Elsevier

NeuroImage

Volume 49, Issue 2, 15 January 2010, Pages 1536-1544
NeuroImage

Reduced variance in monozygous twins for multiple MR parameters: Implications for disease studies and the genetic basis of brain structure

https://doi.org/10.1016/j.neuroimage.2009.09.003Get rights and content

Abstract

Twin studies offer the opportunity to determine the relative contribution of genes versus environment in traits of interest. Here, we investigate the extent to which variance in brain structure is reduced in monozygous twins with identical genetic make-up. We investigate whether using twins as compared to a control population reduces variability in a number of common magnetic resonance (MR) structural measures, and we investigate the location of areas under major genetic influences. This is fundamental to understanding the benefit of using twins in studies where structure is the phenotype of interest.

Twenty-three pairs of healthy MZ twins were compared to matched control pairs. Volume, T2 and diffusion MR imaging were performed as well as spectroscopy (MRS). Images were compared using (i) global measures of standard deviation and effect size, (ii) voxel-based analysis of similarity and (iii) intra-pair correlation.

Global measures indicated a consistent increase in structural similarity in twins. The voxel-based and correlation analyses indicated a widespread pattern of increased similarity in twin pairs, particularly in frontal and temporal regions. The areas of increased similarity were most widespread for the diffusion trace and least widespread for T2. MRS showed consistent reduction in metabolite variation that was significant in the temporal lobe N-acetylaspartate (NAA).

This study has shown the distribution and magnitude of reduced variability in brain volume, diffusion, T2 and metabolites in twins. The data suggest that evaluation of twins discordant for disease is indeed a valid way to attribute genetic or environmental influences to observed abnormalities in patients since evidence is provided for the underlying assumption of decreased variability in twins.

Introduction

Twin studies offer the opportunity to determine the relative contribution of genes versus environment in a trait of interest. Moreover, many studies have used twins discordant for disease to distinguish between genetic and environmental influences on the morphological abnormalities associated with neurological and psychiatric disease. Conditions such as schizophrenia (Narr et al., 2002, Hulshoff Pol et al., 2002a, Styner et al., 2005), Alzheimer's disease (Luxenberg et al., 1987, Andel et al., 2005), autism (Kates et al., 2004), Tourette's syndrome (Hyde et al., 1995) and attention disorders (Reiersen et al., 2008) have been investigated in this manner.

All these investigations have focused on brain volumes obtained from T1-weighted high-resolution MR images. However, there are a host of alternative structural MR parameters describing complementary biological information. These include measurements of T2 relaxation time, water diffusion and metabolite concentration that provide unique information about structural and functional integrity. It is not yet known how these parameters vary in identical twins as compared to unrelated controls.

A number of studies have investigated heritability of brain volume in healthy twins using complex computationally intensive approaches that are not readily amenable to group comparisons in disease states (for example, White et al., 2002, Thompson et al., 2001, Wright et al., 2002). A widely used alternative technique for the objective analysis of quantitative MR imaging parameters between such groups is the voxel-based (VB) approach. The technique, originally applied to volume – known as voxel-based morphometry (Ashburner and Friston, 1997) – has since been extended to the evaluation of changes in other MR parameters such as the T2 relaxation time (for example, Pell et al., 2004). The method enables the objective assessment of changes between groups of subjects across the entire imaging volume. This offers the advantage in twin studies of being able to map the distribution of similarity between twin pairs when compared to healthy age-matched control pairs. The VB approach was therefore selected in this study to investigate the quantitative MRI parameters, volume, T2 relaxation time and diffusion by mapping the degree of similarity in each group. We also looked at the similarity of metabolite information obtained from magnetic resonance spectroscopy (MRS) in twins. This technique has recently been applied to a twin study of schizophrenia (Lutkenhoff et al., 2008).

The aim of this study is twofold:

  • (1)

    to investigate the extent to which the variance in a range of MR measures of brain structure can be reduced by controlling genetic variation; and

  • (2)

    to investigate which areas of the brain are under the most genetic influence for each MR parameter.

Section snippets

Twins pairs

Twenty-three pairs of healthy, monozygous twins were recruited through the Australian Twin Registry (mean age = 30 ± 5 years; 8 male twins pairs, 15 female pairs). All underwent DNA testing, and monozygosity was confirmed in all cases by a standard technique of analysis of eight highly polymorphic markers where the likelihood of dizygosity given identity of these markers is less than 0.001%. Fifteen pairs were right-handed, one pair was left-handed and the rest each consisted of a right- and

Global analysis of standard deviation and effect size

A consistent reduction in standard deviation and effect size was observed in the twin pairs in all the analyses (Table 1) with the exception of the standard deviation measure for the T2 relaxation time which was greater in the twins (see Discussion).

Voxel-based analyses of similarity

Fig. 1 shows the results of the voxel-based analyses. The contrasts twin pair similarity< control pair similarity (twin pair similarity > control similarity pair similarity), indicate areas where the intra-pair similarity is lower (greater) in the twin

Discussion

In the past decade, the growth in genetics and neuroimaging has been dramatic. Structural brain imaging studies of twins lie at the interface of this effort. The benefit of twins is related to the extent to which variance in the parameters of interest is reduced by the control of genetic variation. This study indicates the degree of benefit of using twin pairs and the areas of the brain in which the magnitude of this effect is greatest for a range of MRI structural parameters. Using voxel-based

Acknowledgments

The authors thank the help of Professor John L. Hopper, director of the Australian Twin Registry. This work was funded by the National Health and Medical Research Council (NHMRC).

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