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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.

BACKGROUND: TH1 and TH2 cells have counterregulatory relationships. However, the relationship between asthma, a TH2-predominant condition, and risk of systemic inflammatory diseases such as rheumatoid arthritis (RA), a TH1 condition, is poorly understood. OBJECTIVE: We aimed to determine whether asthma was associated with increased risks of incident RA among adults. METHODS: We conducted a retrospective population-based case-control study that examined existing incident RA cases and controls matched by age, sex, and registration year from the general population in Olmsted County, Minnesota, between January 2002 and December 2007. We performed comprehensive medical record reviews to ascertain asthma status using predetermined asthma criteria. The frequency of a history of asthma before the index date was compared between cases and controls. Logistic regression models were used to adjust for confounding factors. RESULTS: We enrolled 221 RA cases and 218 controls. Of the 221 RA cases, 156 (70.6%) were females, 207 (93.7%) were white, the median age at the index date was 52.5 years, and 53 (24.0%) had a history of asthma. Controls had similar characteristics except that 35 of 218 controls (16.1%) had a history of asthma. After adjustment for sex, age, smoking, body mass index, socioeconomic status, and comorbidity, asthma was significantly associated with increased risks of RA (adjusted odds ratio, 1.74; 95% CI, 1.05-2.90; P = .03). CONCLUSIONS: Despite the counterregulatory relationship between TH1 and TH2 cells, patients with asthma had a significantly higher risk of developing RA than healthy individuals.

Background: Anxiety and depression are frequently comorbid yet phenotypically distinct. This study identifies differences in the clinically observable phenome across a wide variety of physical and mental disorders comparing patients with diagnoses of depression without anxiety, anxiety without depression, or both depression and anxiety. Methods: Using electronic health records for 14 994 participants with depression and/or anxiety in the Mayo Clinic Biobank, a phenotype-based phenome-wide association study (Phe2WAS) was performed to test for differences between these groups across a broad range of clinical diagnoses observed in the electronic health record. Additional analyses were performed to determine the temporal sequencing of diagnoses. Results: Compared to patients diagnosed only with anxiety, those diagnosed only with depression were more likely to have diagnoses of obesity (OR 1.75; p = 1 × 10−27), sleep apnea (OR 1.71; p = 1 × 10−22), and type II diabetes (OR 1.74; p = 9 × 10−18). Compared to those diagnosed only with depression, those diagnosed only with anxiety were more likely to have diagnoses of palpitations (OR 1.91; p = 2 × 10−25), benign skin neoplasms (OR 1.61; p = 2 × 10−17), and cardiac dysrhythmias (OR 1.45; p = 2 × 10−12). Patients with comorbid depression and anxiety were more likely to have diagnoses of other mental health disorders, substance use disorders, sleep problems, and gastroesophageal reflux relative to isolated depression. Conclusions: While depression and anxiety are closely related, this study suggests that phenotypic distinctions exist between depression and anxiety. Improving phenotypic characterization within the broad categories of depression and anxiety could improve the clinical assessment of depression and anxiety. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to identify cytokines and chemokines in patients with adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) that predict changes in disease activity. Methods: Multiplexed immunoassays (Meso Scale Discovery) enabled simultaneous measurement of interferon (IFN)‐regulated chemokines and other pro‐ and anti‐inflammatory cytokines specific to differentiation of specific T‐cell and innate pathways. Cytokine scores were computed for IFNCK (IP‐10, MCP‐1), Th1 (IFNɣ, TNFα, and IL2), Th2 (IL4, IL10, IL12, and IL 13), Th17 (IL6, IL17, IL1β), macrophage (MIP‐1α, MIP‐1β, IL8), and regulatory (IL10, TNFα) factors. Spearman correlation and mixed models were used to examine whether cytokines at a previous visit predict change in disease activity at the next visit. Results: The study included 36 patients (16 DM and 20 JDM) with at least two visits (87 patient intervals between two visits). Mean age (SD) at inclusion was 56.9 (18.4) years for DM and 10.8 (6.6) years in JDM, 67% of patients were female, 89% Caucasian. The mean (SD) physician global, muscle and extra‐muscular disease activity Visual Analog Scale scores at inclusion were 41 (26), 36 (30), and 34 (21) mm, respectively. The change in IFN score from one visit to the next was associated with the change in physician global (P = 0.010) and extramuscular (P < 0.001) disease activity scores. Preliminary results revealed significant correlations of previous IFNCK score and IL‐6 with subsequent disease activity measures, but after adjustment for multiple visits per patient, these associations did not reach statistical significance. Conclusion: There is a potential relationship between IFNCK and other cytokine scores seen in adult and juvenile DM with future disease states. [ABSTRACT FROM AUTHOR]

We examined risks for first hospitalization and the rate, risk factors, costs, and 1‐year outcome of 30‐day readmission among patients admitted for complications of cirrhosis. Data were retrospectively analyzed for adult patients with cirrhosis residing in Minnesota, Iowa, or Wisconsin and admitted from 2010 through 2013 at both campuses of the Mayo Clinic Hospital in Rochester, MN. Readmission was captured at the two hospitals as well as at community hospitals in the tristate area within the Mayo Clinic Health System. The incidence of hospitalization for complications of cirrhosis was 100/100,000 population, with increasing age and male sex being the strongest risks for hospitalization. For the 2,048 hospitalized study patients, the overall 30‐day readmission rate was 32%; 498 (24.3%) patients were readmitted to Mayo Clinic hospitals and 157 (7.7%) to community hospitals, mainly for complications of portal hypertension (52%) and infections (30%). Readmission could not be predicted accurately. There were 146 deaths during readmission and an additional 105 deaths up to 1 year of follow‐up (50.4% total mortality). Annual postindex hospitalization costs for those with a 30‐day readmission were substantially higher ($73,252) than those readmitted beyond 30 days ($62,053) or those not readmitted ($5,719). At 1‐year follow‐up, only 20.4% of patients readmitted within 30 days were at home. In conclusion, patients with cirrhosis have high rates of hospitalization, especially among men over 65 years, and of unscheduled 30‐day readmission. Readmission cannot be accurately predicted. Postindex hospitalization costs are high; nationally, the annual costs are estimated to be more than $4.45 billion. Only 20% of patients readmitted within 30 days are home at 1 year. (Hepatology Communications 2018;2:188–198) [ABSTRACT FROM AUTHOR]

