Heritability of brain structure and glutamate levels in the anterior cingulate and left thalamus assessed with MR: A twin study

Heritability of brain structure and glutamate levels in the anterior cingulate and left thalamus assessed with MR: A twin study
Brian V. Broberg1,2; Christian S. Legind1,2, Rene C. Mandl1,3, Maria H. Jensen1, Simon J. Anhøj1,2, Rikke Hilker1, Egill Rostrup1,2, Birte Y. Glenthøj1
Author affiliations:
1. Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research CINS/ Center for Neuropsychiatric Schizophrenia Research CNSR, Copenhagen University Hospital, Psychiatric Center Glostrup, Copenhagen, Denmark
2. Functional Imaging Unit, Dept. of Diagnostics, Glostrup Hospital, Copenhagen, Denmark
3. Brain Center Rudolf Magnus, Dept. of Psychiatry, UMC Utrecht, the Netherlands
Background
Changes in global and regional brain volumes in schizophrenia are known to be heritable and to cosegregate with illness (McDonald et al., 2002; Peper et al., 2007). Changes in neurochemistry — and particularly changes in glutamate — are most likely linked to changes in brain volume (Kraguljac et al., 2013) but investigations on heritability of glutamate levels are sparse. Several genes associated with glutamate transmission were suggested to be involved in the pathophysiology of schizophrenia (Ripke et al., 2014). Moreover, altered glutamatergic neurochemistry was found in frontal and thalamic areas of both patients with schizophrenia and in prodromal subjects (Egerton et al., 2012; Stone et al., 2009; Théberge et al., 2002). Here we present our initial findings of a twin study in which we assess the heritability of regional cerebral glutamate levels as well as structural brain volumes.
Methods
Population: 18 monozygotic, 13 dizygotic twin pairs con- or discordant for schizophrenia (ICD-10, F. 20-29), 16 monozygotic healthy control pairs and 10 dizygotic healthy control pairs. Nine additional twins were included without their siblings. A 3D-T1W structural image and 1H nuclear magnetic resonance spectra (PRESS) was obtained from each subject using a 3 Tesla Philips MRI system. Total brain (TB), Gray matter (GM), white matter (WM), peripheral GM (pGM), ventricular CSF (vCSF) volumes were calculated using the SIENAX tool provided with FSL. MRS data from the left thalamus and anterior cingulate cortex (ACC) (bilaterally) were processed using LCModel. Metabolite concentrations (Cramer-Rao Lower bound < 20; Full-width half maximum < 12 Hz) were referenced to internal water and corrected for CSF contamination. Outliers detected by Tukey’s outlier labelling were discarded from further analyses.
Results
Brain volumes: ANOVA revealed a significant effect of group (probands, healthy co-twins, healthy controls) for normalized WM (F2,119 = 3.18; p = 0.0453) and TB (F2,119 = 3.49; p = 0.0338). No group effects were detected for pGM, vCSF, and GM. Post-hoc testing revealed significant reductions in the WM (t = 2.25; p = 0.025) and TB (t = 2.46; p = 0.016) of probands compared to healthy controls and trend-level significant reductions in healthy co-twins compared to healthy controls (p = 0.056 for WM and p = 0.061 for TB). Correlations within twin pairs were significant for both MZ and DZ pairs for all volume parameters (both normalized and absolute values), but only significantly higher in MZ compared to DZ pairs when considering absolute volumes.
MRS: No effect of group was identified by ANOVA. Significant correlations (positive) were found in monozygotic twin pairs in both the ACC (n = 56, r = 0.484, p = 0.009)) and the left thalamus (n = 56, r = 0.444, p = 0.018), but not in dizygotic twin pairs (ACC: n = 40, r = -0.123, p = 0.606; left thalamus: n = 40, r = 0.030, p = 0.902). No significant differences were detected between the correlations of monozygotic versus dizygotic twins.
Conclusion
These initial results confirm previous findings of reduced total brain and white matter volume in patients with schizophrenia compared to healthy controls. The stronger correlations in MZ compared to DZ pairs (absolute volumes) suggests a genetic contribution.
Moreover, we found suggestive evidence that glutamate levels in the anterior cingulate cortex and thalamus are heritable. Future work includes a more sophisticated analysis of heritability using structural equation modelling (OpenMx) and investigating the potential of these measures to serve as an endophenotypic marker for schizophrenia.