Evidence accumulates: brain under genetic influence 

 

Utrecht, Netherlands. While showing an impressive growth prenatally, the human brain is incomplete at birth. There is considerable brain growth during childhood with dynamic changes taking place throughout life, probably for adaptation to our environments.

 

Evidence accumulates that brain structure is under considerable genetic influence [Peper et al., 2007]. Puberty, the transitional phase from childhood into adulthood, involves changes in brain morphology that may be essential to optimal adult functioning.

 

Around the onset of puberty gray matter volume starts to decrease, while white matter volume is still increasing [Giedd et al., 1999].

 

 

Thus, while environmental influences may play a role in later stages during puberty, around the onset of puberty brain volumes are already highly heritable.

 

Hilleke Hulshoff Pol in the Netherlands has studied changes in the brain morphology of schizophrenia patients, with baseline comparisons to the non-schizophrenic population. She has explored the influence of genetic and environmental factors using structural magnetic resonance imaging (MRI). 

 

The results have been persuasive, with accumulating evidence of genetic factors that influence the brain structure, opening new insights into the reciprocal gene-environment and developmental pathways.

 

Genetic influences and functional relevance 

 

Twin studies have also shown that genetic effects vary regionally within the brain, with high heritabilities of frontal lobe volumes (90–95%), moderate estimates in the hippocampus (40–69%), and environmental factors influencing several medial brain areas.

 

However, the mechanisms by which interaction between genes and environment occur throughout life as well as dynamics of brain structure and its association with brain functioning still remain unknown. Twin and family studies and newly evolving genetic approaches start to give us a glimpse as to which genes and (interacting) environmental influences are shaping our brains.

 

Brain structure — measured macroscopically using MRI — and the dynamic changes therein, have a functional relevance.

 

Studies revealed that total brain volume is positively correlated with general intelligence. In healthy subjects, the level of intellectual functioning has been positively associated with whole brain, gray, and white matter volumes [Thompson et al., 2001; Posthuma et al., 2002]. More focally, several brain areas were found to be correlated with intelligence. Interestingly, it was also shown that the trajectory changes in cortical thickness throughout adolescence are associated with the level of intelligence.

 

Furthermore, a common set of genes may also cause the association between brain structure and cognitive functions. However, in elderly twins, the associations between frontotemporal brain volumes and executive function were found to be because of common environmental influences shared by twins from the same family [Carmelli et al., 2002].

 

These results point to the possibility that overlapping sets of genes or common environmental influences cause variation in two distinct phenotypes. It might be, for example, that a higher level of cognitive functioning leads a person to select an environment that also increases brain size. The genetic influence on brain size then simply reflects the genetic influences on cognition. Thus, the specific mechanism, pathways, and genes that are involved in human brain morphology and its association with cognitive functions remain elusive.

 

Although genetic effects on morphology of specific gray matter areas in the brain have been studied, the heritability of focal white matter was unknown until recently. Similarly, it was unresolved whether there is a common genetic origin of focal gray matter and white matter structures with intelligence. In our study involving 54 monozygotic and 58 dizygotic twin pairs and their 34 singleton siblings, verbal, and performal intelligence were found to share a common genetic origin with an anatomical neural network involving the frontal, occipital, and parahippocampal gray matter and connecting white matter of the superior occipitofrontal fascicle, and the corpus callosum [Hulshoff Pol et al., 2006].

 

For the genetic analyses, structural equation modeling and voxel-based morphometry were used. To explore the common genetic origin of focal gray matter and white matter areas with intelligence, cross-trait/cross-twin correlations were obtained in which the focal gray matter and white matter densities of each twin are correlated with the psychometric intelligence quotient of his/her cotwin.

 

The results of this study indicate that genes significantly influence white matter density of the superior occipitofrontal fascicle, corpus callosum, optic radiation, and corticospinal tract, as well as gray matter density of the medial frontal, superior frontal, superior temporal, occipital, postcentral, posterior cingulate, and parahippocampal cortices. Moreover, the results show that intelligence shares a common genetic origin with superior occipitofrontal, callosal, and left optical radiation white matter and frontal, occipital, and parahippocampal gray matter (phenotypic correlations up to 0.35).

 

These findings point to a neural network that shares a common genetic origin with human intelligence. Thus, it seems that the individual variation in morphology of areas involved in attention, language, visual, and emotional processing, as well as in sensorimotor processing are strongly genetically influenced.

 

In addition, unique environmental factors influenced vast gray matter and white matter areas surrounding the lateral ventricles (up to 0.50). This finding coincides with the significant environmental influences on lateral ventricle volume [common (0.58) and unique (0.42) with no significant contributions of genes] that was reported previously in this twin sample [Baaré et al., 2001].

 

Clinical implications

 

Considering the high heritabilities for global brain volumes and particular focal brain densities and thicknesses, the search for genes that are involved in brain growth, aging, and brain structure maintenance is important. Such knowledge can help us understand normal developmental and age-associated changes in individual variation in brain functioning.

