Towards personalized medicine in psychiatry : focus on suicide

Indiana University-Purdue University Indianapolis (IUPUI)Psychiatric disorders cost an estimated $273 billion annually. This cost comes largely in the form of lost income and the chronic disability that often strikes people when they are young and can last decades. While the monetary costs are quantifiable, the suffering of each individual patient is no less vital. As many as 1 in 5 persons diagnosed with mental illness will commit suicide, a contributing factor in suicide being the second leading cause of death of people age 15-34. There is a critical need to find better ways to identify and help those who are at risk. Understanding mental illness and improving treatment has been difficult due to the heterogeneous and complex etiology of these illnesses. A significant challenge for the field is integrating findings from diverse laboratories all over the world contributing to the ever expanding literature and translating them into actionable treatment. Our lab employs a convergent functional genomics approach which incorporates multiple independent lines of evidence provided by genetic and functional genomic data published in the primary literature as a Bayesian strategy to prioritize experimental findings. Heritability and genetics clearly play an important role in psychiatric disorders. We looked at schizophrenia and alcoholism in separate case-control analyses in order to identify and prioritize genes related to these disorders. We were able to reproduce these findings in additional independent cohorts using polygenic risk scores. We found overlap in these disorders, and identified possible underlying biological processes. Genetics play an important role in identifying clinical risk, particularly at the population level. At the level of the individual, gene expression may provide more proximal association to disease state, assimilating environmental, genetic, as well as epigenetic influence. We undertook N of 1 analyses in a longitudinally followed cohort of psychiatric participants, identifying genes which change in expression tracking an individual’s change in suicidal ideation. These genes were able to predict suicidal behavior in independent cohorts. When combined with simple clinical instruments these predictions were improved. This work shows how multi level integration of genetic, gene expression, and clinical data could be used to enable precision medicine in psychiatry

Construction of a Database for Socio-Demographic, Medico-Legal, Anatomic, and Genomic Research into Suicide

poster abstractSuicide is a potentially preventable tragedy. Over 180 cases of suicide a year occur in Marion County. We have created a database that permits integration of socio-demographic data, medico-legal information, anatomic images, and genomic results. We have collected over 50 cases to date. We will show results of analyses looking at method of suicide, toxicology results, and genomic biomarker correlates. It is hoped that this resource would permit the study of risk factors and the creation of predictive algorithms that may better identify people at risk, and lead to early intervention and prevention efforts

Aspirin Use and Incident Cardiovascular Disease, Kidney Failure, and Death in Stable Kidney Transplant Recipients: A Post Hoc Analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial

Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients. Whether aspirin may reduce the risk for CVD, death, and kidney failure outcomes is uncertain

CKD classification based on estimated GFR over three years and subsequent cardiac and mortality outcomes: a cohort study

<p>Abstract</p> <p>Background</p> <p>It is unknown whether defining chronic kidney disease (CKD) based on one versus two estimated glomerular filtration rate (eGFR) assessments changes the prognostic importance of reduced eGFR in a community-based population.</p> <p>Methods</p> <p>Participants in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study were classified into 4 groups based on two eGFR assessments separated by 35.3 ± 2.5 months: sustained eGFR < 60 mL/min per 1.73 m²(1 mL/sec per 1.73 m²); eGFR increase (change from below to above 60); eGFR decline (change from above to below 60); and eGFR persistently ≥60. Outcomes assessed in stratified multivariable Cox models included cardiac events and a composite of cardiac events, stroke, and mortality.</p> <p>Results</p> <p>There were 891 (4.9%) participants with sustained eGFR < 60, 278 (1.5%) with eGFR increase, 972 (5.4%) with eGFR decline, and 15,925 (88.2%) with sustained eGFR > 60. Participants with eGFR sustained < 60 were at highest risk of cardiac and composite events [HR = 1.38 (1.15, 1.65) and 1.58 (1.41, 1.77)], respectively, followed by eGFR decline [HR = 1.20 (1.00, 1.45) and 1.32 (1.17, 1.49)]. Individuals with eGFR increase trended toward increased cardiac risk [HR = 1.25 (0.88, 1.77)] and did not significantly differ from eGFR decline for any outcome. Results were similar when estimating GFR with the CKD-EPI equation.</p> <p>Conclusion</p> <p>Individuals with persistently reduced eGFR are at highest risk of cardiovascular outcomes and mortality, while individuals with an eGFR < 60 mL/min per 1.73 m²at any time are at intermediate risk. Use of even a single measurement of eGFR to classify CKD in a community population appears to have prognostic value.</p

