Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation

Abstract

Background Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. Methods A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, ‘at risk mental state’ or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. Results We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). Conclusions Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.

Biomarkers in the Prediction of Cancer-Related Cognitive Impairment: Implications within Supportive Care

“…The single nucleotide substitution (G→A) at nucleotide 196 in the coding sequence causes a missense mutation, from valine (Val) to methionine (Met), at codon 66 of precursor BDNF protein which has been implicated in the abnormal sorting of BDNF into secretory vesicles at the Golgi apparatus and activity-dependent BDNF secretion [18]. However, the association between Val66Met and neurocognitive outcomes in non-cancer human studies have been inconsistent, with some meta-analyses reporting poorer outcomes among Met allele carriers [19][20][21], while other reviews finding no significant relationship [22][23][24]. It may be explained that the risk associated to Val66Met and cognitive impairment is disease-specific, and hence studies regarding Val66Met and CRCI are required.…”