Heritability of brain volume change and its relation to intelligence.

Human brain volumes change throughout life, are highly heritable, and have been associated with general cognitive functioning. Cross-sectionally, this association between volume and cognition can largely be attributed to the same genes influencing both traits. We address the question whether longitudinal changes in brain volume or in surface area in young adults are under genetic control and whether these changes are also related to general cognitive functioning. We measured change in brain volume and surface area over a 5-year interval in 176 monozygotic and dizygotic twins and their non-twin siblings aged 19 to 56, using magnetic resonance imaging. Results show that changes in volumes of total brain (mean = -6.4 ml; 0.5% loss), cerebellum (1.4 ml, 1.0% increase), cerebral white matter (4.4 ml, 0.9% increase), lateral ventricles (0.6 ml; 4.8% increase) and in surface area (-19.7 cm(2),1.1% contraction) are heritable (h(2) = 43%; 52%; 29%; 31%; and 33%, respectively). An association between IQ (available for 91 participants) and brain volume change was observed, which was attributed to genes involved in both the variation in change in brain volume and in intelligence. Thus, dynamic changes in brain structure are heritable and may have cognitive significance in adulthood.

Genes contributing to subcortical volumes and intellectual ability implicate the thalamus.

It has been shown that brain volume and general intellectual ability are to a significant extent influenced by the same genetic factors. Several cortical regions of the brain also show a genetic correlation with intellectual ability, demonstrating that intellectual functioning is probably represented in a heritable distributed network of cortical regions throughout the brain. This study is the first to investigate a genetic association between subcortical volumes and intellectual ability, taking into account the thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens using an extended twin design. Genetic modeling was performed on a healthy adult twin sample consisting of 106 twin pairs and 30 of their siblings, IQ data was obtained from 132 subjects. Our results demonstrate that of all subcortical volumes measured, only thalamus volume is significantly correlated with intellectual functioning. Importantly, the association found between thalamus volume and intellectual ability is significantly influenced by a common genetic factor. This genetic factor is also implicated in cerebral brain volume. The thalamus, with its widespread cortical connections, may thus play a key role in human intelligence.

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.

Genetic and environmental influences on focal brain density in bipolar disorder.

Structural neuroimaging studies suggest the presence of subtle abnormalities in the brains of patients with bipolar disorder. The influence of genetic and/or environmental factors on these brain abnormalities is unknown. To investigate the contribution of genetic and environmental factors on grey and white matter brain densities in bipolar disorder, monozygotic and dizygotic twins concordant and discordant for bipolar disorder were scanned using 1.5 Tesla magnetic resonance imaging and compared with healthy twin pairs. A total of 232 subjects: 49 affected twin pairs (8 monozygotic concordant, 15 monozygotic discordant, 4 dizygotic concordant, 22 dizygotic discordant) and 67 healthy twin pairs (39 monozygotic and 28 dizygotic) were included. After correcting for the effect of lithium, the liability for bipolar disorder was associated with decreased grey matter density in widespread areas of the brain, but most prominent in frontal and limbic regions, and with decreased white matter density in (frontal parts of) the superior longitudinal fasciculi. The genetic risk to develop bipolar disorder was related to decreased grey matter density in the right medial frontal gyrus, precentral gyrus and insula and with decreased white matter density in the superior longitudinal fasciculi bilaterally. In conclusion, pathology in the frontal lobe, especially in parts of the superior longitudinal fasciculus, may be central to the genetic risk to develop bipolar disorder, while widespread grey matter abnormalities appear related to the illness itself.

Longitudinal MRI study in schizophrenia patients and their healthy siblings.

To investigate whether genetic and/or disease-related factors are involved in progressive structural brain changes in schizophrenia, magnetic resonance imaging scans with a 5-year scan interval were acquired in patients, their same-gender siblings and matched healthy controls. Structural equation modelling was applied to assess disease and familial effects. Whole brain and cerebral grey matter volumes decreased excessively in patients compared with their siblings and the controls, suggesting that the progressive brain loss in schizophrenia may be related to the disease process.

Heritability of cortical thickness changes over time in twin pairs discordant for schizophrenia.

