Genetic contributions to human brain morphology and intelligence

Abstract

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.

Figure 1.

Genetically influenced focal GM density brain areas. Heritability estimates of GM density in focal brain areas in healthy adult humans are shown for the significance level thresholded A-map superimposed on axial and sagittal sections through the magnetic resonance image of the standardized reference brain (left) and for the complete A-map (right). The significance level thresholded A-map shows the voxels that had a significant fit of the genetic model compared with the other models based on the likelihood ratio test and using structural equation modeling. Moreover the level of significance was set at χ² > 25.3 for Δdf = 1 and χ² > 29.3 for Δdf = 2 after correction for multiple comparisons according to random field theory (the uncorrected significance levels would have been χ² > 3.8 and χ² > 6.0). Analyses were controlled for age, sex, and handedness. a, Left occipital cortex. b, Right medial frontal gyrus. c, Left and right Heschl's gyrus. d, Left amygdala and right parahippocampal gyrus. R, Right.

Figure 2.

Genetically influenced focal WM density brain areas superimposed on the histologically defined map of the superior occipitofrontal fascicle. Heritability of WM density in focal brain areas in healthy adult humans is shown for the significance level thresholded A-map superimposed on axial and sagittal sections in the left (L) and right (R) hemisphere through the magnetic resonance image of the standardized reference brain (left) and superimposed on the histologically defined map of the occipitofrontal superior fascicle (middle) (reproduced with the permission of K.Z, K.A., and U.B.). The complete A-maps are shown on the right. Note that several of the genetically influenced focal WM density voxels shown on the left also overlapped with the histologically defined maps of the corpus callosum, optic radiation, and corticospinal tract, which are not shown in the middle figures because relatively few voxels overlapped with these white matter tracts. a, Axial section. b, c, Sagittal sections.

Figure 3.

3D representation of genetically influenced focal WM density brain areas superimposed on the histologically defined map of the superior occipitofrontal fascicle. Three-dimensional glass brain representations (top left, left side view; top right, right side view; bottom left, superior view; bottom right, posterior view) of the variance in WM density found to be significantly influenced by genetic factors in healthy adult humans (orange) with the histologically defined map of the occipitofrontal superior fascicle (green) and lateral and third ventricles (blue). See also supplemental movie 1, available at www.jneurosci.org as supplemental material.

Figure 4.

GM density in the right medial frontal cortex (top) and WM density in the left superior occipitofrontal fascicle (bottom). Dots represent values of GM and WM density (varying between 0 and 1) for individual MZ (left) and DZ (right) twin pairs at (x, y, z) (39, 43, 37) (top) and at (−17, 10, 25) (bottom). Twin 1 and twin 2 represent the two individuals of a twin pair. The correlation within MZ twin pairs is much higher than that in DZ twin pairs, indicating that the individual variation in GM and WM density in these areas is primarily determined by genes.

Figure 5.

Cross-trait/cross-twin correlations for GM and WM density and VIQ/PIQ in MZ and DZ twin pairs ranging from 0 to 0.5. The cross-trait/cross-twin correlations were significant for GM density with VIQ in the right parahippocampal gyrus and for WM density with PIQ in the right superior occipitofrontal fascicle. A significant cross-trait/cross-twin correlation indicates that the genes influencing GM and WM density partly overlap with the genes that influence VIQ/PIQ. Note that, for illustration purposes, positive cross-correlations as shown here were not thresholded for significance. By definition, the cross-correlations in voxels that were not significantly determined by genetic factors could not become significant (because both factors, i.e., GM and WM density and VIQ and PIQ measures, have to be determined by genes to allow for inferences that possible mutual genes determine that association). Negative cross-correlations (data not shown) were present, but none of these reached significance. For details on these and other significant cross-trait/cross-twin correlations in the sample, see Table 3. Rt, Right.