Genome-wide association study in two cohorts from a multi-generational mouse advanced intercross line highlights the difficulty of replication due to study-specific heterogeneity

There has been extensive discussion of the Replication Crisis in many fields, including genome-wide association studies

Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity.

Psychostimulant addiction is a heritable substance use disorder; however its genetic basis is almost entirely unknown. Quantitative trait locus (QTL) mapping in mice offers a complementary approach to human genome-wide association studies and can facilitate environment control, statistical power, novel gene discovery, and neurobiological mechanisms. We used interval-specific congenic mouse lines carrying various segments of chromosome 11 from the DBA/2J strain on an isogenic C57BL/6J background to positionally clone a 206 kb QTL (50,185,512-50,391,845 bp) that was causally associated with a reduction in the locomotor stimulant response to methamphetamine (2 mg/kg, i.p.; DBA/2J < C57BL/6J)-a non-contingent, drug-induced behavior that is associated with stimulation of the dopaminergic reward circuitry. This chromosomal region contained only two protein coding genes-heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1) and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome analysis via mRNA sequencing in the striatum implicated a neurobiological mechanism involving a reduction in mesolimbic innervation and striatal neurotransmission. For instance, Nr4a2 (nuclear receptor subfamily 4, group A, member 2), a transcription factor crucial for midbrain dopaminergic neuron development, exhibited a 2.1-fold decrease in expression (DBA/2J < C57BL/6J; p 4.2 x 10-15). Transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of Hnrnph1, but not Rufy1, recapitulated the reduced methamphetamine behavioral response, thus identifying Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity. These results define a novel contribution of Hnrnph1 to neurobehavioral dysfunction associated with dopaminergic neurotransmission. These findings could have implications for understanding the genetic basis of methamphetamine addiction in humans and the development of novel therapeutics for prevention and treatment of substance abuse and possibly other psychiatric disorders

Depression is Associated with Myocardial Infarction within a Two-Year Period among Adults in China

We examined whether baseline depression is associated with MI within a two-year period among adults aged 45+ in China and whether the association varies by sociodemographic characteristics. Two-year longitudinal data from a nationally representative sample of people aged 45+ in China were analyzed (N = 15,226). MI within the 2-year period was coded dichotomously. Baseline depression, assessed by the 10-item Center for Epidemiological Studies Depression scale, was used as a dichotomous and a continuous variable. After adjusting for medical conditions, lifestyle and sociodemographic characteristics, the odds of having an MI within the 2-year period were 46% greater for respondents with clinically significant depression at baseline than those without. There was a dose-response relationship between symptom severity and the probability of having an MI. The association did not vary by sociodemographic characteristics. Findings suggest that depression screening and treatment may reduce MI cases in China and beyond

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2

Acknowledgements The authors would like to acknowledge Dr David A. Blizard for his role in the development of the ideas that led to this study and feedback on the manuscript, Professor Helen Macdonald for valuable advice on study design, Dr Leslie R. Noble for help with the UK Biobank data, and Dr Joseph P. Gyekis for help genotyping cohort 2 mice. The authors would like to acknowledge funding from the University of Aberdeen for the Maxwell computer cluster, the Elphinstone and IMS studentship for AIHC; a Schweppe Foundation Career Development Award (AAP), and the NIH (NIAMS (AL: R01AR056280) and NIDA (AAP:R01DA021336, AAP:R21DA024845, AAP:T32MH020065, NMG:F31DA03635803), NIGMS (NMG:T32GM007197), NHGRI (MA:R01HG002899))Peer reviewedPostprin

Multimorbidity and Mental Health Trajectories Among Middle-Aged and Older U.S. Adults During the COVID-19 Pandemic: Longitudinal Findings From the COVID-19 Coping Study

