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100_ Shared genetics between schizophrenia (SCZ) and Substance Use Disorders (SUDs)

Research Question and Aims

Substance use disorders (SUDs) are highly heritable conditions characterized by persistent and harmful patterns of psychoactive substance use. Individuals with schizophrenia (SCZ) are disproportionately affected by SUDs, which contributes to worse clinical outcomes, increased morbidity, and elevated mortality [PMID: 19325163]. Recent genomic studies have highlighted significant shared genetic risk between SCZ and various SUDs, suggesting partially overlapping biological mechanisms [PMID: 34472679, PMID: 38906991, PMID: 37252880]. However, the specific genetic pathways underlying this comorbidity remain insufficiently understool.

In recent analyses of our group, we explored the shared genetic architecture between SCZ and several SUDs using large-scale GWAS summary statistics and a range of complementary genomic methods. Among these, polygenic risk score (PRS) analyses revealed promising evidence suggesting that genetic liability to specific SUDs may contribute to SCZ risk. To further validate these findings, replication in independent samples is critical.

In this sense, with this proposal, we aim to replicate and extend our PRS findings by analyzing an independent schizophrenia sample. Specifically, we propose to:
1. Assess whether polygenic risk scores for cannabis use disorder (CanUD), problematic alcohol use (PAU), tobacco use disorder (TUD), and opioid use disorder (OUD) are associated with schizophrenia case-control status in the PsyCourse cohort.
2. Evaluate the generalizability and robustness of observed associations across independent clinical populations.

Analytic Plan

Participants
In this study, we aim to replicate polygenic risk score (PRS) associations between substance use disorders (SUDs) and schizophrenia (SCZ) using summary statistics from large-scale GWAS meta-analyses and cross-sectional data from the PsyCourse dataset. This dataset includes sociodemographic, clinical, and genomic data from individuals diagnosed with schizophrenia (N = 647) and healthy controls (N = 466).

Phenotype data – Schizophrenia diagnosis
Diagnostic status for schizophrenia is based on established clinical assessments conducted within the PsyCourse study protocol. Case-control status will serve as the primary outcome variable in the PRS analyses.

Genotype data
Genotyping in PsyCourse was performed using the Illumina Global Screening Array. Imputation was conducted using the Haplotype Reference Consortium panel on the Michigan Imputation Server. High-quality post-imputation dosage files will be used for PRS analyses, applying standard quality control filters (e.g., MAF > 1%, INFO > 0.9).

Analytic Plan – PRS for SUDs in SCZ
We will apply a cross-trait PRS framework to examine the polygenic contribution of substance use disorders to schizophrenia. GWAS summary statistics from the largest available European-ancestry meta-analyses will be used as discovery datasets:

Cannabis use disorder (CanUD): 32,436 cases and 563,331 controls [PMID: 37985822]
Problematic alcohol use (PAU): 113,325 cases and 639,923 controls [PMID: 38062264]
Tobacco use disorder (TUD): 174,021 cases and 565,874 controls [PMID: 38632388]
Opioid use disorder (OUD): 19,978 cases and 282,607 controls [PMID: 36171425]

Polygenic scores will be constructed using PRS-CS, a Bayesian regression method that accounts for linkage disequilibrium. PRSs will be calculated in the PsyCourse sample using PLINK v1.9. Logistic regression models will be used to test associations between each SUD-derived PRS and schizophrenia case-control status, adjusting for age, sex, and the first 10 ancestry principal components (PCs). We will report variance explained (Nagelkerke’s R²) and statistical significance for each model.

Since the prevalence of SUDs differ in males and females, sex will be included as a covariate in all analyses. Sex-stratified analyses will also be performed.

Resources needed

v1_ever_smkd
v1_age_smk
v1_no_cig
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v1_scid_dsm_dx
v1_scid_dsm_dx_cat
v1_nrpsy_mwtb