Another observation from our results is that miRNA belonging to a miRNA family act cooperatively to control the expression of a single mRNA target. For example, members of the hsa-miR-34 family (hsa-miR-34b and hsa-miR-34c) clustered into miRNA module M brown, and were shown to target numerous hub genes in the neuronal expression associated mRNA modules, M turquoise and M yellow. This miRNA family has been shown to play role in a wide range of human disease phenotypes including neuropsychiatric and neurodegenerative disorders, and is also reported to be upregulated in the PFC of human chronic alcoholics [20, 47, 48]. In addition, we identified that hsa-miR-34c-5p and hsa-miR-34b-5p cooperatively target neuronatin (NNAT; rs1780705) and proteosome subunit beta, type 5 (PSMB5; rs10137082)–two mRNA hub genes with significant eQTLs that were also associated with AD (p< 10−3) in the COGA sample. Our most significant eQTL signal was associated with glutatamate decarboxylase (GAD1) expression, the rate-limiting enzyme in GABA biosynthesis and previously implicated in AD. GAD1 was also cooperatively targeted by the hsa-miR-34 family of miRNAs [55, 78]. Thus, our observations here corroborate a priori evidence implicating the involvement of the hsa-miR-34 family in alcohol addiction phenotypes and reinforce its significance.
