevalence of antisocial personality disorder (ASPD) in individuals affected by substance use disorders (SUD). However, there is limited information on the specific patterns of association of ASPD with SUD severity and specific SUD diagnostic criteria. We investigated the association of alcohol, cannabis, cocaine, opioid, and tobacco use disorders (AUD, CanUD, CocUD, OUD, and TUD, respectively) in 1,660 individuals with ASPD and 6,640 controls matched by sex (24% female), age, and racial/ethnic background in a sample ascertained for addiction-related traits. Generalized linear regressions were used to test the association of ASPD with the five DSM-5 SUD diagnoses, their severity (i.e., mild, moderate, severe), and their individual diagnostic criteria. We found that ASPD is associated with the diagnosis and severity of AUD (Odds Ratio, ORs=1.89 and 1.25), CanUD (ORs=2.13 and 1.32), and TUD (ORs=1.50 and 1.21) ( ps <.003). Of the specific diagnostic criteria, the "hazardous use" criterion showed the strongest association with ASPD across the five SUDs investigated (from OR TUD =1.88 to OR CanUD =1.37). However, when criteria of different SUDs were included in the same model, ASPD was independently associated only with TUD "hazardous use" and CocUD "attempts to quit". Attempting to quit cocaine was inversely related to the presence of ASPD and remained significant (OR=0.57, 95% confidence interval = 0.36-0.89) after controlling for interactive effects with sex. The current work provides novel insights into how different SUDs, their severity, and their diagnostic criteria associate with ASPD, potentially furthering our understanding of the impact of polysubstance addiction on mental health.

Hourglass, a rapid analysis framework for heterogeneous bioimaging data, identifies sex disparity in IL-6/STAT3-associated immune phenotypes in pancreatic cancer.

Integration and mining of bioimaging data remains a challenge and lags behind the rapidly expanding digital pathology field. We introduce Hourglass, an open-access analytical framework that streamlines biology-driven visualization, interrogation, and statistical assessment of multiparametric datasets. Cognizant of tissue and clinical heterogeneity, Hourglass systematically organizes observations across spatial and global levels and within patient subgroups. Applied to an extensive bioimaging dataset, Hourglass promptly consolidated a breadth of known interleukin-6 (IL-6) functions via its downstream effector STAT3 and uncovered a so-far unknown sexual dimorphism in the IL-6/STAT3-linked intratumoral T-cell response in human pancreatic cancer. As an R package and cross-platform application, Hourglass facilitates knowledge extraction from multi-layered bioimaging datasets for users with or without computational proficiency and provides unique and widely accessible analytical means to harness insights hidden within heterogeneous tissues at the sample and patient level. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Barriers and facilitators to deprescribing before surgery: A qualitative study of providers and older adults.

INTRODUCTION: Deprescribing, the collaborative process between providers and patients to streamline medication regimen, may reduce the risk of adverse events following surgery among older adults with multimorbidity. However, barriers and facilitators to deprescribing for surgery has not been explored. METHODS: We conducted a qualitative study of Primary Care Providers (PCP) and patients aged 65 and older who were scheduled for surgery. We used the Theoretical Domains Framework, which informed the interview guide and analysis. RESULTS: A total of 16 participants (n=8 providers, n=8 patients) were included. Themes were regarding: 1) attitudes towards deprescribing before surgery, 2) perceived benefits of deprescribing before surgery, 3) patient-provider relationship and shared decision-making, 4) hope for surgery, 5) barriers to deprescribing before surgery, and 6) preferences for deprescribing follow-up. CONCLUSION: Our study findings regarding provider- and patient-related barriers and facilitators for deprescribing and desired processes before surgery may inform future deprescribing intervention targets before surgery.

Polysubstance addiction patterns among 7,989 individuals with cocaine use disorder.

To characterize polysubstance addiction (PSA) patterns of cocaine use disorder (CoUD), we performed a latent class analysis (LCA) in 7,989 participants with a lifetime DSM-5 diagnosis of CoUD. This analysis identified three PSA subgroups among CoUD participants (i.e., low, 17%; intermediate, 38%; high, 45%). While these subgroups varied by age, sex, and racial-ethnic distribution (p < 0.001), there was no difference with respect to education or income (p > 0.05). After accounting for sex, age, and race-ethnicity, the CoUD subgroup with high PSA had higher odds of antisocial personality disorder (OR = 21.96 vs. 6.39, difference-p = 8.08✕10-6), agoraphobia (OR = 4.58 vs. 2.05, difference-p = 7.04✕10-4), mixed bipolar episode (OR = 10.36 vs. 2.61, difference-p = 7.04✕10-4), posttraumatic stress disorder (OR = 11.54 vs. 5.86, difference-p = 2.67✕10-4), antidepressant medication use (OR = 13.49 vs. 8.02, difference-p = 1.42✕10-4), and sexually transmitted diseases (OR = 5.92 vs. 3.38, difference-p = 1.81✕10-5) than the low-PSA CoUD subgroup. These findings underscore the importance of modeling PSA severity and comorbidities when examining the clinical, molecular, and neuroimaging correlates of CoUD.