N. E. M. van Haren

Genetic contributions to human brain morphology and intelligence

Variation in gray matter (GM) and white matter (WM) volume of the adult human brain is primarily genetically determined. Moreover, total brain volume is positively correlated with general intelligence, and both share a common genetic origin. However, although genetic effects on morphology of specific GM areas in the brain have been studied, the heritability of focal WM is unknown. Similarly, it is unresolved whether there is a common genetic origin of focal GM and WM structures with intelligence. We explored the genetic influence on focal GM and WM densities in magnetic resonance brain images of 54 monozygotic and 58 dizygotic twin pairs and 34 of their siblings. For genetic analyses, we used structural equation modeling and voxel-based morphometry. To explore the common genetic origin of focal GM and WM areas with intelligence, we obtained cross-trait/cross-twin correlations in which the focal GM and WM densities of each twin are correlated with the psychometric intelligence quotient of his/her cotwin. Genes influenced individual differences in left and right superior occipitofrontal fascicle (heritability up to 0.79 and 0.77), corpus callosum (0.82, 0.80), optic radiation (0.69, 0.79), corticospinal tract (0.78, 0.79), medial frontal cortex (0.78, 0.83), superior frontal cortex (0.76, 0.80), superior temporal cortex (0.80, 0.77), left occipital cortex (0.85), left postcentral cortex (0.83), left posterior cingulate cortex (0.83), right parahippocampal cortex (0.69), and amygdala (0.80, 0.55). Intelligence shared a common genetic origin with superior occipitofrontal, callosal, and left optical radiation WM and frontal, occipital, and parahippocampal GM (phenotypic correlations up to 0.35). These findings point to a neural network that shares a common genetic origin with human intelligence.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25) and intracranial volumes (d=−0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

Brain MRI abnormalities in schizophrenia : same genes or same environment ?

BACKGROUNDnStructural brain volume abnormalities are among the most extensively studied endophenotypes in schizophrenia. Bivariate genetic model fitting (adjusted to account for selection) was used to quantify the genetic relationship between schizophrenia and brain volumes and to estimate the heritability of these volumes.nnnMETHODnWe demonstrated by simulation that the adjusted genetic model produced unbiased estimates for endophenotype heritability and the genetic and environmental correlations. The model was applied to brain volumes (whole brain, hippocampus, third and lateral ventricles) in a sample of 14 monozygotic (MZ) twin pairs concordant for schizophrenia, 10 MZ discordant pairs, 17 MZ control pairs, 22 discordant sibling pairs, three concordant sibling pairs, and 114 healthy control subjects.nnnRESULTSnWhole brain showed a substantial heritability (88%) and lateral ventricles substantial common environmental effects (67%). Whole brain showed a significant genetic correlation with schizophrenia, whereas lateral ventricles showed a significant individual specific correlation with schizophrenia. There were significant familial effects for hippocampus and third ventricle, but the analyses could not resolve whether these were genetic or environmental in origin (around 30%each).nnnCONCLUSIONSnUsing genetic model fitting on twin and sibling data we have demonstrated differential sources of covariation between schizophrenia and brain volumes, genetic in the case of whole brain volume and individual specific environment in the case of lateral ventricles.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen’s d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Psychosis and brain volume changes during the first five years of schizophrenia

The underlying mechanisms explaining brain volume changes in schizophrenia are not yet understood, but psychosis might be related to these changes. Forty-eight patients with first-episode schizophrenia underwent Magnetic Resonance Imaging brain scanning at inclusion and after five years. An association was found between longer duration of psychosis, larger gray matter volume decrease and larger ventricular volume increase. These findings strongly suggest that psychosis contributes to brain volume reductions found in schizophrenia.

Brain Plasticity and Intellectual Ability Are Influenced by Shared Genes

Although the adult brain is considered to be fully developed and stable until senescence when its size steadily decreases, such stability seems at odds with continued human (intellectual) development throughout life. Moreover, although variation in human brain size is highly heritable, we do not know the extent to which genes contribute to individual differences in brain plasticity. In this longitudinal magnetic resonance imaging study in twins, we report considerable thinning of the frontal cortex and thickening of the medial temporal cortex with increasing age and find this change to be heritable and partly related to cognitive ability. Specifically, adults with higher intelligence show attenuated cortical thinning and more pronounced cortical thickening over time than do subjects with average or below average IQ. Genes influencing variability in both intelligence and brain plasticity partly drive these associations. Thus, not only does the brain continue to change well into adulthood, these changes are functionally relevant because they are related to intelligence.