BACKGROUND: Cortical thickness and surface area changes have repeatedly been found in schizophrenia. Whether progressive loss in cortical thickness and surface area are mediated by genetic or disease related factors is unknown. Here we investigate to what extent genetic and/or environmental factors contribute to the association between change in cortical thickness and surface area and liability to develop schizophrenia. METHOD: Longitudinal magnetic resonance imaging study over a 5-year interval. Monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia were compared with healthy control twin pairs using repeated measures analysis of variance (RM-ANOVA) and structural equation modeling (SEM). Twins discordant for schizophrenia and healthy control twins were recruited from the twin cohort at the University Medical Centre Utrecht, The Netherlands. A total of 90 individuals from 46 same sex twin pairs were included: 9 MZ and 10 DZ discordant for schizophrenia and 14 MZ and 13 (11 complete and 2 incomplete) DZ healthy twin-pairs. Age varied between 19 and 57years. RESULTS: Higher genetic liability for schizophrenia was associated with progressive global thinning of the cortex, particularly of the left superior temporal cortex. Higher environmental liability for schizophrenia was associated with global attenuated thinning of the cortex, and including of the left superior temporal cortex. Cortical surface area change was heritable, but not significantly associated with higher genetic or environmental liability for schizophrenia. CONCLUSIONS: Excessive cortical thinning, particularly of the left superior temporal cortex, may represent a genetic risk marker for schizophrenia.

Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia.

BACKGROUND: Whole brain tissue volume decreases in schizophrenia have been related to both genetic risk factors and disease-related (possibly nongenetic) factors; however, whether genetic and environmental risk factors in the brains of patients with schizophrenia are differentially reflected in gray or white matter volume change is not known. METHODS: Magnetic resonance imaging (1.5 T) brain scans of 11 monozygotic and 11 same-gender dizygotic twin pairs discordant for schizophrenia were acquired and compared with 11 monozygotic and 11 same-gender dizygotic healthy control twin pairs. RESULTS: Repeated-measures volume analysis of covariance revealed decreased whole brain volume in the patients with schizophrenia as compared with their co-twins and with healthy twin pairs. Decreased white matter volume was found in discordant twin pairs compared with healthy twin pairs, particularly in the monozygotic twin pairs. A decrease in gray matter was found in the patients compared with their co-twins and compared with the healthy twins. CONCLUSIONS: The results suggest that the decreases in white matter volume reflect the increased genetic risk to develop schizophrenia, whereas the decreases in gray matter volume are related to environmental risk factors. Study of genes involved in the (maintenance) of white matter structures may be particularly fruitful in schizophrenia.

Overlapping and segregating structural brain abnormalities in twins with schizophrenia or bipolar disorder.

CONTEXT: The nosologic dichotomy between schizophrenia and bipolar disorder (BD) as formulated by Kraepelin is currently being questioned, stimulated by the finding that schizophrenia and BD partly share a common genetic origin. Although both disorders are characterized by changes in brain structure, family studies suggest more segregating than overlapping neuroanatomical abnormalities in both disorders. OBJECTIVES: To investigate whether patients with schizophrenia and patients with BD display overlapping abnormalities in brain volumes and cortical thickness and whether these are caused by shared genetic or environmental influences. DESIGN: Magnetic resonance imaging findings of monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia, twin pairs concordant and discordant for BD, and healthy twin pairs were compared using structural equation modeling. SETTING: The Netherlands Twin Register and University Medical Center Utrecht. PARTICIPANTS: A total of 310 individuals from 158 (152 complete and 6 incomplete) twin pairs were included: 26 pairs discordant for schizophrenia (13 MZ and 13 DZ), 49 pairs with BD (9 MZ and 4 DZ concordant; 14 MZ and 22 DZ discordant), and 83 healthy twin pairs (44 MZ and 39 DZ). MAIN OUTCOME MEASURES: Estimates of additive genetic and unique environmental associations between schizophrenia and BD with overlapping and nonoverlapping volumes and cortical thickness. RESULTS: Higher genetic liabilities for schizophrenia and BD were associated with smaller white matter volume, thinner right (and left) parahippocampus, thinner right orbitofrontal cortex, and thicker temporoparietal and left superior motor cortices; higher environmental liabilities were associated with thinner right medial occipital cortex. Genetic liability for schizophrenia was associated with thicker right parietal cortex; for BD, with larger intracranial volume. CONCLUSIONS: Brain structures reflect overlapping and segregating genetic liabilities for schizophrenia and BD. The overlapping smaller white matter volume and common areas of thinner cortex suggest that both disorders share genetic (neurodevelopmental) roots.

Influence of genes and environment on brain volumes in twin pairs concordant and discordant for bipolar disorder.

