Genome-wide association studies of lifetime and frequency cannabis use in 131,895 individuals.

Cannabis is one of the most widely used drugs globally. Decriminalization of cannabis is further increasing cannabis consumption. We performed genome-wide association studies (GWASs) of lifetime (N=131,895) and frequency (N=73,374) of cannabis use. Lifetime cannabis use GWAS identified two loci, one near CADM2 (rs11922956, p=2.40E-11) and another near GRM3 (rs12673181, p=6.90E-09). Frequency of use GWAS identified one locus near CADM2 (rs4856591, p=8.10E-09; r2 =0.76 with rs11922956). Both traits were heritable and genetically correlated with previous GWASs of lifetime use and cannabis use disorder (CUD), as well as other substance use and cognitive traits. Polygenic scores (PGSs) for lifetime and frequency of cannabis use associated cannabis use phenotypes in AllofUs participants. Phenome-wide association study of lifetime cannabis use PGS in a hospital cohort replicated associations with substance use and mood disorders, and uncovered associations with celiac and infectious diseases. This work demonstrates the value of GWASs of CUD transition risk factors.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz; European ancestry N = 161,405; African ancestry N = 15,846), cannabis use disorder (CanUD; European ancestry N = 886,025; African ancestry N = 120,208), and ever-regular tobacco smoking (Smk; European ancestry N = 805,431; African ancestry N = 24,278) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17-0.62). Genetic instrumental variable analyses suggested the presence of shared heritable factors, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for these shared genetic factors. We identified 327 pleiotropic loci with 439 lead SNPs in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both shared genetic factors and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations.

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N = 130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across hundreds of biomarkers, health, and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from the UK Biobank (UKB; N = 334,659). We observed consistent positive genetic correlations with substance use and obesity in both cohorts. Other genetic correlations were discrepant, including positive genetic correlations between coffee intake and psychiatric illnesses, pain, and gastrointestinal traits in 23andMe that were absent or negative in the UKB, and genetic correlations with cognition that were negative in 23andMe but positive in the UKB. Phenome-wide association study using polygenic scores of coffee intake derived from 23andMe or UKB summary statistics also revealed consistent associations with increased odds of obesity- and red blood cell-related traits, but all other associations were cohort-specific. Our study shows that the genetics of coffee intake associate with substance use and obesity across cohorts, but also that GWAS performed in different populations could capture cultural differences in the relationship between behavior and genetics.

High Juvenile Mortality Overwhelms Benefits of Mating Potential for Reproductive Fitness.

AbstractAn individual's access to mates (i.e., its "mating potential") can constrain its reproduction but may also influence its fitness through effects on offspring survival. For instance, mate proximity may correspond with relatedness and lead to inbreeding depression in offspring. While offspring production and survival might respond differently to mating potential, previous studies have not considered the simultaneous effects of mating potential on these fitness components. We investigated the relationship of mating potential with both production and survival of offspring in populations of a long-lived herbaceous perennial, Echinacea angustifolia. Across 7 years and 14 sites, we quantified the mating potential of maternal plants in 1,278 mating bouts and followed the offspring from these bouts over 8 years. We used aster models to evaluate the relationship of mating potential with the number of offspring that emerged and that were alive after 8 years. Seedling emergence increased with mating potential. Despite this, the number of offspring surviving after 8 years showed no relationship to mating potential. Our results support the broader conclusion that the effect of mating potential on fitness erodes over time because of demographic stochasticity at the maternal level.

Characterization of patients with atopic dermatitis based on flare patterns and severity of disease: A Danish population-based study.

BACKGROUND: Flare patterns are not routinely considered in the severity classification or in clinical decision-making of atopic dermatitis (AD), but frequent or severe flares may contribute considerably to the disease burden. OBJECTIVES: To characterize patients with AD in relation to their flare pattern and compare flare patterns to disease severity, life quality and treatment satisfaction. METHODS: Patients with AD from the Danish Skin Cohort were included if they had active AD with and available data on number of flare-ups within the last 12 months. Categorical variables were presented as frequencies and percentages, whereas numerical variables were presented as median and interquartile ranges (IQR). Between-group differences were tested with chi-squared tests. RESULTS: A total of 1557 patients were included, with 57 reporting 0 flares, 698 (1-5 flares), 324 (6-10 flares) and 478 reporting >10 flares during the past 12 months. Both the severity measured by PO-SCORAD and the impairment of life quality measured by DLQI were higher among patients with more flares (median [IQR] PO-SCORAD: 13.0 [5.6-22.3], 29.7 [20.8-40.6], 36.3 [26.7-47.6]and 42.9 [30.7-55.6], respectively for the four flares strata, and median [IQR] DLQI: 1.0 [0.0-2.0], 3.0 [1.0-7.0], 4.0 [1.8-9.0] and 7.0 [3.0-11.0]). Satisfaction with the current treatment was generally higher among patients with no flares. However, 36.8%, 24.6% and 23.7% of patients with 1-5, 6-10 and >10 flares reported being extremely or very satisfied with their current treatment. CONCLUSIONS: Patients with many flares often report a higher severity and impairment of life quality compared to patients with fewer flares. Information on flaring could benefit treatment decisions, thereby decreasing undertreatment of patients with mild AD but severe flaring.

Juvenile survival increases with dispersal distance and varies across years: 15 years of evidence in a prairie perennial.

Juvenile survival is critical to population persistence and evolutionary change. However, the survival of juvenile plants from emergence to reproductive maturity is rarely quantified. This is especially true for long-lived perennials with extended pre-reproductive periods. Furthermore, studies rarely have the replication necessary to account for variation among populations and cohorts. We estimated juvenile survival and its relationship to population size, density of conspecifics, distance to the maternal plant, age, year, and cohort for Echinacea angustifolia, a long-lived herbaceous perennial. In 14 remnant prairie populations over seven sampling years, 2007-2013, we identified 886 seedlings. We then monitored these individuals annually until 2021 (8-15 years). Overall, juvenile mortality was very high; for almost all cohorts fewer than 10% of seedlings survived to age 8 or to year 2021. Only two of the seedlings reached reproductive maturity within the study period. Juvenile survival increased with distance from the maternal plant and varied more among the study years than it did by age or cohort. Juvenile survival did not vary with population size or local density of conspecific neighbors. Our results suggest that low juvenile survival could contribute to projected population declines.

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.

Phenomewide Association Study of Health Outcomes Associated With the Genetic Correlates of 25 Hydroxyvitamin D Concentration and Vitamin D Binding Protein Concentration.

While it is known that vitamin D deficiency is associated with adverse bone outcomes, it remains unclear whether low vitamin D status may increase the risk of a wider range of health outcomes. We had the opportunity to explore the association between common genetic variants associated with both 25 hydroxyvitamin D (25OHD) and the vitamin D binding protein (DBP, encoded by the GC gene) with a comprehensive range of health disorders and laboratory tests in a large academic medical center. We used summary statistics for 25OHD and DBP to generate polygenic scores (PGS) for 66,482 participants with primarily European ancestry and 13,285 participants with primarily African ancestry from the Vanderbilt University Medical Center Biobank (BioVU). We examined the predictive properties of PGS25OHD, and two scores related to DBP concentration with respect to 1322 health-related phenotypes and 315 laboratory-measured phenotypes from electronic health records. In those with European ancestry: (a) the PGS25OHD and PGSDBP scores, and individual SNPs rs4588 and rs7041 were associated with both 25OHD concentration and 1,25 dihydroxyvitamin D concentrations; (b) higher PGS25OHD was associated with decreased concentrations of triglycerides and cholesterol, and reduced risks of vitamin D deficiency, disorders of lipid metabolism, and diabetes. In general, the findings for the African ancestry group were consistent with findings from the European ancestry analyses. Our study confirms the utility of PGS and two key variants within the GC gene (rs4588 and rs7041) to predict the risk of vitamin D deficiency in clinical settings and highlights the shared biology between vitamin D-related genetic pathways a range of health outcomes.

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case-control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. RESULTS: The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10-12) and rs2228260 within XBP1 (P = 3.68 × 10-8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10-6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10-9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10-6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. CONCLUSIONS: Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

Perioperative Characteristics and Outcomes of Fontan Versus Non-Fontan Patients Undergoing Combined Heart-Liver Transplantation: A Retrospective Cohort Study.

OBJECTIVES: Combined heart-liver transplantation (CHLT) is becoming increasingly frequent as a maturing population of patients with Fontan-palliated congenital heart disease develop advanced liver fibrosis or cirrhosis. The authors present their experience with CHLT for congenital and noncongenital indications, and identify characteristics associated with poor outcomes that may guide intervention in high-risk patients. DESIGN: This was a single-center retrospective cohort study. SETTING: This study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee. PARTICIPANTS: The study included 16 consecutive adult recipients of CHLT at the authors' institution between April 2017 and February 2022. INTERVENTIONS: Eleven patients underwent transplantation for Fontan indications, and 5 were transplanted for non-Fontan indications. MEASUREMENTS AND MAIN RESULTS: Compared with non-Fontan patients, Fontan recipients had longer cardiopulmonary bypass duration (199 v 119 minutes, p =m0.002), operative times (786 v 599 minutes, p = 0.01), and larger blood product transfusions (15.4 v 6.3 L, p = 0.18). Six of 16 patients required extracorporeal membrane oxygenation (ECMO), of whom 4 were Fontan patients who subsequently died. Patients who required ECMO had lower 5-hour lactate clearance (0.0 v 3.5 mmol/L, p = 0.001), higher number of vasoactive infusions, lower pulmonary artery pulsatility indices (0.58 v 1.77, p = 0.03), and higher peak inspiratory pressures (28.0 v 18.5 mmHg, p = 0.01) after liver reperfusion. CONCLUSIONS: Combined heart-liver transplantation in patients with Fontan-associated end-organ disease is particularly challenging and associated with higher recipient morbidity compared with non-Fontan-related CHLT. Early hemodynamic intervention for signs of ventricular dysfunction may improve outcomes in this growing high-risk population.

Cross-ancestry genetic investigation of schizophrenia, cannabis use disorder, and tobacco smoking.

Individuals with schizophrenia frequently experience co-occurring substance use, including tobacco smoking and heavy cannabis use, and substance use disorders. There is interest in understanding the extent to which these relationships are causal, and to what extent shared genetic factors play a role. We explored the relationships between schizophrenia (Scz), cannabis use disorder (CanUD), and ever-regular tobacco smoking (Smk) using the largest available genome-wide studies of these phenotypes in individuals of African and European ancestries. All three phenotypes were positively genetically correlated (rgs = 0.17 - 0.62). Causal inference analyses suggested the presence of horizontal pleiotropy, but evidence for bidirectional causal relationships was also found between all three phenotypes even after correcting for horizontal pleiotropy. We identified 439 pleiotropic loci in the European ancestry data, 150 of which were novel (i.e., not genome-wide significant in the original studies). Of these pleiotropic loci, 202 had lead variants which showed convergent effects (i.e., same direction of effect) on Scz, CanUD, and Smk. Genetic variants convergent across all three phenotypes showed strong genetic correlations with risk-taking, executive function, and several mental health conditions. Our results suggest that both horizontal pleiotropy and causal mechanisms may play a role in the relationship between CanUD, Smk, and Scz, but longitudinal, prospective studies are needed to confirm a causal relationship.

Mid-term real world outcomes of the Hydrus® Microstent in open angle glaucoma.

PURPOSE: To evaluate the mid-term clinical results and the safety aspects of the Hydrus® Microstent (Ivantis, Inc, Irvine, CA) in a real-life setting. DESIGN: Retrospective case series. METHODS: Hydrus® Microstent was implanted in phakic eyes (88 eyes, 87.1%) and in pseudophakic eyes (13 eyes, 12.9%), respectively. Mean follow-up time was 16 ± 9 months with 27 eyes having a follow-up time of more than 24 months. MAIN OUTCOME MEASURES: The primary endpoint was reduction in IOP compared to baseline. Target IOP levels were set at ≤20 mmHg, ≤18 mmHg and ≤15 mmHg. Kaplan-Meier survival was defined as a reduction in IOP of ≥20% compared to baseline. Secondary endpoints were reduction in number of glaucoma medications and safety assessments addressing visual acuity, adverse events, re-surgery rate and identification of factors that made the implantation more difficult. RESULT: 101 eyes underwent Hydrus® implantation. The mean preoperative IOP was 21.60 mmHg (SD 6.6) on 2.18 (SD 1.3) medications. After a mean follow up time of 16 months, the mean IOP was reduced to 14.61 ± 3.7 mmHg on 1.12 (SD 1.1) medication classes (p < 0.001). Mean decrease in IOP was 26.7%. Analysis of the target IOP levels showed that in 29%, 34% and 35% of cases an IOP of ≤15 mmHg, ≤18 mmHg and ≤20 mmHg respectively could be achieved. BCVA improved from 0.56 ± 0.3 at baseline to 0.85 ± 0.3 more than 24 months after surgery (p < 0.001). The rate of re-operation was low at <3%. Adverse events occurred in 4 eyes (<4%). CONCLUSION: This study underlines the effectiveness and the safety of the Hydrus® Microstent in an elective setting, but it also demonstrates certain limits and risk factors of this procedure.

