We discovered that one gene (ARHGEF15) was consistently upregulated in all investigated brain regions of AUD cases compared to controls. ARHGEF15 encodes a specific guanine nucleotide exchange factor for the activation of Ras homolog family member A (RhoA), a GTPase, which has been linked to higher blood pressure and hypertension over the Rho/ROCK signaling cascade [40]. It is postulated that the Rho Guanine Nucleotide Exchange Factor 15 negatively regulates excitatory synapse development by suppressing the synapse-promoting activity of EPHB2 [41]. EPHB2 deficiency has been linked to depression-like behaviors and memory impairments in animal studies [42]. In line with this, genetic variation within ARHGEF15 has been associated with hematocrit, red blood cell count, and hemoglobin concentration [43], but also with psychiatric traits, such as neuroticism and worries [44] as well as bipolar disorder [45].