 

Moreover, it enhances our knowledge of individual variation in brain functioning and facilitates the interpretation of the morphological changes found in psychiatric disorders such as schizophrenia [van Haren et al., 2007]. Also, it allows future efforts to find particular genes responsible for brain structures to be concentrated in areas that are under considerable genetic influence [Hulshoff Pol et al., 2006]. 

 

A genetic approach to find genes involved in brain structure that has been applied in several studies is that of diseases with a clear genetic etiology such as Huntington's disease, Down syndrome, Williams syndrome, and Velocardiofacial syndrome. A review reveals for these diseases besides disease specific brain changes, decreases in total brain, white matter, and hippocampus volumes, irrespective of the genes and/or chromosomes involved. This suggests that many genes are probably involved in the individual variation of these measures [Peper et al., in press].

 

It is important to investigate which environmental factors have an influence on the expression of genes (as found in DNA– methylation). Additionally, the study of interaction between genes and environmental factors is warranted. Furthermore, the simultaneous effects of multiple genes and possibly the interaction among genes, also needs investigation as the high heritability of a complex quantitative phenotype such as brain volume cannot be explained by a single-gene polymorphism.

 

Conclusion

---

This special report was adapted from research materials provided by the European College of Neuropsychopharmacology.

---

 

Genetic influences on human brain structure: a review of brain imaging studies in twins. Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Hulshoff Pol HE. Hum Brain Mapp 2007;28:464-473.

 

Abstract. Twin studies suggest that variation in human brain volume is genetically influenced. The genes involved in human brain volume variation are still largely unknown, but several candidate genes have been suggested. An overview of structural Magnetic Resonance (brain) Imaging studies in twins is presented, which focuses on the influence of genetic factors on variation in healthy human brain volume. Twin studies have shown that genetic effects varied regionally within the brain, with high heritabilities of frontal lobe volumes (90-95%), moderate estimates in the hippocampus (40-69%), and environmental factors influencing several medial brain areas. High heritability estimates of brain structures were revealed for regional amounts of gray matter (density) in medial frontal cortex, Heschl's gyrus, and postcentral gyrus. In addition, moderate to high heritabilities for densities of Broca's area, anterior cingulate, hippocampus, amygdala, gray matter of the parahippocampal gyrus, and white matter of the superior occipitofrontal fasciculus were reported. The high heritability for (global) brain volumes, including the intracranium, total brain, cerebral gray, and white matter, seems to be present throughout life. Estimates of genetic and environmental influences on age-related changes in brain structure in children and adults await further longitudinal twin-studies. For prefrontal cortex volume, white matter, and hippocampus volumes, a number of candidate genes have been identified, whereas for other brain areas, only a few or even a single candidate gene has been found so far. New techniques such as genome-wide scans may become helpful in the search for genes that are involved in the regulation of human brain volume throughout life.

 

Brain development during childhood and adolescence: a longitudinal MRI study. Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL. Nat Neurosci 1999;2:861-863.

 

Abstract. Pediatric neuroimaging studies, up to now exclusively cross sectional, identify linear decreases in cortical gray matter and increases in white matter across ages 4 to 20. In this large-scale longitudinal pediatric neuroimaging study, we confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20.

 

|  Full Text  | 

 

Genetic contributions to human brain morphology and intelligence. Hulshoff Pol HE, Schnack HG, Posthuma D, Mandl RC, Baare WF, van Oel C, van Haren NE, Collins L, Evans AC, Amunts K, Burgel U, Zilles K, de Geus EJ, Boomsma DI, Kahn RS. J Neurosci 2006;26:10235-10242.

 

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.

 

|  Full Text  |  PDF  | 

 

A bivariate genetic analysis of cerebral white matter hyperintensities and cognitive performance in elderly male twins. Carmelli D, Reed T, DeCarli C. Neurobiol Aging 2002;23:413--420.

 

Abstract. White matter hyperintensities (WMHs) are frequently observed On MRI scans of elderly nondemented people and have been associated in the past with cognitive impairment and physical dysfunction. Individual differences in the prevalence and severity of WMHs have been documented and more recently we reported on the significant contribution of genetic influences to this variability. The objective of the present study was to further investigate, in the context of a behavioral genetic paradigm, the nature of the association between WMHs and cognitive and physical function. MRI brain scans and a battery of neuropsychological and physical function tests were given to 142 male-male twin pairs [72 monozygotic (MZ) and 70 dizygotic (DZ)] participants in the 4th exam of the NHLBI Twin Study. Biometric genetic modeling was used to estimate the genetic and/or environmental covariation between WMHs and cognitive and physical summary scores. The phenotypic association between WMHs and cognitive function in this sample of twins was modest but statistically significant. Genetic analyses of cognitive and physical function summary scores found that 55% to 70% of the observed variability was due to genetic influences. A further decomposition of the phenotypic association between WMHs and cognitive function found that 70% to 100% of the phenotypic covariation was due to common genetic effects. Similar results explained the association between WMHs and performance on two physical function tests. We conclude from these analyses that common genetic influences explain to a large extent previously observed phenotypic associations between large amounts of WMHs and poor cognitive and physical function in the elderly.

