Serotonin and the Brain's Rich Club-Association Between Molecular Genetic Variation on the TPH2 Gene and the Structural Connectome

Abstract

The rich club comprises a densely mutually connected set of hub regions in the brain, thought to serve as a processing and integration core. We assessed the impact of normal variation of the tryptophane hydroxylase 2 gene's promotor region (TPH2 rs4570625) on structural connectivity of the rich club pathways by means of a candidate gene association design. Tryptophane hydroxylase 2 (TPH2) is a rate-limiting enzyme in the biosynthesis of serotonin and is known to inhibit, in addition to its role as a trans-synaptic messenger, axonal and dendritic growth. The TPH2 T-variant has been associated with reduced mRNA expression and reduced serotonin levels, which may particularly influence the development of macroscale anatomical connectivity. Here, we show larger mean connectivity in the rich club in carriers of the T-variant, suggesting potential effects of upregulation of neural connectivity growth in this central core system. In addition, by edge-removal statistics, we show that the TPH2-associated higher levels of rich club connectivity are of importance for the functioning of the total structural network. The observed association is speculated to result from an effect of serotonin levels on brain development, potentially leading to stronger structural connectivity in heavily interconnected hubs.