Other genes that were among the top hits, but not GWS, have functions with potential links to SUDs. The genes GRIN2B and FTO, associated with progression from opioid use to dependence; and PTPRZ1, associated with cocaine TD have all previously been linked to SUD traits. Different variants than the one identified in this study in GRIN2B have been associated with OD [45] and chronic ketamine use [44]. Its protein product directly binds calcium/calmodulin-dependent protein kinase 2-alpha (encoded by CAMK2A), which can lead to synaptic long-term potentiation by facilitated CAMK2 response to synaptic calcium [55]. We previously identified this pathway as an important modulator of OD risk [13] and this result strengthens the evidence that an individual’s propensity to establish and reinforce substance-specific neural circuits may be an important factor driving their genetic predisposition to SUDs, and that calcium homeostasis may at least partially drive that propensity. FTO has also been associated with addictive behaviors. Although initially identified as a regulator of eating and obesity traits [56, 57], though probably not through an effect of FTO itself but rather as a
