The effect of the DISC1 Ser704Cys polymorphism on striatal dopamine synthesis capacity: an [18F]-DOPA PET study

Abstract

Whilst the role of the Disrupted-in-Schizophrenia 1 (DISC1) gene in the aetiology of major mental illnesses is debated, the characterisation of its function lends it credibility as a candidate. A key aspect of this functional characterisation is the determination of the role of common non-synonymous polymorphisms on normal variation within these functions. The common allele (A) of the DISC1 SNP rs821616 encodes a serine at the Ser704Cys polymorphism, and has been shown to increase the phosphorylation of extracellular signal-regulated protein Kinases 1 and 2 (ERK1/2) which stimulate the phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We therefore set out to test the hypothesis that human serine (A) homozygotes would show elevated dopamine synthesis capacity compared to cysteine homozygotes and heterozygotes (TT and AT) for rs821616. [18F]-DOPA PET was used to index striatal dopamine synthesis capacity as the influx rate constant Kceri in healthy volunteers DISC1 rs821616 serine homozygotes (N = 46) and healthy volunteers DISC1 rs821616 cysteine homozygotes and heterozygotes (N = 56), matched for age, gender, ethnicity and using three scanners. We found DISC1 rs821616 serine homozygotes exhibited a significantly higher striatal Kceri compared to cysteine homozygotes and heterozygotes (p = 0.012) explaining 6.4% of the variance (partial eta squared=0.064). Our finding is consistent with its previous association with heightened activation of ERK1/2, which stimulates tyrosine hydroxylase activity for dopamine synthesis. This could be a potential mechanism mediating risk for psychosis, lending further credibility to the fact that DISC1 is of functional interest in the aetiology of major mental illness.