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Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572., Methods: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date., Results: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572., Conclusions: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2020.)

Background: We compared male and female American veterans with schizophrenia or bipolar disorder regarding clinical characteristics associated with lifetime suicidal ideation and behavior. Subsequent mortality, including death by suicide, was also assessed., Methods: Data from questionnaires and face-to-face evaluations were collected during 2011-2014 from 8,049 male and 1,290 female veterans with schizophrenia or bipolar disorder. In addition to comparing male-female characteristics, Cox regression models-adjusted for demographic information, medical-psychiatric comorbidities, and self-reported suicidal ideation and behavior-were used to examine gender differences in associations of putative risk factors with suicide-specific and all-cause mortality during up to six years of follow-up., Results: Women overall were younger, more likely to report a history of suicidal behavior, less likely to be substance abusers, and had lower overall mortality during follow-up. Among women only, psychiatric comorbidity was paradoxically associated with lower all-cause mortality (hazard ratio [HR]=0.53, 95% CI, 0.29-0.96, p = 0.037 for 1 disorder vs. none; HR=0.44, 95% CI, 0.25-0.77, p = 0.004 for ≥2 disorders vs. none). Suicide-specific mortality involved relatively few events, but crude rates were an order of magnitude higher than in the U.S. general and overall veteran populations., Limitations: Incomplete cause-of-death information and low statistical power for male-female comparisons regarding mortality., Conclusions: Female veterans with SMI differed from females in the general population by having a higher risk of suicide attempts. They also had more lifetime suicide attempts than male veterans with same diagnoses. These differences should inform public policy and clinical planning., Competing Interests: Declaration of Competing Interest Dr. Harvey has received consulting fees or travel reimbursements from Boehringer Ingelheim, Intra-Cellular Therapies, Minerva, Otsuka America (Otsuka Digital Health), Sanofi Pharma, Sunovion Pharma, Takeda Pharma, and Teva during the past year. He receives royalties from the Brief Assessment of Cognition in Schizophrenia, and he has a research grant from Takeda and from the Stanley Medical Research Foundation. These activities are unrelated to the content of this paper., (Published by Elsevier B.V.)

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: Using data from a Department of Veterans Affairs study of schizophrenia (SZ) and bipolar I disorder (BP), we evaluated lifetime risks for suicidal ideation and behavior. We were interested in the prevalence and correlates of these outcomes, in populations of patients with severe mental illness (SMI), who have not been compared directly in previous studies despite data on high risk in each group separately., Method: Data were collected on demographic factors, medical and psychiatric comorbidity, cognitive and functional status, and lifetime suicidal ideation or behavior in a study of veterans with SZ (N = 3942) or BP (N = 5414). In-person diagnosis and evaluation, including performance-based assessments of cognition and functional skills, make this study unique compared to studies of completed suicide. Multinomial logistic regression examined how risk factors, including major depression and negative symptoms in SCZ patients, correlated with ideation and behavior., Results: A lifetime history of suicidal ideation or behavior was reported by a majority of Veterans with SZ (69.9%) or BP (82.3%). Lower risk was found for patients with SZ vs. BP (odds ratio [OR] = 0.82 for ideation; OR = 0.81 for behavior). The highest risk was found for patients with multiple psychiatric comorbidities (OR = 2.61 for ideation; OR = 3.82 for behavior). Clinical factors (e.g., psychiatric comorbidity) contributed more of the variance in the predictive model than demographic factors., Conclusions: A history of suicidal ideation or behavior is common among US Veterans with SZ or BP, and specific demographic and clinical attributes correlate with variation in risk. These findings underscore the need for continuous monitoring for suicidal ideation and behavior in veteran populations with SMI, as well as the development of better risk predictions, including genomic factors. Although PTSD is a major current focus in veteran populations, the large number of veterans with SZ or BP and their high suicide risk suggests a greater clinical focus may be warranted., (Published by Elsevier Ltd.)

A key step in genomic studies is to assess high throughput measurements across millions of markers for each participant's DNA, either using microarrays or sequencing techniques. Accurate genotype calling is essential for downstream statistical analysis of genotype-phenotype associations, and next generation sequencing (NGS) has recently become a more common approach in genomic studies. How the accuracy of variant calling in NGS-based studies affects downstream association analysis has not, however, been studied using empirical data in which both microarrays and NGS were available. In this article, we investigate the impact of variant calling errors on the statistical power to identify associations between single nucleotides and disease, and on associations between multiple rare variants and disease. Both differential and nondifferential genotyping errors are considered. Our results show that the power of burden tests for rare variants is strongly influenced by the specificity in variant calling, but is rather robust with regard to sensitivity. By using the variant calling accuracies estimated from a substudy of a Cooperative Studies Program project conducted by the Department of Veterans Affairs, we show that the power of association tests is mostly retained with commonly adopted variant calling pipelines. An R package, GWAS.PC, is provided to accommodate power analysis that takes account of genotyping errors (http://zhaocenter.org/software/)., (© 2016 WILEY PERIODICALS, INC.)

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses, including Schizophrenia (SZ) and Bipolar Disorder (BP). Cognitive performance in patients with bipolar disorder or schizophrenia has been found to be very similar in underlying structure, and recent research has suggested genomic linkage to several different cognitive phenotypes. In addition, recent evidence from the Cognitive Genomics Consortium (COGENT) study, focusing on a pooled population of more than 35,000 healthy European ancestry patients from 24 studies, reported an estimated SNP heritability of 21.5%. The current study examined the genomic correlates of cognitive and functional skills performance in 8,051 U.S. veterans with either SZ or BP. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and Functional Capacity (FC) measures among BPI and SZ patients, using a subset of tests from the MATRICS Consensus cognitive battery (MCCB) and the UCSD Performance based skills assessment brief version (UPSAB). In conjunction with the VA Million Veteran Program, and using a customized Affymetrix Axiom genotyping array for samples from 3,388 SZ and 4,663 BP CSP #572 patients (N=8,051 total), we conducted genome-wide association analyses for European Americans (3,952) and African Americans (2,598) separately. There are no SNPs with genome-wide statistically significant results for either EA or AA samples. We also applied MetaXcan to calculate gene-level test statistics across 44 tissues and did not identify any associated genes. However, based on the comparison between summary statistics from this study and those from published GWAS of 55 diseases/traits, there is statistically significant evidence of genetic correlation between cognitive function and schizophrenia (1.7E09), but not bipolar illness. No SNPs with strong evidence of association with cognitive performance were identified in this study, but genetic correlation analysis between this study and published GWAS on schizophrenia from other studies suggests shared factors between cognitive functions and schizophrenia. Later analyses will perform targeted examination of the linkage of previously identified genes and SNPs to overall performance and specific cognitive phenotypes. [ABSTRACT FROM AUTHOR]