Impact of COMT haplotypes on functional connectivity density and its association with the gene expression of dopamine receptors

Catechol- O -methyltransferase ( COMT ) affects brain connectivity via modulating the dopamine system, with an expected greater effect of haplotypes than single-nucleotide polymorphism (SNP). The action pathway from COMT to dopamine to connectivity is theoretically dependent on the gene expression of dopamine receptors. Here, we aimed to investigate the impact of COMT haplotypes on brain functional connectivity density (FCD) in hundreds of healthy young subjects, and to disclose the association between the COMT -FCD statistical map and the spatial expression of the dopamine receptor genes. We found an inverted U-shaped modulation of COMT haplotypes on FCD in the left inferior parietal lobule that is mainly connected to the frontal and parietal cortices, with APS homozygotes exhibiting greater FCD than the other five groups. However, we failed to identify any significant effect of any SNP on FCD. Utilizing gene expression data collected from Allen human brain atlas, we found the COMT -FCD statistical map was significantly associated with the expression patterns of the dopamine receptor genes. Our results suggest that COMT haplotypes have greater impact on functional connectivity than a single genetic variation and that the association between COMT and functional connectivity may be dependent on the gene expression of dopamine receptors.