The gene which is closest to the peak association signal and which also harbours another associated SNP, rs705648 (p=1.78×10-6), is the peroxisomal trans-2-enoyl-coA reductase (PECR). PECR appears to be a key enzyme of fatty acid metabolism as it catalyzes the reduction of medium chain (unsaturated) enoyl-CoAs to saturated acyl-CoAs which may then undergo oxidation in mitochondria for energy production. This pathway, originating from triglycerides, is particularly important in conditions of starvation when energy supply is switched from utilization of glucose to fatty acids. In this condition, PECR needs to be up-regulated. Triglycerides are typically increased in the blood of alcohol dependent individuals.68,69 PECR reduces C-C double bonds in not only even-chain, but also in odd-chain fatty acids. On degradation to acetyl-CoA, odd-chain fatty acids end up with propionyl-CoA, which requires carboxylation to an even-chain fatty acid. This step is mediated through methyl-malonyl-CoA, an intermediate formed by the essential cofactors methyl-tetrahydrofolate as the methyl-donor, and vitamin B12. Folate deficiency, often observed in alcohol-dependent patients,70 may therefore interfere with this pathway and prevent the availability of a sufficient supply of acetyl-CoA. Expression
