Taken together, these findings strongly support the hypothesis that SH3BP5-NR2C2 harbors causal loci for alcohol and nicotine co-dependence. This region can be represented by two independent markers located in two independent LD blocks, and it might harbor two independent causal loci that are in LD with these independent blocks. The first causal locus might be rs9868848 in ZFYVE20 in block 1 that is a non-synonymous variant (Leu591Pro) located in a coding region. It could significantly alter the RNA secondary structure. It was functional in brain and PBMC with nominal cis- and trans-acting regulatory effects (Table 1). Its minor allele protected against risk for alcohol and nicotine co-dependence. Two other SNPs (rs28445844 in NR2C2 and rs2306853 in ZFYVE20) in LD with this SNP could also slightly alter the RNA secondary structures, and rs2306853 is located in an exonic splicing silencer or enhancer (Table S2). Alternatively, SH3BP5-CAPN7 (block 2) might possibly harbor a second putative causal locus, because the most significant SNP in this region was rs1318937 in SH3BP5 and this SNP could also slightly alter the RNA secondary structures (Table S2).
