Elucidating the genetic and environmental influences on brain structure and on brain structure changes over time is important for the basic understanding of brain aging. Although more work is needed to determine the extent of genetic and environmental influences on brain structure, results to date across different studies are generally consistent for most measures that have been examined (reviewed by Glahn et al., 2007
; Peper et al., 2007
; Schmitt et al., 2007a
). That is, the heritability—the proportion of phenotypic variance due to genes—of different regions of interest (ROIs) has been similar across studies.
One notable exception is the lateral ventricles. There has been substantial variability of heritability estimates in twin studies of left and right lateral ventricular volumes, ranging from zero to nearly 0.80. As can be seen in , the heritability of lateral ventricular volume based on magnetic resonance imaging (MRI) has been reported in five adult twin samples (including our own) and two child and adolescent twin samples. There was also an earlier computed tomography study utilizing an adult twin sample. We restrict this summary to twin studies because they provide a suitable way of differentiating genetic and family environmental sources of resemblance (Kendler and Neale, 2009
). Adoption studies can also disentangle these sources of variance, but we are unaware of adoption studies with the necessary neuroimaging data.
Heritability of lateral ventricular volume (ordered by average age of sample)
Given that lateral ventricular expansion is a ubiquitous, albeit nonspecific, feature of normal brain aging (Pfefferbaum et al., 2004
), it is perhaps intuitive to think that enlargement would be due primarily to accumulated environmental insults over the lifespan. However, the wide variability in the heritability estimates casts doubt on this explanation. The inconsistent results are particularly puzzling given the relative consistency of other brain structure heritability estimates plus the fact that the lateral ventricles are one of the easiest ROIs to delineate and measure reliably. This inconsistency leaves us with some as yet unresolved questions: Is the volume of the ventricles under some degree of genetic control or not? If it is, does the degree of genetic control differ as a function of age? If it is not under genetic control, what accounts for the high heritability reported in some studies? Is it just sampling and methodological differences across studies or something more systematic?
Clarifying the extent of genetic and environmental influences on lateral ventricular volume is an essential first step in determining whether ventricular volume or expansion may also be a useful endophenotype. Ventricular expansion is greater than normal in many aging-related disorders. If it is under significant genetic control and not simply secondary to growth or shrinkage of surrounding brain tissue, a thorough understanding of brain aging will require the elucidation of the genetic factors that influence normal and pathological age-related lateral ventricular expansion. Thus, despite being nonspecific, lateral ventricular volume might be a useful endophenotype and an appropriate phenotype for genetic association studies. We sought to re-evaluate the extant twin studies of the lateral ventricles in an effort to account for the highly discrepant heritability findings, and to determine whether the well-known age-related increase in the volume and variability of the lateral ventricles is associated with changes in genetic or environmental factors.