Background and Objectives This study aimed to examine the associations between multimorbidity at the COVID-19 pandemic onset and subsequent longitudinal trajectories of depressive symptoms, anxiety symptoms, and loneliness in middle-aged and older adults over a 12-month follow-up. Research Design and Methods Data were from monthly online questionnaires in the COVID-19 Coping Study of U.S. adults aged &ge;55 from April/May 2020 through April/May 2021 (N = 4,024). Multimorbidity was defined as having &ge;2 versus &lt;2 chronic conditions at baseline. Mental health outcomes were assessed monthly as depressive symptoms (8-item Center for Epidemiologic Studies Depression scale), anxiety symptoms (5-item Beck Anxiety Inventory), and loneliness (3-item UCLA Loneliness Scale). We used multivariable-adjusted population- and attrition-weighted mixed-effects linear models to examine the longitudinal associations between multimorbidity and mental health symptoms. Results Multimorbidity at the pandemic onset was associated with elevated depressive (b = 0.37; 95% CI: 0.16&ndash;0.59) and anxiety (b = 0.39; 95% CI: 0.15&ndash;0.62) symptoms at baseline. Changes in symptoms for all three mental health outcomes were nonlinear over time, with worsening symptoms over the first 6 months of the pandemic (April/May to September/October 2020), followed by improvement in symptoms over the subsequent 6 months (September/October 2020 to April/May 2021). Middle-aged and older adults with multimorbidity experienced faster rates of change in anxiety symptoms and loneliness than those without multimorbidity, with persistently elevated mental health symptomatology throughout the follow-up. Discussion and Implications Results highlight the unique and persistent mental health risks experienced by middle-aged and older adults with multimorbidity during the COVID-19 pandemic. The observed improvements in symptoms underscore the mental resilience of these individuals, indicating their adaptation to the ongoing pandemic. &nbsp;</p

Cardiovascular Risk Factors Are Associated With Future Cancer

BACKGROUND The extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown. OBJECTIVES This study investigated the association of standard CVD risk factors, CVD biomarkers, pre-existing CVD, and ideal cardiovascular (CV) health metrics with the development of future cancer. METHODS This study prospectively followed Framingham Heart Study and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants free of cancer at baseline and ascertained histology-proven cancer. This study assessed the association of baseline CV risk factors, 10-year atherosclerotic (ASCVD) risk score, established CVD biomarkers, prevalent CVD, and the American Heart Association (AHA) Life's Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates. RESULTS Among 20,305 participants (mean age 50 +/- 14 years; 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 years (quartile 1 to 3: 13.3 to 15.0 years). Traditional CVD risk factors, including age, sex, and smoking status, were independently associated with cancer (p < 0.001 for all). Estimated 10-year ASCVD risk was also associated with future cancer (hazard ratio [HR]: 1.16 per 5% increase in risk; 95% confidence interval [CI] 1.14 to 1.17; p < 0.001). The study found that natriuretic peptides (tertile 3 vs. tertite 1; HR: 1.40; 95% 0:1.03 to 1.91; p 0.035) were associated with incident cancer but not high-sensitivity troponin (p 0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with tower future cancer risk (HR: 0.95 per 1-point increase in the AHA health score; 95% CI: 0.92 to 0.99; p = 0.009). CONCLUSIONS CVD risk, as captured by traditional CVD risk factors, 10-year ASCVD risk score, and natriuretic peptide concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a lower risk of future cancer. These data suggest that the association between CVD and future cancer is attributable to shared risk factors. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Long-distance RNA transport enables local protein synthesis at metabolicallyactive sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for RNA transport in which RNA granules “hitchhike” on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as a molecular tether between RNA granules and lysosomes. ANXA11 possesses an N-terminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. RNA granule transport requires ANXA11, and amyotrophic lateral sclerosis (ALS) mutations impair RNA granule transport in neurons by disrupting their interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in ALS

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development

Association of Cardiometabolic Disease With Cancer in the Community

BACKGROUND: Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear. OBJECTIVES: The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer. METHODS: FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models. RESULTS: Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all). CONCLUSIONS: Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus

During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C virus (HCV). By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA), exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth