1Psychiatr. Genet. 2011 Jun 21: 125-31
TitleDual association of a TRKA polymorphism with schizophrenia.
AbstractAn interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.
We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.
Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor.
An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.
SCZ Keywordsschizophrenia
2J. Neurosci. 2012 Apr 32: 5964-72
TitleRelationship of a variant in the NTRK1 gene to white matter microstructure in young adults.
AbstractThe NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower fractional anisotropy in healthy adults. We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy-a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test reproducibility of results. The false discovery rate method corrected for voxelwise multiple comparisons. NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple-comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure.
SCZ Keywordsschizophrenia
3Neuroimage 2013 Nov 82: 146-53
TitleRelation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in healthy young adults.
AbstractThe NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3'-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults is related to common variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain. To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6 2.2 years; range: 20-29 years) with 105-gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) - a DTI measure of white matter integrity. FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p=0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders.
SCZ Keywordsschizophrenia
4Schizophr. Res. 2016 Apr 172: 94-100
TitlePrefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity.
Abstractschizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (?(2)=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r=-.624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies.
SCZ Keywordsschizophrenia