A systematic review of the effect of genes mediating neurodevelopment and neurotransmission on brain morphology: Focus on schizophrenia

Structural brain abnormalities have been extensively investigated as potential endophenotypes of schizophrenia. Apart from enlarged ventricles and whole brain volume reductions, no other consistently replicated brain morphometric abnormalities have emerged from these studies. The differential effect of genetic variants on brain morphometry could be a major source of variability underlying such inconsistent findings. Schizophrenia is a polygenic disorder, wherein the complex interplay between common risk variants of small effect, rare risk alleles of large effect as well as epigenetic interactions confer vulnerability and mediate the final expression of the clinical phenotype. A comprehensive understanding of the effect of risk genes on brain morphometry is essential for linking the structural endophenotype/s that can be linked with the genetic diathesis for development of schizophrenia. We systematically reviewed published literature to examine the effect of genes mediating neurodevelopment and brain signalling on brain morphometry. A majority of polymorphisms of the above genes was shown to be associated with whole brain and regional volumetric reductions; but importantly, many genes showed mixed effects, i.e., both volume reductions and increases. Modelling such complex interactions of the large number of risk genes on brain volume in vivo poses considerable practical challenges in having adequate sample sizes as well as imaging data for reliable quantification. Therefore, it is recommended that the field should move beyond association studies of the morphometric effect of single or limited number of gene polymorphisms in clinical populations to modelling the complex epistatic and epigenetic interactions in silico or using animal and cellular models.