Genetic reports abstractHeritability of brain volumes in older adults: the Older Australian Twins Study
Introduction
The development of the human brain is under the influence of both genetic and environmental factors. The classical method to examine these influences is the twin design, as monozygotic (MZ) twins share all their genes, whereas dizygotic (DZ) twins share on average only 50% of their segregating DNA (Plomin et al., 1994). The twin design is used to estimate the “heritability” of a trait, which is the proportion of the observable differences between individuals that is because of genetic factors. Previous studies have reported heritability for a number of structural brain measures, which include brain volume (BV) (Kremen et al., 2010, Pfefferbaum et al., 2000, Thompson et al., 2001), brain surface complexity (Gatt et al., 2012, White et al., 2002), white matter fractional anisotropy, (Chiang et al., 2011, Kochunov et al., 2010) and cortical thickness (Gatt et al., 2012, Panizzon et al., 2009, Winkler et al., 2010). A recent meta-analysis of BV heritability (Blokland et al., 2012) reported that comparing the results of different studies was difficult because of the demographic or methodological differences. However, a collation of the published data showed the influence of genes on brain structures to be in the range of 73%–91% for intracranial volume (ICV), 46%–94% for BV, 64%–89% for cerebrum, 56%–82% for gray matter (GM), 80%–88% for white matter (WM), 26%–84% for the frontal lobe, 30%–86% for the parietal lobe, 55%–88% for the temporal lobe, and 32%–74% for the occipital lobe (Baare et al., 2001, DeStefano et al., 2009, Geschwind et al., 2002, Gilmore et al., 2010, Wallace et al., 2006, Yoon et al., 2010a). It should be noted however, that most of these studies were performed on individuals younger than 65 years.
We found only 7 studies that examined BV heritability in individuals aged older than 65 years (Carmelli et al., 2002, DeStefano et al., 2009, Geschwind et al., 2002, Pfefferbaum et al., 2000, Pfefferbaum et al., 2001, Pfefferbaum et al., 2004, Sullivan et al., 2001). These studies reported moderate heritability for key BVs, e.g. 64% heritability for cerebrum (Geschwind et al., 2002), 46% for total BV (DeStefano et al., 2009), 54% for total frontal, 47% for total parietal, 46% for total temporal, and 28% for total occipital lobes (Geschwind et al., 2002). However, these studies had a number of limitations: the study by DeStefano et al. (2009) was a family study which usually has a lower power compared with a twin design; the other 6 studies were twin designs but were all performed on male twins only; and the study by Pfefferbaum et al. (2001) had a small sample size (15 MZ and 18 DZ pairs). Moreover, these studies selected a rather narrow range of brain volumetric measures, and therefore they do not give a comprehensive picture of heritability across multiple brain regions. Pfefferbaum et al., 2000, Pfefferbaum et al., 2001, Pfefferbaum et al., 2004 studied the corpus callosum, lateral ventricles, and ICV; Geschwind et al. (2002) reported on right and left frontal, temporal, occipital and parietal lobes, and the hemispheres; Sullivan et al. (2001) reported on the hippocampus, corpus callosum, and ICV; and Carmelli et al. (2002) reported on the right and left frontal, temporal, occipital and parietal lobes, and 2 cerebrospinal fluid (CSF) measures. To address these limitations and gaps in the literature, the present study used the twin design, included a large number of male and female twins, and studied a considerable number of brain volumetric measures, including ICV, cerebrum, cerebellum, total GM, total WM, hemispheric volumes, right and left lobar, GM and WM volumes, and the frontal, temporal, occipital, parietal and cerebellar lobes. These structures show significant volume changes in late lifetime, and therefore studying the reason of their changes would shed light on a better understanding of the aging process.
