In 1865, Francis Galton wrote that twins offer a “means of distinguishing between the effects of tendencies received at birth, and of those that were imposed by the circumstances of their after lives; in other words, between the effects of nature and nurture.”
The standard assumption of genetic studies on twins has been that greater disease concordance rates in monozygotic (MZ) versus dizygotic (DZ) twins is evidence for a genetic susceptibility component [Boomsma et al., 2002; Kato et al., 2005]. However, findings from recent clinical and molecular research have widened this narrow view. In this article, we review clinical studies of twins that have addressed nature versus nurture issues, and how these studies do not account for all the observed phenotype discordance among twin pairs. Next, we discuss epigenetic evidence that although MZ twins have the same or very similar DNA sequence, gene expression and DNA modification patterns can differ significantly. This challenges the conventional paradigm that MZ twins are identical genetic controls in which environment is the only differing variable [Cardno and Gottesman, 2000]. These new insights about epigenetic DNA modifications and their effects on gene expression and phenotype may increase our understanding of diverse phenotypes from personality traits to neuropsychiatric disease. The new paradigm is not one of nature versus nurture, but of a complex and dynamic interaction between DNA sequence, epigenetic DNA modifications, environment, gene expression, and environmental factors that all combine to influence phenotype.
These new insights about epigenetic DNA modifications and their effects on gene expression and phenotype may increase our understanding of diverse phenotypes from personality traits to neuropsychiatric disease. The new paradigm is not one of nature versus nurture, but of a complex and dynamic interaction between DNA sequence, epigenetic DNA modifications, environment, gene expression, and environmental factors that all combine to influence phenotype.
Classical Twin Study Designs: Genes and Environment
Over the last century, Galton's nature versus nurture dichotomy influenced classical twin studies by stimulating two categories of inquiry: (1) studies aimed at identifying environmental risk factors causing discordance between MZ twins [Kato et al., 2005], and (2) studies aimed at identifying genetic determinants of disease or other phenotypes. In the first category is the landmark Minnesota Study of Twins Reared Apart, which challenged the notion that environment plays a significant role in determining a wide variety of phenotypes [Bouchard et al., 1990]. Extensive physical and psychological evaluations of MZ and DZ twin pairs, some separated and raised apart since early childhood, were performed to quantify the degree of phenotypic discordance among MZ twin pairs [Bouchard et al., 1990; Markon et al., 2002]. The intraclass correlation of scores on numerous tests (R) within pairs of twins raised apart: MZA (RMZA) or raised together: MZT (RMZT) was expressed as a ratio (RMZA/RMZT). As expected, adult MZ twins were similar on many physiological and psychological traits. The surprising discovery was that for some phenotypes, this similarity was present to the same degree whether the MZ twins were raised together or not, suggesting that environmental factors had limited influence, at least in producing within-MZ-twin differences. For example, correlations within MZT and MZA twin pairs on personality measurements were almost identical (e.g., RMZA = 0.50 and RMZT = 0.49 on the Multidimensional Personality Questionnaire (MPQ)). The RMZA/RMZT ratio for the MPQ was 1.02, compared with 1.01 for fingerprint ridge counts.
Other studies have explored the role of prenatal and postnatal environmental influences on neuropsychiatric disease penetrance. For example, Torrey et al. 1994 studied MZ twin pairs discordant for schizophrenia and found that only 30% of the MZ twin pairs had neurological or behavioral differences by the age of 5. These results suggest that while significant prenatal and neonatal events may have an influence on adult-onset schizophrenia, these events cannot entirely account for the discordance in diagnosis [Torrey et al., 1994]. The alternate hypothesis is that factors other than DNA sequence and major environmental events affect susceptibility to diseases such as schizophrenia.
