In summary, we found T carriers of SNP-2 and A carriers for SNP-3 had reduced hippocampus concentration compared to individuals homozygous for the C allele of these variants. VEGF is an angiogenic protein demonstrated in rats to induce neurogenesis in the subventricular and subgranular zones of the hippocampus dentate gyrus (6
), and to protect the hippocampus from neurotoxicity such as through glutamate excesses (7
). Rat models further support VEGF-induced neurogenesis as a key mediator of beneficial effects of environmental enrichment and exercise on hippocampus-dependent memory and learning (8
). The current findings suggest that effects of VEGFA
in hippocampus found in rats extend to humans; specific variation in VEGFA
may contribute to individual differences in hippocampus structure and potentially function.
The SNPs are intronic with unclear function. Evidence suggests that some VEGFA
introns contain transcription factor binding sites and these areas may be important in the regulation of VEGF production and/or influence splicing (10
). Therefore, it seems possible that the SNP-2 and SNP-3 (or other variants in LD with them) may alter VEGF expression in the hippocampus, which then influences hippocampal development, and/or plasticity in adulthood. Of note, the specific cytoarchitectural contributions, such as differences in neuronal size or packing density, to the morphological changes cannot be concluded from these neuroimaging data (11
). Although VEGF has direct effects on neurogenesis, it also has effects on astroglia and endothelial cells (6
) and thus changes in these cell populations may also contribute to the morphological changes.
The ethnic heterogeneity within the subject sample is an important potential limitation. Although we did not detect differences in hippocampus morphology between ethnic groups and effects of the VEGFA genotypes were similar in the groups, it is still possible that population stratification influenced our findings, and replication in larger, more homogeneous samples will be important. Additionally, in order to have comparable group sizes, we grouped minor allele heterozygotes and homozygotes; this is consistent with a dominant model but would also have reasonable power if the alleles were codominant (the most likely case where the markers studied are in LD with an ungenotyped functional variant). If the correct mode of effect is recessive, then there is the potential for Type II error in analyses for SNP-1 and SNP-4. These results should be considered preliminary, especially owing to the modest sample size, and replication studies are warranted.
The findings support the importance of further study of VEGFA
variation as a potentially substantial factor in influencing human variation in hippocampus-related functions, including mnemonic functioning, learning and resilience to stress. Moreover, as VEGF has been demonstrated to mediate therapeutic effects of antidepressant treatments and recovery from neurological injury in rodents (1
), further understanding of effects of VEGFA
variation may have important implications in identifying individuals more vulnerable to hippocampus pathology, as well as those neuropsychiatric populations most likely to benefit from VEGF-mediated interventions.