CONTEXT: Structural neuroimaging studies suggest the presence of subtle abnormalities in the brains of patients with bipolar disorder. The influence of genetic and/or environmental factors on these brain abnormalities is unknown. OBJECTIVE: To investigate the contribution of genetic and environmental factors on brain volume in bipolar disorder. DESIGN: Magnetic resonance imaging (1.5 T) brain scans of monozygotic (MZ) or dizygotic (DZ) twins concordant and discordant for bipolar disorder were compared with healthy twin pairs. SETTING: Subjects were recruited from the population, the Netherlands Twin Register, and the twin pair cohort at the University Medical Center Utrecht, Utrecht, The Netherlands. PARTICIPANTS: A total of 234 subjects including 50 affected twin pairs (9 MZ concordant; 15 MZ discordant; 4 DZ concordant; 22 DZ discordant) and 67 healthy twin pairs (39 MZ and 28 DZ) were included. MAIN OUTCOME MEASURES: Volumes of the intracranium, cerebrum, cerebellum, lateral and third ventricle, and gray and white matter from the cerebrum and frontal, parietal, temporal, and occipital lobes, both with and without correction for lithium use. To estimate the influence of additive genetic, common, and unique environmental factors, structural equation modeling was applied. RESULTS: Bipolar disorder was associated with a decrease in total cortical volume. Decreases in white matter were related to the genetic risk of developing bipolar disorder (bivariate heritability, 77%; 95% confidence interval, 38% to 100%). Significant environmental correlations were found for cortical gray matter. These relationships all became more pronounced when data were corrected for lithium use. CONCLUSIONS: Focusing on genes controlling white matter integrity may be a fruitful strategy in the quest to discover genes implicated in bipolar disorder. Elucidating the mechanism by which lithium attenuates brain matter loss may lead to the development of neuroprotective drugs.

Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.

CONTEXT: Structural brain abnormalities have consistently been found in schizophrenia, with increased familial risk for the disease associated with these abnormalities. Some brain volume changes are progressive over the course of the illness. Whether these progressive brain volume changes are mediated by genetic or disease-related factors is unknown. OBJECTIVE: To investigate whether genetic and/or environmental factors are associated with progressive brain volume changes in schizophrenia. DESIGN: Longitudinal 5-year follow-up in monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia and healthy comparison twin pairs using brain magnetic resonance imaging. SETTING: Participants were recruited from the twin pair cohort at the University Medical Center Utrecht. PARTICIPANTS: A total of 92 participants completed the study: 9 MZ and 10 DZ twin pairs discordant for schizophrenia and 14 MZ and 13 DZ healthy twin pairs. MAIN OUTCOME MEASURES: Percentage volume changes of the whole brain; cerebral gray and white matter of the frontal, temporal, parietal, and occipital lobes; cerebellum; and lateral and third ventricles over time between and within twin pairs were compared using repeated measures analysis of covariance. Structural equation modeling was applied to estimate contributions of additive genetic and common and unique environmental factors. RESULTS: Significant decreases over time in whole brain and frontal and temporal lobe volumes were found in patients with schizophrenia and their unaffected co-twins compared with control twins. Bivariate structural equation modeling using cross-trait/cross-twin correlations revealed significant additive genetic influences on the correlations between schizophrenia liability and progressive whole brain (66%; 95% confidence interval [CI], 51%-100%), frontal lobe (76%; 95% CI, 54%-100%), and temporal lobe (79%; CI, 56%-100%) volume change. CONCLUSION: The progressive brain volume loss found in patients with schizophrenia and their unaffected co-twins is at least partly attributable to genetic factors related to the illness.

Gray and white matter density changes in monozygotic and same-sex dizygotic twins discordant for schizophrenia using voxel-based morphometry.

Global gray matter brain tissue volume decreases in schizophrenia have been associated to disease-related (possibly nongenetic) factors. Global white matter brain tissue volume decreases were related to genetic risk factors for the disease. However, which focal gray and white matter brain regions best reflect the genetic and environmental risk factors in the brains of patients with schizophrenia remains unresolved. 1.5-T MRI brain scans of 11 monozygotic and 11 same-sex dizygotic twin-pairs discordant for schizophrenia were compared to 11 monozygotic and 11 same-sex dizygotic healthy control twin-pairs using voxel-based morphometry. Linear regression analysis was done in each voxel for the average and difference in gray and white matter density separately, in each twin-pair, with group (discordant, healthy) and zygosity (monozygotic, dizygotic) as between subject variables, and age, sex and handedness as covariates. The t-maps (critical threshold value mid R:tmid R: > 6.0, P < 0.05) revealed a focal decrease in gray matter density accompanied by a focal increase in white matter density in the left medial orbitofrontal gyrus and a focal decrease in white matter density in the left sensory motor gyrus in twin-pairs discordant for schizophrenia as compared to healthy twin-pairs. Focal changes in left medial (orbito)frontal and left sensory motor gyri may reflect the increased genetic risk to develop schizophrenia. Focal changes in the left anterior hemisphere may therefore be particularly relevant as endophenotype in genetic studies of schizophrenia.