Twin studies aimed at determining the magnitude of genetic influence on disease susceptibility have often relied on quantitative estimates of heritability: the proportion of total phenotypic variation attributable to additive genetic effects. Heritability (h2) can be calculated as twice the difference between MZ and DZ concordance, based on the assumption that MZ twins have identical genomes, while DZ twins have half the genetic variation present in unrelated individuals [Boomsma et al., 2002; Visscher et al., 2008]. It is also presumed that MZ and DZ co-twins have a similar degree of difference between their pre- and postnatal environments [Guo, 2001]. A greater phenotype concordance rate in MZ versus DZ twins therefore provides evidence for a genetic component in the phenotype of interest [Boomsma et al., 2002; Kato et al., 2005]. Using this approach, heritability estimates for schizophrenia have been reported to be as high as 80% [Cardno and Gottesman, 2000]; with heritability for bipolar at 62–79% [Bertelsen, 2004], and depression 21–45% [Kendler et al., 1992]. However, these relatively high heritability estimates can obscure the substantial discordance among a large proportion of MZ twin pairs; for schizophrenia, the MZ concordance rate is in the range of 41–65% [Cardno and Gottesman, 2000].
Clinical diagnosis in psychiatry is of course somewhat subjective, but objective brain phenotypes such as volume show similar heritability. Rijsdijk et al. 2005 compared the brain volumes (whole brain, hippocampus, third and lateral ventricles) of MZ twins concordant and discordant for schizophrenia, healthy MZ twins, discordant sibling pairs, concordant sibling pairs, and healthy control subjects. These comparisons generated heritability estimates of 88% for whole-brain volume, while for lateral ventricle size, 67% of the variation was attributed to common environmental effects [Rijsdijk et al., 2005]. Brain morphology changes in schizophrenia twins were also examined in a recent Dutch study, which reported that intracranial and whole-brain corrected frontal lobe volumes are smaller in discordant MZ twins compared to healthy MZ twins [Baare et al., 2001]. This study also reported that both MZ and DZ discordant twins have smaller whole-brain, parahippocampal, and hippocampal volumes than healthy twins, and that affected twins have yet smaller whole-brain volumes than their non-schizophrenic co-twins. The hippocampal size findings were replicated in a Finnish twin study [van Erp et al., 2004]. Together, these observations indicate the presence of a genetic influence on brain volumes, but the additional reduction in whole-brain volume observed in the affected compared to the unaffected co-twins suggests that other factors must also modulate brain volume [Baare et al., 2001].
It is now clear that structural genes comprise only a small proportion of the genome (∼1%) [Lander et al., 2001], and that phenotype can be profoundly affected by changes in the amount, timing, and location of gene transcription, which are regulated by both genetic and environmental factors [Sullivan et al., 2003; Marcus, 2004; Gibson, 2008; Ramos and Olden, 2008]. In retrospect, it is naïve to suppose that direct, linear relationships between DNA sequence and phenotype should arise at all. Global phenotypes are the product of complex networks of genes, proteins, and tissues that accept environmental inputs, so phenotypes represent an emergent property of a dynamic biological system rather than the deterministic output of either genetic or environmental inputs [Bhalla and Iyengar, 1999; Koch and Laurent, 1999]. This is especially relevant to diseases of the brain, since many complex brain functions are not anatomically localized and, even when controlled by a defined brain structure, arise from dynamic patterns of activation of large neural networks.
Traditional twin studies are based in part on the assumption that there are deterministic effects of gene sequence and environmental events on phenotype. This perspective does not account for the stochastic nature of many biological and biochemical processes, nor the complex interaction between environmental influences and phenotype. One molecular mechanism that could be both a source of stochastic variation in gene expression and a mediator of environmental effects on phenotype is epigenetics. Epigenetic factors that may cause MZ twin pairs to diverge and account to a large degree for some of their phenotypic discordance include skewed X-inactivation in female MZ (FMZ) twins, imprinting, and other modifications of chromosomal DNA and gene expression, especially through DNA methylation [Gringras and Chen, 2001; Boomsma et al., 2002; Rosa et al., 2008].
Epigenetic factors that may cause MZ twin pairs to diverge and account to a large degree for some of their phenotypic discordance include skewed X-inactivation in FMZ twins, imprinting, and other modifications of chromosomal DNA and gene expression, especially through DNA methylation.