Cross-phenotype relationship between opioid use disorder and suicide attempts: new evidence from polygenic association and Mendelian randomization analyses
Authors: Huang Yunqi , Chen Dongru , Levin Albert M. , Ahmedani Brian K. , Frank Cathrine , Li Miaoxin , Wang Qiang , Gui Hongsheng , Sham Pak C. 
Published: November 2022

AbstractIMPORTANCEClinical epidemiological studies have found high rates of comorbidity between suicide attempts (SA) and opioid use disorder (OUD). However, the patterns of correlation and causation between them are still not clear due to psychiatric confounding.OBJECTIVETo investigate the pairwise associations and interrogate the potential bidirectional relationship between OUD and SA using genetically based methods.DESIGN, SETTING, AND PARTICIPANTSWe utilized raw phenotypes and genotypes from UK Biobank, and summary statistics from Million Veteran Program, Psychiatric Genomic Consortium, iPSYCH, and International Suicide Genetics Consortium. Statistical genetics tools were used to perform epidemiological association, genetic correlation, polygenic risk score prediction, and Mendelian randomizations (MR). Analyses were conducted to examine the OUD-SA relationship with and without controlling for psychiatric disease status (e.g., major depressive disorder [MDD]).MAIN OUTCOMES AND MEASURESOUD and SA with or without major psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and alcohol use disorder).RESULTSStrong correlations between OUD and SA were observed at both phenotypic level (overall samples [OR=2.94,P=1.59 ×10−14]; non-psychiatric subgroup [OR=2.15,P=1.07 ×10−3]) and genetic level (r2=0.4 and 0.5 with or without conditioning on MDD). The higher genetic susceptibility to SA can increase the polygenic risk of OUD (OR=1.08, false discovery rate [FDR] =1.71 ×10−3), while the higher susceptibility to OUD can also increase the risk of SA (OR=1.09, FDR =1.73 ×10−6). However, predictive abilities for both were much weakened after controlling for influence of psychiatric diseases. A combination of different MR analyses suggested a possible causal association from SA to OUD (2-sample univariable MR: OR=1.14,P= 0.001; multivariable MR: OR=1.08,P= 0.001).CONCLUSIONS AND RELEVANCEThis study provided new genetic evidence underlying the strong OUD-SA comorbidity. While controlling for the influence of psychiatric diseases, there is still some clue on possible causal association between SA genetic liability and the risk for OUD. Future prevention strategy for each phenotype needs to take into consideration of screening for the other one.Key PointsQuestionDoes opioid use disorder (OUD) have a potentially causal role in the risk for suicide attempts (SA), or vice versa?FindingsIn this observational study with raw data from >150,000 UK Biobank samples and genome-wide association summary statistics from >600,000 individuals, positive phenotypic and genetic associations were observed between OUD and SA, whether or not controlling for major psychiatric disorders. Comprehensive Mendelian randomization analyses (one-sample and two-sample) suggested the genetic liability for SA was associated with increased risk for OUD. However, they were still underpowered to reveal the putative causal association from OUD to SA.MeaningThis genomics-based study supports a strong genetic association underlying the OUD-SA comorbidity. Though both phenotypes are intertwined with other psychiatric disorders, there also exists an independent bidirectional relationship between OUD and SA.