Trainee participation during screening colonoscopy does not affect ADR at subsequent surveillance, but may result in early follow-up

Background and study aims: Training future endoscopists is essential to meet rising demands for screening and surveillance colonoscopies. Studies have shown conflicting results regarding the influence of trainees on adenoma detection rates (ADR). It is unclear whether trainee participation during screening adversely affects ADR at subsequent surveillance and whether it alters surveillance recommendations. Patients and methods: A retrospective analysis of average-risk screening colonoscopies and surveillance exams over a subsequent 10-year period was performed. The initial inclusion criteria were met by 5208 screening and 2285 surveillance exams. Patients with poor preparation were excluded. The final analysis included 7106 procedures, including 4922 screening colonoscopies and 2184 surveillance exams. Data were collected from pathology and endoscopy electronic databases. The primary outcome was the ADR with and without trainee participation. Surveillance recommendations were analyzed as a secondary outcome. Results: Trainees participated in 1131 (23 %) screening and in 232 (11 %) surveillance exams. ADR did not significantly differ ( P = 0.19) for screening exams with trainee participation (19.5 %) or those without (21.4 %). ADRs were higher at surveillance exams with (22.4 %) and without (27.5 %) trainee participation. ADR at surveillance was not adversely affected by trainee participation during the previous colonoscopy. Shorter surveillance intervals were given more frequently if trainees participated during the initial screening procedure ( P = 0.0001). Conclusions: ADR did not significantly differ in screening or surveillance colonoscopies with or without trainee participation. ADR at surveillance was not adversely affected by trainee participation during the previous screening exam. However, trainee participation may result in shorter surveillance recommendations

Genetic Decomposition of the Heritable Component of Reported Childhood Maltreatment

BACKGROUND: Decades of research have shown that environmental exposures, including self-reports of trauma, are partly heritable. Heritable characteristics may influence exposure to and interpretations of environmental factors. Identifying heritable factors associated with self-reported trauma could improve our understanding of vulnerability to exposure and the interpretation of life events. METHODS: We used genome-wide association study summary statistics of childhood maltreatment, defined as reporting of abuse (emotional, sexual, and physical) and neglect (emotional and physical) (N = 185,414 participants). We calculated genetic correlations (rg) between reported childhood maltreatment and 576 traits to identify phenotypes that might explain the heritability of reported childhood maltreatment, retaining those with |rg| > 0.25. We specified multiple regression models using genomic structural equation modeling to detect residual genetic variance in childhood maltreatment after accounting for genetically correlated traits. RESULTS: In 2 separate models, the shared genetic component of 12 health and behavioral traits and 7 psychiatric disorders accounted for 59% and 56% of heritability due to common genetic variants (single nucleotide polymorphism–based heritability [h2SNP]) of childhood maltreatment, respectively. Genetic influences on h2SNP of childhood maltreatment were generally accounted for by a shared genetic component across traits. The exceptions to this were general risk tolerance, subjective well-being, posttraumatic stress disorder, and autism spectrum disorder, identified as independent contributors to h2SNP of childhood maltreatment. These 4 traits alone were sufficient to explain 58% of h2SNP of childhood maltreatment. CONCLUSIONS: We identified putative traits that reflect h2SNP of childhood maltreatment. Elucidating the mechanisms underlying these associations may improve trauma prevention and posttraumatic intervention strategies

Genome-wide association studies and cross-population meta-analyses investigating short and long sleep duration

Sleep duration has been linked to a wide range of negative health outcomes and to reduced life expectancy. We present genome-wide association studies of short ( ≤ 5 h) and long ( ≥ 10 h) sleep duration in adults of European (N = 445,966), African (N = 27,785), East Asian (N = 3141), and admixed-American (N = 16,250) ancestry from UK Biobank and the Million Veteran Programme. In a cross-population meta-analysis, we identify 84 independent loci for short sleep and 1 for long sleep. We estimate SNP-based heritability for both sleep traits in each ancestry based on population derived linkage disequilibrium (LD) scores using cov-LDSC. We identify positive genetic correlation between short and long sleep traits (rg = 0.16 ± 0.04; p = 0.0002), as well as similar patterns of genetic correlation with other psychiatric and cardiometabolic phenotypes. Mendelian randomisation reveals a directional causal relationship between short sleep and depression, and a bidirectional causal relationship between long sleep and depression