Medical and genetic correlates of long-term buprenorphine treatment in the electronic health records.

Despite the benefits associated with longer buprenorphine treatment duration (i.e., >180 days) (BTD) for opioid use disorder (OUD), retention remains poor. Research on the impact of co-occurring psychiatric issues on BTD has yielded mixed results. It is also unknown whether the genetic risk in the form of polygenic scores (PGS) for OUD and other comorbid conditions, including problematic alcohol use (PAU) are associated with BTD. We tested the association between somatic and psychiatric comorbidities and long BTD and determined whether PGS for OUD-related conditions was associated with BTD. The study included 6686 individuals with a buprenorphine prescription that lasted for less than 6 months (short-BTD) and 1282 individuals with a buprenorphine prescription that lasted for at least 6 months (long-BTD). Recorded diagnosis of substance addiction and disorders (Odds Ratio (95% CI) = 22.14 (21.88-22.41), P = 2.8 × 10-116), tobacco use disorder (OR (95% CI) = 23.4 (23.13-23.68), P = 4.5 × 10-111), and bipolar disorder (OR(95% CI) = 9.70 (9.48-9.92), P = 1.3 × 10-91), among others, were associated with longer BTD. The PGS of OUD and several OUD co-morbid conditions were associated with any buprenorphine prescription. A higher PGS for OUD (OR per SD increase in PGS (95%CI) = 1.43(1.16-1.77), P = 0.0009), loneliness (OR(95% CI) = 1.39(1.13-1.72), P = 0.002), problematic alcohol use (OR(95%CI) = 1.47(1.19-1.83), P = 0.0004), and externalizing disorders (OR(95%CI) = 1.52(1.23 to 1.89), P = 0.0001) was significantly associated with long-BTD. Associations between BTD and the PGS of depression, chronic pain, nicotine dependence, cannabis use disorder, and bipolar disorder did not survive correction for multiple testing. Longer BTD is associated with diagnoses of psychiatric and somatic conditions in the EHR, as is the genetic score for OUD, loneliness, problematic alcohol use, and externalizing disorders.

Development and multi-site external validation of a generalizable risk prediction model for bipolar disorder.

Bipolar disorder is a leading contributor to disability, premature mortality, and suicide. Early identification of risk for bipolar disorder using generalizable predictive models trained on diverse cohorts around the United States could improve targeted assessment of high risk individuals, reduce misdiagnosis, and improve the allocation of limited mental health resources. This observational case-control study intended to develop and validate generalizable predictive models of bipolar disorder as part of the multisite, multinational PsycheMERGE Network across diverse and large biobanks with linked electronic health records (EHRs) from three academic medical centers: in the Northeast (Massachusetts General Brigham), the Mid-Atlantic (Geisinger) and the Mid-South (Vanderbilt University Medical Center). Predictive models were developed and valid with multiple algorithms at each study site: random forests, gradient boosting machines, penalized regression, including stacked ensemble learning algorithms combining them. Predictors were limited to widely available EHR-based features agnostic to a common data model including demographics, diagnostic codes, and medications. The main study outcome was bipolar disorder diagnosis as defined by the International Cohort Collection for Bipolar Disorder, 2015. In total, the study included records for 3,529,569 patients including 12,533 cases (0.3%) of bipolar disorder. After internal and external validation, algorithms demonstrated optimal performance in their respective development sites. The stacked ensemble achieved the best combination of overall discrimination (AUC = 0.82-0.87) and calibration performance with positive predictive values above 5% in the highest risk quantiles at all three study sites. In conclusion, generalizable predictive models of risk for bipolar disorder can be feasibly developed across diverse sites to enable precision medicine. Comparison of a range of machine learning methods indicated that an ensemble approach provides the best performance overall but required local retraining. These models will be disseminated via the PsycheMERGE Network website.

