A Multivariate Genomic Investigation of the Externalizing Spectrum and Suicide Risk.
paper
Primary
Public
Preprint
- Authors
- Barr, Peter B; Stephenson, Mallory; Poore, Holly E; Chatzinakos, Chris; Qin, Xuejun; Ashley-Koch, Allison E; Hauser, Elizabeth R; Meyers, Jacquelyn L; Peterson, Roseann E; Sanchez-Roige, Sandra; Mallard, Travis T; Dick, Danielle M; Harden, K Paige; COGA Collaborators; Aslan, Mihaela; Harvey, Philip D; Beckham, Jean C; Bigdeli, Tim B; Kimbrel, Nathan A
- Year
- 2025
- Journal
- medRxiv : the preprint server for health sciences
- PMID
- 40894127
- DOI
- 10.1101/2025.08.19.25332327
- PMCID
- PMC12393625
Suicidal thoughts and behaviors originate from heterogeneous mechanisms, including behavioral disinhibition characteristic of "externalizing" disorders (e.g., substance use disorders, antisocial personality disorder, etc.). Prior work has demonstrated strong genetic overlap between externalizing and suicide attempts. In the current analysis, we investigate the co-occurrence between a broader array of suicide phenotypes (i.e., suicide deaths, non-fatal attempts, suicidal ideation) and the externalizing spectrum using data from the Million Veteran Program (MVP) Cohort. We leverage the large-scale MVP database to (1) estimate a latent genomic factor for externalizing comprised of MVP data (MVP-EXT) using genomic structural equation modeling (GenomicSEM), (2) validate these results against prior externalizing models and other traits, (3) examine the genetic overlap between externalizing and suicide outcomes using multiple approaches (e.g., genetic correlations, polygenic scores, and post mortem brain tissue of suicide deaths), and (4) explore whether phenotypic externalizing is prospectively associated with death by suicide. We identify 155 loci in our meta-analysis of European-like (EUR-like, N = 310,498) and African-like (AFR-like, N = 99,949) MVP participants. MVP-EXT showed a strong genetic correlation with a prior, non-MVP externalizing factor (rG = 0.87, 95% CI = 0.83, 0.91) and suicide attempt in both EUR-like (rG = 0.67, 95% CI = 0.60, 0.74) and AFR-like (rG = 0.62, 95% CI = 0.42, 0.81) veterans. MVP-EXT polygenic scores were associated with suicidal ideation (OR = 1.09, 95% CI = 1.05, 1.13) and suicide attempts (OR = 1.20, 95% CI = 1.13, 1.27) in independent cohorts. MVP-EXT associated genes showed significant enrichment particularly within inhibitory neurons in suicide deaths compared to deaths from other causes. A phenotypic score for externalizing was prospectively associated with death by suicide in MVP (HR = 1.39, 95% CI = 1.33, 1.45). In total, our results reiterate that, while the relation between suicide with internalizing disorders has generally received more attention, externalizing is an important risk factor for suicide related behaviors. Greater attention should be paid to these problems as potential antecedents of suicide-related behaviors.
Multivariate GWAS models of externalizing in MVP.Final models for EUR-like (Panel A) and AFR-like (Panel B) populations used in the subsequent multivariate GWASs. Df = degrees of freedom. AIC = Akaike’s information criterion, CFI = comparative fit index, SRMR = standardized root mean squared residual.
Genetic correlations across populations.Genetic correlations (and 95% confidence intervals) between MVP-EXT and suicide attempt (SUI) and suicidal ideation (IDE) for both European-like and African-like results (Panel A). Genetic overlap between MVP-EXT and SUI using bivariate MiXeR in European-like results (Panel B). Venn diagram depicting the estimated number of influencing variants in thousands shared (grey) between and unique to suicide attempt (SUI, blue) and externalizing (MVP-EXT, orange). Conditional quantile–quantile (Q–Q) plots show observed versus expected −log10 p values in SUI and MVP-EXT as a function of the significance of association with the other trait. Log likelihood curves show goodness of model fit as a function of the count of shared influential variants.
Polygenic associations between MVP-EXT PGS in COGA and Add Health.European-like, African-like, and meta-analysis associations between MVP-EXT PGS and suicide attempt (SUI) and suicidal ideation (IDE) in COGA and Add Health (Panel A). Proportion of individuals reporting lifetime suicide attempt across MVP-EXT PGS deciles (left) and phenotypic factor score deciles (right) in European-like and African-like COGA participants (Panel B).
