The strong association of a large region near ADRA2A (adrenoceptor alpha 2A) also provides a promising potential biological mechanism. Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. These receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the CNS. Alpha2A and alpha2C subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in central noradrenergic neurons, and the alpha2A subtype inhibits transmitter release at high neural stimulation frequencies. This gene encodes alpha2A subtype and it contains no introns in either its coding or untranslated sequences. There is an extensive literature on the gene and many findings suggesting association to ADHD (e.g., Kim et al., 2010; Roman et al., 2005; Roman et al., 2003; Waldman et al., 2006), as well as metabolic traits (e.g., glycemic phenotypes, blood pressure) (for meta-analysis see Talmud et al., 2011) and substance abuse (Clarke et al., 2012; Merenakk et al., 2011; Prestes et al., 2007). Given the neurobiological implications, this gene should be considered a strong candidate in future alcohol abuse studies. The