Background & Aims Restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the surgical procedure most commonly selected for patients with familial adenomatous polyposis (FAP) or ulcerative colitis that is refractive to medical treatment. Pouchitis is the most common complication in patients with ulcerative colitis after IPAA, but is thought to rarely occur in patients with FAP. We investigated the frequency of pouchitis and other pouch-related complications in patients with FAP after IPAA. Methods We performed a retrospective cohort study of all patients with FAP who underwent IPAA at a single tertiary institution from 1992 through 2015 (n = 113). Patients were identified using International Classification of Diseases-9 diagnostic and current procedural terminology codes. We obtained relevant demographic and clinical data from patients’ electronic medical records. The frequencies of pouchitis and pouch-related complications were determined. Results Twenty-five patients (22.1%) developed pouchitis (mean time to pouchitis, 4.1 years) and 88 did not (77.9%). Patients with pouchitis showed a trend toward developing late (>90 days after IPAA) pouch-related complications (56.0% of patients with pouchitis developed late complications, compared with 36.4% without). In patients who developed pouchitis, the disease course was acute in 72.0% and chronic in 28.0%. Of those treated, 69.6% responded to antibiotics, 13.0% became dependent on antibiotics, and 13.0% developed antibiotic resistance. Conclusions Pouchitis is more prevalent in patients with FAP than previously believed. Although pouchitis seems to occur later in patients with FAP than in patients with ulcerative colitis, and have a milder course, it should be considered a common complication among patients with FAP following IPAA. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is often comorbid with other chronic mental and physical health conditions. Although the literature widely acknowledges the association of many chronic conditions with the risk of MDD, the relative importance of these conditions on MDD risk in the presence of other conditions is not well investigated. In this study, we aimed to quantify the relative contribution of selected chronic conditions to identify the conditions most influential to MDD risk in adults and identify differences by age. Methods: This study used electronic health record (EHR) data on patients empanelled with primary care at Mayo Clinic in June 2013. A validated EHR-based algorithm was applied to identify newly diagnosed MDD patients between 2000 and 2013. Non-MDD controls were matched 1:1 to MDD cases on birth year (±2 years), sex, and outpatient clinic visits in the same year of MDD case diagnosis. Twenty-four chronic conditions defined by Chronic Conditions Data Warehouse were ascertained in both cases and controls using diagnosis codes within 5 years of index dates (diagnosis dates for cases, and the first clinic visit dates for matched controls). For each age group (45 years or younger, between 46 and 60, and over 60 years), conditional logistic regression models were used to test the association between each condition and subsequent MDD risk, adjusting for educational attainment and obesity. The relative influence of these conditions on the risk of MDD was quantified using gradient boosting machine models. Results: A total of 11,375 incident MDD cases were identified between 2000 and 2013. Most chronic conditions (except for eye conditions) were associated with risk of MDD, with different association patterns observed depending on age. Among 24 chronic conditions, the greatest relative contribution was observed for diabetes mellitus for subjects aged ≤ 60 years and rheumatoid arthritis/osteoarthritis for those over 60 years. Conclusions: Our results suggest that specific chronic conditions such as diabetes mellitus and rheumatoid arthritis/osteoarthritis may have greater influence than others on the risk of MDD. [ABSTRACT FROM AUTHOR]

Objective: To identify shared and differential molecular pathways in blood and affected muscle between adult dermatomyositis (DM) and juvenile DM, and their association with clinical disease activity measures., Methods: Gene expression of transcription factors and cytokines involved in differentiation and effector function of T cell subsets, regulatory T cells and follicular Th cells, were analyzed in the blood from 21 newly diagnosed adult and 26 juvenile DM subjects and in 15 muscle specimens (7 adult and 8 juvenile DM) using a custom RT2 Profiler PCR Array. Disease activity was determined and measured by established disease activity tools., Results: The most prominent finding was the higher blood expression of Th17-related cytokines [retinoic acid-related orphan receptor-γ, interferon regulatory factor 4, interleukin (IL)-23A, IL-6, IL-17F, and IL-21] in juvenile DM at baseline. In contrast, adult patients with DM showed increased blood levels of STAT3 and BCL6 compared with juvenile DM. In muscle, GATA3, IL-13, and STAT5B were found at higher levels in juvenile patients with DM compared with adult DM. Among 25 patients (11 adult and 14 juvenile DM) who had blood samples at baseline and at 6 months, increased expression of IL-1β, STAT3, STAT6, STAT5B, and BCL6 was associated with an improvement in global extramuscular disease activity., Conclusion: We observed differences in gene expression profiling in blood and muscle between new-onset adult and juvenile DM. Cytokine expression in the blood of juvenile patients with new-onset DM was dominated by Th17-related cytokines compared with adult patients with DM. This may reflect the activation of different Th pathways between muscle and blood., Competing Interests: The authors have no conflicts of interest.