Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

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.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Objective: 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 mental and physical health problems, prior pharmacological treatments, and aggregate genetic factors has potential to inform risk stratification and mitigation strategies. Methods: In this study of 3,942 SCZ and 5,414 BPI patients receiving VA care, self-reported SB and ideation were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). These cross-sectional data were integrated with electronic health records (EHR), and compared by lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. Polygenic scores (PGS) for traits related to psychiatric disorders, substance use, and cognition were constructed using available genomic data, and exploratory genome-wide association studies were performed to identify and prioritize specific loci. Results: Only 20% of veterans who self-reported SB had a corroborating ICD-9/10 code in their EHR; and among those who denied prior behaviors, more than 20% reported new-onset SB at follow-up. SB were associated with a range of psychiatric and non-psychiatric diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking, suicide attempt, and major depressive disorder were also associated with attempt and ideation. Conclusions: Among individuals with a diagnosed mental illness, a GWAS for SB did not yield any significant loci. Self-reported SB were strongly associated with clinical variables across several EHR domains. Overall, clinical and polygenic analyses point to sequelae of substance-use related behaviors and other psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in clinical settings, underscoring the value of regular screening based on direct, in-person assessments, especially among high-risk individuals.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.

Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis.

BACKGROUND AND AIMS: The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis). DESIGN: Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families. SETTING: Six sites in the United States. PARTICIPANTS: European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample. MEASUREMENTS: Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment. FINDINGS: In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R2 0.13-0.20%). CONCLUSIONS: Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education).

FinnTwin12 Cohort: An Updated Review.

This review offers an update on research conducted with FinnTwin12 (FT12), the youngest of the three Finnish Twin Cohorts. FT12 was designed as a two-stage study. In the first stage, we conducted multiwave questionnaire research enrolling all eligible twins born in Finland during 1983-1987 along with their biological parents. In stage 2, we intensively studied a subset of these twins with in-school assessments at age 12 and semistructured poly-diagnostic interviews at age 14. At baseline, parents of intensively studied twins were administered the adult version of the interview. Laboratory studies with repeat interviews, neuropsychological tests, and collection of DNA were made of intensively studied twins during follow-up in early adulthood. The basic aim of the FT12 study design was to obtain information on individual, familial and school/neighborhood risks for substance use/abuse prior to the onset of regular tobacco and alcohol use and then track trajectories of use and abuse and their consequences into adulthood. But the longitudinal assessments were not narrowly limited to this basic aim, and with multiwave, multirater assessments from ages 11 to 12, the study has created a richly informative data set for analyses of gene-environment interactions of both candidate genes and genomewide measures with measured risk-relevant environments. Because 25 years have elapsed since the start of the study, we are planning a fifth-wave follow-up assessment.