Browsing by Author "Harvey, Philip D."

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    Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies
    (medRxiv, 2024-07-29) Monson, Eric T.; Colbert, Sarah M. C.; Andreassen, Ole A.; Ayinde, Olatunde O.; Bejan, Cosmin A.; Ceja, Zuriel; Coon, Hilary; DiBlasi, Emily; Izotova, Anastasia; Kaufman, Erin A.; Koromina, Maria; Myung, Woojae; Nurnberger, John I., Jr.; Serretti, Alessandro; Smoller, Jordan W.; Stein, Murray B.; Zai, Clement C.; Suicide Working Group of the Psychiatric Genomics Consortium; Aslan, Mihaela; Barr, Peter B.; Bigdeli, Tim B.; Harvey, Philip D.; Kimbrel, Nathan A.; Patel, Pujan R.; Cooperative Studies Program (CSP) #572; Ruderfer, Douglas; Docherty, Anna R.; Mullins, Niamh; Mann, J. John; Psychiatry, School of Medicine
    Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.
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    Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System
    (American Medical Association, 2022-09-14) Bigdeli, Tim B.; Voloudakis, Georgios; Barr, Peter B.; Gorman, Bryan R.; Genovese, Giulio; Peterson, Roseann E.; Burstein, David E.; Velicu, Vlad I.; Li, Yuli; Gupta, Rishab; Mattheisen, Manuel; Tomasi, Simone; Rajeevan, Nallakkandi; Sayward, Frederick; Radhakrishnan, Krishnan; Natarajan, Sundar; Malhotra, Anil K.; Shi, Yunling; Zhao, Hongyu; Kosten, Thomas R.; Concato, John; O'Leary, Timothy J.; Przygodzki, Ronald; Gleason, Theresa; Pyarajan, Saiju; Brophy, Mary; Huang, Grant D.; Muralidhar, Sumitra; Gaziano, J. Michael; Aslan, Mihaela; Fanous, Ayman H.; Harvey, Philip D.; Roussos, Panos; Cooperative Studies Program (CSP); Million Veteran Program (MVP); Psychiatry, School of Medicine
    Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. Design, setting, and participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. Main outcomes and measures: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Results: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. Conclusions and relevance: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.