There is considerable comorbidity across externalizing and internalizing behavior dimensions of psychopathology. We applied genomic structural equation modeling (gSEM) to genome-wide association study (GWAS) summary statistics to evaluate the factor structure of externalizing and internalizing psychopathology across 16 traits and disorders among European-ancestry individuals (ns = 16,400 to 1,074,629). We conducted GWAS on factors derived from well-fitting models. Downstream analyses served to identify biological mechanisms, explore drug repurposing targets, estimate genetic overlap between the externalizing and internalizing spectra, and evaluate causal effects of psychopathology liability on physical health. Both a correlated factors model, comprising two factors of externalizing and internalizing risk, and a higher-order single-factor model of genetic effects contributing to both spectra demonstrated acceptable fit. GWAS identified 409 lead single nucleotide polymorphisms (SNPs) associated with externalizing and 85 lead SNPs associated with internalizing, while the second-order GWAS identified 256 lead SNPs contributing to broad psychopathology risk. In bivariate causal mixture models, nearly all externalizing and internalizing causal variants overlapped, despite a genetic correlation of only 0.37 (SE = 0.02) between them. Externalizing genes showed cell-type specific expression in GABAergic, cortical, and hippocampal neurons, and internalizing genes were associated with reduced subcallosal cortical volume, providing insight into the neurobiological underpinnings of psychopathology. Genetic liability for externalizing, internalizing, and broad psychopathology exerted causal effects on pain, general health, cardiovascular diseases, and chronic illnesses. These findings underscore the complex genetic architecture of psychopathology, identify potential biological pathways for the externalizing and internalizing spectra, and highlight the physical health burden of psychiatric comorbidity.

Dr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Enthion Pharmaceuticals, and Clearmind Medicine; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics. Drs. Kranzler and Gelernter hold U.S. patent 10,900,082 titled: "Genotype-guided dosing of opioid agonists," issued 26 January 2021. The other authors have no disclosures to make.

This work was supported by the Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center and by Department of Veterans Affairs grants I01 BX004820 to H.R.K., National Institute on Alcohol Abuse and Alcoholism grant AA028292 to R.L.K, and KNAW (Royal Netherlands Academy of Arts and Sciences) Academy Professor Award (PAH/6635) to D.I.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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GWAS Summary Statistics used for the present study can be accessed at the following locations: UK Biobank (http://www.nealelab.is/uk-biobank/), dbGaP accession phs001672 for Million Veteran Program (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001672), iPSYCH (https://ipsych.dk/en/research/downloads/), Psychiatric Genetics Consortium (https://pgc.unc.edu/for-researchers/download-results/), the Social Science Genetic Association Consortium (https://thessgac.com/), GWAS catalog (https://www.ebi.ac.uk/gwas/publications/28979981; https://www.ebi.ac.uk/gwas/publications/33532862), Gelernter Lab website (https://medicine.yale.edu/lab/gelernter/stats/), Global Biobank Meta-analysis Initiative (https://www.globalbiobankmeta.org/resources), and the Diabetes Genetics Replication and Meta-Analysis Consortium (https://diagram-consortium.org/downloads.html).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced in the present study are available upon reasonable request to the authors. Upon acceptance in a peer-reviewed journal, summary statistics produced will be made publicly available.