Exploring genetic risk for catatonia in a genome wide association study and polygenic risk score analysis.

BACKGROUND: Catatonia is an under-recognized disorder characterized by psychomotor (increased, decreased, or abnormal) changes, affective symptoms, and disturbance of volition, which may arise in the setting of decompensated psychiatric or non-psychiatric medical disorders. Genetic studies of catatonia are limited, and to the best of our knowledge no prior genome wide association studies of catatonia have been performed to date. METHODS: First we performed a genome wide association study of catatonia regardless of etiology (psychiatric or non-psychiatric). Secondarily we evaluated whether there was an elevated genetic risk profile for predisposing psychiatric disorders (schizophrenia spectrum disorder, bipolar affective disorder, etc.) in patients with catatonia. We used a matched case control design and applied polygenic risk scores to evaluate for a shared polygenetic contribution to catatonia from common psychiatric phenotypes that show a high prevalence of catatonia in their decompensated states. RESULTS: Anxiety, bipolar affective disorder, schizophrenia spectrum disorder and cross disorder polygenic risk scores were significantly associated with catatonia case status in both unadjusted and adjusted logistic regression models for the European Ancestry set even after correcting for multiple comparisons. Depression, Alzheimer's, Autism Spectrum Disorder and Obsessive Disorder polygenic risk scores were not significantly associated with catatonia status in participants of European Ancestry. In the African Ancestry set, no psychiatric polygenic risk scores were significantly associated with catatonia status in either the unadjusted or adjusted regression models. CONCLUSIONS: Even after controlling for relevant covariates, anxiety, bipolar affective disorder, schizophrenia spectrum disorder and cross disorders were significantly associated with catatonia status suggesting that there might be a shared genetic risk for those disorders amongst patients with catatonia.

Examination of Brief Parent-Based Interventions to Reduce Drinking Outcomes on a Nationally Representative Sample of Teenagers.

PURPOSE: Examine brief parent interventions (PBIs) on a nationally representative sample of teenagers (ages 15-18 years) to change drinking, teens declining (i.e., saying no) to ride with impaired drivers, and increase parent communication about alcohol. METHODS: Parent-teen dyads (N = 1,176) recruited from a web panel completed online surveys at baseline (T1), 30 days (T2), 6 months (T3), and 12 months (T4) post baseline (Psex: 54% female; Tsex: 49% female; Tage: M = 16.33, SD = 1.09; 76% White, 27% Hispanic). Dyads were randomly assigned to: Active Control (n = 390, 33.1%), Surgeon General (SG; n = 393, 33.4%), or Mothers Against Drunk Driving PBI (MADD; n = 393, 33.4%). Aim 1 was an intent-to-treat analysis of the efficacy comparing the Active Control, SG, and MADD conditions on typical weekend drinking and declining riding with an impaired driver from T1 to T4. Aim 2 examined differences in parent communication at T2 by different levels of engagement. Aim 3 examined differences in efficacy comparing the SG and MADD engagement subgroups at T4. Aims were evaluated by comparing means using Tukey's test to reduce experiment-wise error. RESULTS: Aim 1 revealed no differences in drinking, but participants in the SG and MADD conditions were able to maintain increases in declining riding with impaired drivers. Aim 2 revealed highly engaged participants reported higher parent communication than moderate and low participants. Aim 3 revealed some highly engaged participants reported less drinking and more declining riding with impaired drivers. DISCUSSION: PBIs may be successful in helping teens decline rides with impaired drivers. Highly engaged parents reported more positive program outcomes than moderate and low engaged parents.

Genetic Liability to Posttraumatic Stress Disorder Symptoms and Its Association With Cardiometabolic and Respiratory Outcomes.