Heritability of the brain measures might change over the lifespan. Although many brain phenotypes have been genetically studied, evidence for the changes of brain heritability with age comes mostly from the neuroimaging studies of brain volume. For example, increments of heritability of BVs during development and early adulthood have been illustrated (Lenroot et al., 2009, Wallace et al., 2006). On the other hand, although very few studies have examined the changes of BV heritability in late life, and as listed previously they might have some limitations, decrement of the heritability of BVs after reaching adulthood is suggested (Geschwind et al., 2002, Pedersen, 2000, Pfefferbaum et al., 2000). Changes in the genetics of brain cognition with age have also been observed in a review study (Lee et al., 2010). One possible reason for these changes is the interaction of genes and environment, which is able to alter the number and variety of active genes or change their level of activity (Chiang et al., 2011, Plomin et al., 1994, Sarah et al., 2007, Walsh, 1980). Aging is associated with a reduction of brain volume (Jernigan et al., 2001, Resnick et al., 2000, Scahill et al., 2003, Trollor and Valenzuela, 2001), impairments in brain diffusivity (Kochunov et al., 2011) and cortical thinning (Brans et al., 2010), and it is important to understand the relative influence of genetic and environmental factors on these changes (Kremen et al., 2012).
Many brain phenotypes have been observed to show different genetic influences in men and women, and examples include total BV (Everaerd et al., 2012, Faass et al., 2013, Posthuma et al., 2000), brain WM integrity (Chiang et al., 2011) and WM hyperintesity volume (Atwood et al., 2004), brain functional connectivity (Damoiseaux et al., 2012), and more phenotypes as reviewed previously (Vink et al., 2012). However, the studies that have investigated sex differences of genetic influences in specific brain regions are very rare. Such examples would include the observation of sex-specific messenger RNA expression levels in medial preoptic area and ventromedial hypothalamus (Faass et al., 2013), differential influences of the X chromosome on different brain regions (Lentini et al., 2012), and the sex-specific influences of brain-derived neurotrophic factor gene on hippocampus, frontal cortex, and hypothalamus in an animal study (Chourbaji et al., 2012). These preliminary reports suggest that brain regions might vary in the degree to which sex influences genetic expression.
In this study, we analyzed data from the Older Australian Twins Study (OATS) to investigate heritability of brain volume in late life. Fifty-three global and lobar brain volumetric measures were selected. Based on previous reports, we hypothesized that brain structures would be highly heritable in older adults (Geschwind et al., 2002, Pfefferbaum et al., 2004, Sullivan et al., 2001), that genetic influences would decrease with age (Pfefferbaum et al., 2000) and that heritability would be higher in men (Chiang et al., 2011) and in the left hemisphere (Eyler et al., 2012, Thompson et al., 2001). We also expected to find high genetic correlations between the volumetric measures (Glahn et al., 2007, Hulshoff Pol et al., 2006c, Schmitt et al., 2010). To the best of our knowledge, this study for the first time examined the genetic contribution to certain brain volumes in an older cohort of twins, and the influence of age, sex, and laterality on these contributions.
Section snippets
Participants
Participants were drawn from the OATS, a population-based study of twins aged 65 years or older (Sachdev et al., 2009a) living in the 3 eastern states of Australia (New South Wales, Victoria, and Queensland) and registered with the Australian Twin Registry (www.twins.org.au). Individuals who consented to participate were included if they had a consenting co-twin and were sufficiently competent in English to complete a neuropsychological assessment in that language. They were excluded if they
Volumetric measures
The mean volumes of the brain measures, their age correlations, test of volumetric differences between men and women and between right and left hemispheres, in addition to the estimations of ICCs for the MZ and DZ twins are presented in Table 1 (measures were corrected for ICV, scanner, age and sex for ICC estimations and for ICV, scanner, and either of age or sex for sex/age correlations). Most of the volumetric measures showed negative correlations with age, including the total brain volume
Discussion
This study showed that the effect of genetic factors on total and regional brain volumes is relatively high in the late life. Reductions of genetic influences with age, as environmental influences increased, was observed in 18 total and regional volumetric measures, whereas CSF was the only measure with a significant heritability increment with age. Similarly, 18 total and regional measures significantly showed a higher genetic influence in men compared with women, whereas no finding for a
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
This study was supported by an NHMRC/ARC Strategic Award Grant of the Aging Well, Aging Productively Program (ID No. 401126), and facilitated with access to the Australian Twin Registry. The authors thank all current and past OATS staff members for their contributions to data analysis, especially the following individuals: New South Wales (Pamela Azar, Henry Brodaty, John Crawford, Tanya Duckworth, Kristan Kang, Fiona Kumfor, Andrea Lammel, Alissa Nichles, Peter Schofield, Alison Walker, Shaily
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