Symptom dimensions are associated with progressive brain volume changes in schizophrenia.

BACKGROUNDnThere is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression).nnnMETHODSnGlobal brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders.nnnRESULTSnIn patients, the disorganization dimension was associated with change in total brain (β=-0.295, p=0.003) and cerebellar (β=-0.349, p<0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes.nnnCONCLUSIONnHeterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies.

Brain volume reductions in medication-naive patients with schizophrenia in relation to intelligence quotient.

BACKGROUNDnGlobal brain abnormalities such as brain volume loss and grey- and white-matter deficits are consistently reported in first-episode schizophrenia patients and may already be detectable in the very early stages of the illness. Whether these changes are dependent on medication use or related to intelligence quotient (IQ) is still debated.nnnMETHODnMagnetic resonance imaging scans were obtained for 20 medication-naive patients with first-episode schizophrenia and 26 matched healthy subjects. Volume measures of total brain grey and white matter, third and lateral ventricles and cortical thickness/surface were obtained. Differences between the groups were investigated, taking into account the effect of intelligence.nnnRESULTSnMedication-naive patients showed statistically significant reductions in whole-brain volume and cerebral grey- and white-matter volume together with lateral ventricle enlargement compared to healthy subjects. IQ was significantly lower in patients compared to controls and was positively associated with brain and white-matter volume in the whole group. No significant differences in cortical thickness were found between the groups but medication-naive patients had a significantly smaller surface in the left superior temporal pole, Heschls gyrus and insula compared to controls.nnnCONCLUSIONSnOur findings suggest that brain volume loss is present at illness onset, and can be explained by the reduced surface of the temporal and insular cortex. These abnormalities are not related to medication, but IQ.

Reciprocal causation models of cognitive vs volumetric cerebral intermediate phenotypes for schizophrenia in a pan-European twin cohort.

In aetiologically complex illnesses such as schizophrenia, there is no direct link between genotype and phenotype. Intermediate phenotypes could help clarify the underlying biology and assist in the hunt for genetic vulnerability variants. We have previously shown that cognition shares substantial genetic variance with schizophrenia; however, it is unknown if this reflects pleiotropic effects, direct causality or some shared third factor that links both, for example, brain volume (BV) changes. We quantified the degree of net genetic overlap and tested the direction of causation between schizophrenia liability, brain structure and cognition in a pan-European schizophrenia twin cohort consisting of 1243 members from 626 pairs. Cognitive deficits lie upstream of the liability for schizophrenia with about a quarter of the variance in liability to schizophrenia explained by variation in cognitive function. BV changes lay downstream of schizophrenia liability, with 4% of BV variation explained directly by variation in liability. However, our power to determine the nature of the relationship between BV deviation and schizophrenia liability was more limited. Thus, while there was strong evidence that cognitive impairment is causal to schizophrenia liability, we are not in a position to make a similar statement about the relationship between liability and BV. This is the first study to demonstrate that schizophrenia liability is expressed partially through cognitive deficits. One prediction of the finding that BV changes lie downstream of the disease liability is that the risk loci that influence schizophrenia liability will thereafter influence BV and to a lesser extent. By way of contrast, cognitive function lies upstream of schizophrenia, thus the relevant loci will actually have a larger effect size on cognitive function than on schizophrenia. These are testable predictions.

Erratum : Reciprocal causation models of cognitive vs volumetric cerebral intermediate phenotypes for schizophrenia in a pan-European twin cohort (Molecular Psychiatry (2015) 20, 1386-1396; DOI:10.1038/mp.2014.152)

Correction to: Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.152 Following publication of the above article, the authors noticed that the tenth author’s last name was presented incorrectly. The author’s name should have been listed as HE Hulshoff Pol. The publisher regrets the error.