Importance: Posttraumatic stress disorder (PTSD) has been reported to be a risk factor for several physical and somatic symptoms. However, the genetics of PTSD and its potential association with medical outcomes remain unclear. Objective: To examine disease categories and laboratory tests from electronic health records (EHRs) that are associated with PTSD polygenic scores. Design, Setting, and Participants: This genetic association study was conducted from July 15, 2021, to January 24, 2023, using EHR data from participants across 4 biobanks. The polygenic scores of PTSD symptom severity (PGS-PTSD) were tested with all available phecodes in Vanderbilt University Medical Center's biobank (BioVU), Mass General Brigham (MGB), Michigan Genomics Initiative (MGI), and UK Biobank (UKBB). The significant medical outcomes were tested for overrepresented disease categories and subsequently tested for genetic correlation and 2-sample mendelian randomization (MR) to determine genetically informed associations. Multivariable MR was conducted to assess whether PTSD associations with health outcomes were independent of the genetic effect of body mass index and tobacco smoking. Exposures: Polygenic score of PTSD symptom severity. Main Outcomes and Measures: A total of 1680 phecodes (ie, International Classification of Diseases, Ninth Revision- and Tenth Revision-based phenotypic definitions of health outcomes) across 4 biobanks and 490 laboratory tests across 2 biobanks (BioVU and MGB). Results: In this study including a total of 496 317 individuals (mean [SD] age, 56.8 [8.0] years; 263 048 female [53%]) across the 4 EHR sites, meta-analyzing associations of PGS-PTSD with 1680 phecodes from 496 317 individuals showed significant associations to be overrepresented from mental health disorders (fold enrichment = 3.15; P = 5.81 × 10-6), circulatory system (fold enrichment = 3.32; P = 6.39 × 10-12), digestive (fold enrichment = 2.42; P = 2.16 × 10-7), and respiratory outcomes (fold enrichment = 2.51; P = 8.28 × 10-5). The laboratory measures scan with PGS-PTSD in BioVU and MGB biobanks revealed top associations in metabolic and immune domains. MR identified genetic liability to PTSD symptom severity as an associated risk factor for 12 health outcomes, including alcoholism (ß = 0.023; P = 1.49 × 10-4), tachycardia (ß = 0.045; P = 8.30 × 10-5), cardiac dysrhythmias (ß = 0.016, P = 3.09 × 10-5), and acute pancreatitis (ß = 0.049, P = 4.48 × 10-4). Several of these associations were robust to genetic effects of body mass index and smoking. We observed a bidirectional association between PTSD symptoms and nonspecific chest pain and C-reactive protein. Conclusions and Relevance: Results of this study suggest the broad health repercussions associated with the genetic liability to PTSD across 4 biobanks. The circulatory and respiratory systems association was observed to be overrepresented in all 4 biobanks.

The genetic contribution to the comorbidity of depression and anxiety: a multi-site electronic health records study of almost 178 000 people.

BACKGROUND: Depression and anxiety are common and highly comorbid, and their comorbidity is associated with poorer outcomes posing clinical and public health concerns. We evaluated the polygenic contribution to comorbid depression and anxiety, and to each in isolation. METHODS: Diagnostic codes were extracted from electronic health records for four biobanks [N = 177 865 including 138 632 European (77.9%), 25 612 African (14.4%), and 13 621 Hispanic (7.7%) ancestry participants]. The outcome was a four-level variable representing the depression/anxiety diagnosis group: neither, depression-only, anxiety-only, and comorbid. Multinomial regression was used to test for association of depression and anxiety polygenic risk scores (PRSs) with the outcome while adjusting for principal components of ancestry. RESULTS: In total, 132 960 patients had neither diagnosis (74.8%), 16 092 depression-only (9.0%), 13 098 anxiety-only (7.4%), and 16 584 comorbid (9.3%). In the European meta-analysis across biobanks, both PRSs were higher in each diagnosis group compared to controls. Notably, depression-PRS (OR 1.20 per s.d. increase in PRS; 95% CI 1.18-1.23) and anxiety-PRS (OR 1.07; 95% CI 1.05-1.09) had the largest effect when the comorbid group was compared with controls. Furthermore, the depression-PRS was significantly higher in the comorbid group than the depression-only group (OR 1.09; 95% CI 1.06-1.12) and the anxiety-only group (OR 1.15; 95% CI 1.11-1.19) and was significantly higher in the depression-only group than the anxiety-only group (OR 1.06; 95% CI 1.02-1.09), showing a genetic risk gradient across the conditions and the comorbidity. CONCLUSIONS: This study suggests that depression and anxiety have partially independent genetic liabilities and the genetic vulnerabilities to depression and anxiety make distinct contributions to comorbid depression and anxiety.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.