DGKH genetic risk variant influences gene expression in bipolar affective disorder

DGKH is a replicated risk gene of bipolar disorder (BD). However, the pathophysiological role of the coded protein, diacylglycerol kinase eta, remains elusive.

In this proof-of-concept study we isolated mRNA from peripheral blood and fibroblasts of heterozygote DGKH risk variants carriers (risk haplotype rs994856/rs9525580/rs9525584 GAT) with bipolar disorder and non-risk variant carriers with and without bipolar disorder. Gene expression of DGKH1, DGKH2, INPP5E, PI4K2B, PIK4CA, PLCG2, PRKCA, PRKCD, PRKCE and PRKCH was analysed by qRT PCR.

DGKH1 expression was increased in peripheral blood of risk variant carriers (p=0.027). In fibroblast cells, PRKCD expression was significantly increased in DGKH GAT carriers (p=0.037). Patients with a current depressive episode had lower PRKCD levels and lithium treatment was associated with increased PRKCA expression (p=0.005, and p=0.033).

No homozygote risk variant carriers and no healthy risk variant carriers were included due to their infrequency. Bipolar patients carrying the GAT haplotype were older with marginal significance, as age had also an influence on DGKH expression levels but not on PRKCD levels, replication with better age-matched samples and also bigger samples are needed.

The results add evidence for the role of fibroblast cells and peripheral blood as useful tools in the functional characterisation of risk gene variants. Also a combination of genotyping and peripheral gene expression analysis could proof useful in the search of biomarkers for endophenotypes. Furthermore, we could confirm the role of the inositol-1,4,5-triphosphate second messenger pathway and protein kinase C in the pathogenesis of BD.