 

Quantitative genetic modeling of variation in human brain morphology. Baaré WFC, Hulshoff Pol HE, Boomsma DI, Posthuma D, de Geus EJC, Schnack HG, van Haren NEM, van Oel CJ, Kahn RS. Cereb Cortex 2001;11:816--824.

 

Abstract. White matter hyperintensities (WMHs) are frequently observed On MRI scans of elderly nondemented people and have been associated in the past with cognitive impairment and physical dysfunction. Individual differences in the prevalence and severity of WMHs have been documented and more recently we reported on the significant contribution of genetic influences to this variability. The objective of the present study was to further investigate, in the context of a behavioral genetic paradigm, the nature of the association between WMHs and cognitive and physical function. MRI brain scans and a battery of neuropsychological and physical function tests were given to 142 male-male twin pairs [72 monozygotic (MZ) and 70 dizygotic (DZ)] participants in the 4th exam of the NHLBI Twin Study. Biometric genetic modeling was used to estimate the genetic and/or environmental covariation between WMHs and cognitive and physical summary scores. The phenotypic association between WMHs and cognitive function in this sample of twins was modest but statistically significant. Genetic analyses of cognitive and physical function summary scores found that 55% to 70% of the observed variability was due to genetic influences. A further decomposition of the phenotypic association between WMHs and cognitive function found that 70% to 100% of the phenotypic covariation was due to common genetic effects. Similar results explained the association between WMHs and performance on two physical function tests. We conclude from these analyses that common genetic influences explain to a large extent previously observed phenotypic associations between large amounts of WMHs and poor cognitive and physical function in the elderly.

 

|  Full Text  |  PDF  |

 

Focal Gray Matter Changes in Schizophrenia across the Course of the Illness: A 5-Year Follow-Up Study. van Haren NE, Hulshoff Pol HE, Schnack HG, Cahn W, Mandl RC, Collins DL, Evans AC, Kahn RS. Neuropsychopharmacology 2007;32:2057-2066.

 

Abstract. Recent volumetric magnetic resonance imaging (MRI) studies have suggested brain volume changes in schizophrenia to be progressive in nature. Whether this is a global process or some brain areas are more affected than others is not known. In a 5-year longitudinal study, MRI whole brain scans were obtained from 96 patients with schizophrenia and 113 matched healthy comparison subjects. Changes over time in focal gray and white matter were measured with voxel-based morphometry throughout the brain. Over the 5-year interval, excessive decreases in gray matter density were found in patients in the left superior frontal area (Brodmann areas 9/10), left superior temporal gyrus (Brodmann area 42), right caudate nucleus, and right thalamus as compared to healthy individuals. Excessive gray matter density decrease in the superior frontal gray matter was related to increased number of hospitalizations, whereas a higher cumulative dose of clozapine and olanzapine during the scan interval was related to lesser decreases in this area. In conclusion, gray matter density loss occurs across the course of the illness in schizophrenia, predominantly in left frontal and temporal cortices. Moreover, the progression in left frontal density loss appears to be related to an increased number of psychotic episodes, with atypical antipsychotic medication attenuating these changes.

 

The association between brain volume and intelligence is of genetic origin. Posthuma D, de Geus EJ, Baare WF, Hulshoff Pol HE, Kahn RS, Boomsma DI. Nat Neurosci 2002;5:83--84.

 

To the editor. The recent study by Thompson and colleagues reported high heritability of gray-matter volume in several cortical regions using voxel-based MRI techniques. Gray matter substantially correlated with general intelligence, or 'g'. These findings prompt three major questions: (i) is the high heritability specific to gray-matter volume, (ii) is the correlation with g specific to gray-matter volume and (iii) is the correlation between gray-matter volume and g of genetic or environmental origin? We addressed the first question in a large Dutch sample of twins and their siblings (258 Dutch adults from 112 extended twin families)2. We found high heritability for total brain gray-matter volume (Table 1), comparable to the estimate reported by Thompson and colleagues1. In addition, we found high heritability for total brain white-matter volume.

 

|  PDF  | 

 

Genetic influences on brain structure. Thompson PM, Cannon TD, Narr KL, van Erp T, Poutanen VP,Huttunen M, Lonnqvist J, Standertskjold-Nordenstam CG, Kaprio J, Khaledy M, Dail R, Zoumalan CI, Toga AW. Nat Neurosci2001;4:1253--1258.

 

Abstract. Here we report on detailed three-dimensional maps revealing how brain structure is influenced by individual genetic differences. A genetic continuum was detected in which brain structure was increasingly similar in subjects with increasing genetic affinity. Genetic factors significantly influenced cortical structure in Broca's and Wernicke's language areas, as well as frontal brain regions (r2(MZ) > 0.8, p < 0.05). Preliminary correlations were performed suggesting that frontal gray matter differences may be linked to Spearman's g, which measures successful test performance across multiple cognitive domains (p < 0.05). These genetic brain maps reveal how genes determine individual differences, and may shed light on the heritability of cognitive and linguistic skills, as well as genetic liability for diseases that affect the human cortex.

 

 

Name

Email

Website

Title

Comment

smaller | bigger

I have read and agree to the Terms of Usage.

Add Comment