Individuals with a family history of alcohol dependence are at increased risk for all substance use disorders (SUDs). Common genetic, morphological, and personality characteristics are thought to contribute to the greater addiction susceptibility among this population. The identification of predictors of resilience to any SUD could improve our understanding of the etiology of addiction and guide future prevention and interventions efforts. Aberrant dopaminergic transmission and frontostriatal circuitry have been identified in substance dependent individuals and their unaffected relatives in association with greater impulsivity. Therefore, the current study sought to evaluate variation in the C957T polymorphism of the dopamine D2 receptor gene (SNP rs6277) and volume of the orbitofrontal cortex (OFC) and caudate nucleus as predictors of resilience to SUD among individuals at high familial risk and normal controls. Families with multiple cases of alcohol dependence, known as multiplex families, are ideal for studying disease-related genotypes and endophenotypes. The present study included offspring from multiplex alcohol dependence families and control families who received annual clinical diagnostic assessments, MRI scans, and provided blood samples for genotyping. Binary logistic mixed model regression analyses were conducted to quantify the relationships between genetic and morphological variation and SUD onset by age 20. The results revealed a significant association between C957T variation and resilience in young adulthood (p = .046). A risk by gene interaction was also observed for OFC volume, such that among HR offspring only, DRD2 genotype was a significant predictor of total OFC volume (p = .034). The identification of mechanisms mediating the association between DRD2 variation and resilience to SUD could contribute to the development of future preventative interventions for high-risk individuals
