shown to be important epigenetic regulators in cancer cells [47–49] and, relevant to this study, reward circuitry in depression [50] and alcohol withdrawal [51, 52]. The fact that KDM4A has known interactions with medications that are used to treat other psychiatric conditions, such as depression, or target dopaminergic or serotonergic systems, as well as drugs used in opioid anesthetics, suggests that KDM4 demethylases may be implicated in relevant biology for opioid behaviors and could represent promising druggable targets [53]. However, the biology of this locus could be more complex. Although the credible set analysis suggested that the most probable causal variants are located in KDM4A, the lead variant in this region, rs3791033, is an eQTL for several other nearby genes PTPRF, HYI, ST3GAL3, MED8, CCDC24, ATP6V0B, WDR65, ARTN, TIE1. Our second strongest signal was rs640561, which is near the gene LRRIQ3, which is a protein-coding gene of leucine rich repeats and IQ Motif Containing 3. rs640561, or SNPs in strong LD, have been previously associated with other substance use traits, including smoking [54–56] and alcohol consumption [56], schizophrenia [57], education attainment and math ability [58], but the mechanism whereby this SNP affects OUD liability is largely unknown. Lastly, the gene-set