Cell-type enrichment for MVP-EXT results in post-mortem brain tissue.Cell type enrichment across suicide deaths vs deaths from other causes (Panel A). Cell-type clusters (Panel B). Tests for cell-type enrichment across European-like, African-like, and meta-analysis results (Panel C).
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| Name | Type |
|---|---|
| Add Health | cohort |
| ADHD | phenotype |
| African American | cohort |
| African-like local | cohort |
| African-like population local | cohort |
| African reference panels local | cohort |
| AFR-like local | cohort |
| AFR-like participants local | cohort |
| AFR-like population local | cohort |
| AFR-like results local | cohort |
| AFR-like veterans local | cohort |
| age | phenotype |
| airflow obstruction | phenotype |
| alcohol | phenotype |
| Alcohol-related death local | phenotype |
| Alcohol Use Disorder | phenotype |
| alcohol use disorders | phenotype |
| astroglia | anatomy |
| attention deficit hyperactivity disorder | phenotype |
| AUD | phenotype |
| behavioral disinhibition | phenotype |
| binge drinking | phenotype |
| birth cohort | cohort |
| brain tissue | anatomy |
| cell type enrichment local | phenotype |
| chronic conditions local | phenotype |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| deaths from other causes local | phenotype |
| deaths of despair local | phenotype |
| Deaths of despair local | phenotype |
| dorsolateral prefrontal cortex | anatomy |
| Drug-related death local | phenotype |
| electronic health records | cohort |
| EUR-like local | cohort |
| EUR-like participants local | cohort |
| EUR-like population local | cohort |
| EUR-like veterans local | cohort |
| European-like local | cohort |
| European-like population local | cohort |
| European reference panels local | cohort |
| EXT1.0 local | cohort |
| EXT1.0 local | phenotype |
| external cohorts | cohort |
| externalizing behavior | phenotype |
| Externalizing Consortium GWAS (EXT1.0) local | cohort |
| externalizing disorders | phenotype |
| Externalizing-related traits local | phenotype |
| EXT-factor scores local | drug |
| GABA | phenotype |
| genetic similarity local | cohort |
| homelessness | phenotype |
| impulsivity | phenotype |
| internalizing disorders | phenotype |
| Latent externalizing factor local | phenotype |
| lifetime smoking | phenotype |
| Liver cirrhosis | phenotype |
| major depressive disorder | phenotype |
| marginalized populations local | cohort |
| Million Veteran Program | cohort |
| mood disorders | phenotype |
| Mood-related disorders local | phenotype |
| Mood-related problems local | phenotype |
| mortality | phenotype |
| MOS-ATTN local | phenotype |
| multiple morbidities local | phenotype |
| MVP | cohort |
| MVP 1.0 Axiom array local | drug |
| MVP-EXT local | cohort |
| MVP-EXT local | gene |
| MVP-EXT local | phenotype |
| MVP-EXT PGS local | drug |
| MVP-EXT PGS local | phenotype |
| MVP participants | cohort |
| NAFR-like local | cohort |
| National Death Index | cohort |
| NEUR-like local | cohort |
| non-Hispanic whites | cohort |
| non-suicide deaths local | phenotype |
| OPCs | anatomy |
| phenotypic factor score local | phenotype |
| postmortem brain | anatomy |
| Post-Traumatic Stress Disorder | phenotype |
| Q-SNPs local | variant |
| race-ethnicity local | cohort |
| Race-ethnicity local | phenotype |
| sex | phenotype |
| SMOK | phenotype |
| social support | phenotype |
| Substance addiction and disorders local | phenotype |
| substance use | phenotype |
| SUD | phenotype |
| SUI | phenotype |
| suicide | phenotype |
| suicide outcomes | phenotype |
| Suicide-related mortality local | phenotype |
| suicide-related outcomes local | phenotype |
| Suicide related outcomes local | phenotype |
| Suicide-related outcomes local | phenotype |
| tobacco dependence | phenotype |
| tobacco use | phenotype |
| TOPMed reference panel local | cohort |
| TUD | phenotype |
| unemployment | phenotype |
| United States | cohort |
| VA’s National PTSD Brain Bank local | cohort |
| Veteran population local | cohort |
| veterans | cohort |
| viral hepatitis C | phenotype |
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| 40894127.pdf | 713403 bytes | 2026-05-15 | View |
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