Genetic Architecture and Molecular Neuropathology of Human Cocaine Addiction.

We integrated genomic and bioinformatic analyses, utilizing data from the largest genome-wide association study (GWAS) of cocaine dependence (CD; n=6,546; 82.37% with CD; 57.39% male) and the largest post-mortem gene-expression sample of individuals with cocaine use disorder (CUD; n=36; 51.35% with CUD; 100% male). Our genome-wide analyses identified one novel gene (NDUFB9) associated with the genetic predisposition to CD in African-Americans. The genetic architecture of CD was similar across ancestries. Individual genes associated with CD demonstrated modest overlap across European and African-Americans, but the genetic liability to CD converged on many similar tissue types (brain, heart, blood, liver) across ancestries. In a separate sample, we investigated the neuronal gene expression associated with CUD by using RNA sequencing of dorsal-lateral pre-frontal cortex neurons. We identified 133 genes differentially expressed between CUD cases and cocaine-free controls, including previously implicated candidates for cocaine use/addiction (FOSB, ARC, KCNJ9/GIRK3, NR4A2, JUNB and MECP2). Differential expression analyses significantly correlated across European and African-Americans. While genes significantly associated with CD via genome-wide methods were not differentially expressed, two of these genes (NDUFB9 and C1qL2) were part of a robust gene co-expression network associated with CUD involved in neurotransmission (GABA, acetylcholine, serotonin and dopamine) and drug addiction. We then used a “guilt-by-association” approach to unravel the biological relevance of NDUFB9 and C1qL2 in the context of CD. In sum, our study furthers the understanding of the genetic architecture and molecular neuropathology of human cocaine addiction and provides a framework for translating biological meaning to otherwise obscure genome-wide associations. SIGNIFICANCE STATEMENT Our study: 1) further clarifies the genetic and neurobiological contributions to cocaine addiction, 2) provides a rapid approach for generating testable hypotheses for specific candidates identified by genome-wide research and 3) investigates the cross-ancestral biological contributions to cocaine use disorder/dependence for individuals of European- and African-American ancestries.