The mechanism of emergenesis

Since each individual produced by the sexual process contains a unique set of genes, very exceptional combinations of genes are unlikely to appear twice even within the same family. E. O. Wilson (1978)The intraclass correlations of monozygotic twins who were separated in infancy and reared apart (MZA twins) provide estimates of trait heritability, and the Minnesota Study of Twins Reared Apart [MISTRA: Bouchard et al. (1990), The sources of human psychological differences: the Minnesota study of twins reared apart, Science 250, 223-228] has demonstrated that MZA pairs are as similar in most respects as MZ pairs reared together. Some polygenic traits--e.g. stature, IQ, harm avoidance, negative emotionality, interest in sports--are polygenic-additive, so pairs of relatives resemble one another on the given trait in proportion to their genetic similarity. But the existence and the intensity of other important psychological traits seem to be emergent properties of gene configurations (or configurations of independent and partially genetic traits) that interact multiplicatively rather than additively. Monozygotic (MZ) twins may be strongly correlated on such emergenic traits, while the similarity of dizygotic (DZ) twins, sibs or parent-offspring pairs may be much less than half that of MZ pairs. Some emergenic traits, although strongly genetic, do not appear to run in families. MISTRA has provided at least two examples of traits for which MZA twins are strongly correlated, and DZA pairs correlate near zero, while DZ pairs reared together (DZTs) are about half as similar as MZTs. These findings suggest that even more traits may be emergenic than those already identified. Studies of adoptees reared together (who are perhaps more common than twins reared apart) may help to identify traits that are emergenic, but that also are influenced by a common rearing environment.     

Genetic and environmental contributions to population group differences on the Raven's Progressive Matrices estimated from twins reared together and apart

We carried out two studies to test the hypothesis that genetic and environmental influences explain population group differences in general mental ability just as they do individual differences within a group. We estimated the heritability and environmentality of scores on the diagrammatic puzzles of the Raven's Coloured and/or Standard Progressive Matrices (CPM/SPM) from two independent twin samples and correlated these estimates with group differences on the same items. In Study 1, 199 pairs of 5- to 7-year-old monozygotic (MZ) and dizygotic (DZ) twins reared together provided estimates of heritability and environmentality for 36 puzzles from the CPM. These estimates correlated with the differences between the twins and 94 Serbian Roma (both rs=0.32; Ns=36; ps<0.05). In Study 2, 152 pairs of adult MZ and DZ twins reared apart provided estimates of heritability and environmentality for 58 puzzles from the SPM. These estimates correlated with the differences among 11 diverse samples including (i) the reared-apart twins, (ii) another sample of Serbian Roma, and (iii) East Asian, White, South Asian, Coloured and Black high school and university students in South Africa. In 55 comparisons, group differences were more pronounced on the more heritable and on the more environmental items (mean rs=0.40 and 0.47, respectively; Ns=58; ps<0.05). After controlling for measurement reliability and variance in item pass rates, the heritabilities still correlated with the group differences, although the environmentalities did not. Puzzles found relatively difficult (or easy) by the twins were those found relatively difficult (or easy) by the others (mean r=0.87). These results suggest that population group differences are part of the normal variation expected within a universal human cognition.     

Fourier analysis of facial profiles of young twins

Twins studies provide a powerful approach to determining the relative contribution of genetics and environment to observed variation. Such studies assume trait differences in monozygous (MZ) twins are due to environmental factors and those in dizygous (DZ) twins are due to both genetic and environmental factors. This study quantitated facial profiles of twins using Fourier equations, determining their value in profile analysis and the assessment of the genetic contribution to facial shape. Standardized profile slide photographs of 79 pairs of 4-6 year-old twins (37 MZ pairs, 42 DZ pairs) were scanned and x and y coordinates were extracted from each profile using sellion and Camper's plane as references. The coordinates were subjected to Fourier analysis and the normalised vertex projection coefficients were studied. The means of the differences between coefficients for MZ co-twins did not differ significantly from that of DZ co-twins, although the DZ group showed higher mean differences in the higher harmonics. Subjective examination of superimposed reconstructions showed wider variation between DZ co-twins than MZ co-twins. Correct classification of twins by discriminant function analysis using Fourier coefficients was similar for both groups (MZ: 70.3%; DZ: 73.8%). Fourier analysis could quantitate facial profiles of young children and differentiate some details, but was unable to discriminate between genetic and environmental influences, and any possible interactions between these influences, on their overall facial profiles at this developmental stage.     

Genetic and environmental correlations among serum lipids and apolipoproteins in elderly twins reared together and apart.

Genetic and environmental correlations among five serum-lipid measures were examined in the Swedish Adoption/Twin Study of Aging. The sample included 302 twin pairs; 146 of these twin pairs were separated at an early age and were reared apart. The lipid measures examined include total cholesterol, HDL-cholesterol, triglycerides, and apolipoproteins A-I and B. Genetic and environmental correlations were evaluated for two different age groups, formed by dividing the sample at the median. The younger group included individuals 41.8-65.4 years of age at the midpoint of testing, although only 24 individuals were < 50 years of age. The older group included all those > 65.4 years of age, up to age 87 years of age. Substantial genetic correlations were found within each age group, although there is no evidence for a single genetic factor common to all five lipids. The comparison of twins reared together with twins reared apart allowed estimation of the effects of shared rearing environment; however, shared rearing environment only appears to be a significant mediator of the phenotypic correlation between apolipoprotein B and cholesterol in the older group. Examination of the genetic and environmental covariances suggests that the relative contributions of genetic factors are lower in the older group. Nonshared environmental factors are relatively more important mediators of phenotypic correlations among the serum lipids in individuals > 65.4 years of age than they are for the younger group. Sex differences in the mediation of these serum lipids were not as clear.     

Genetic and environmental influences on bilateral dental asymmetry in Northwest Indian twins

The role of genetic and environmental factors on dental asymmetry (in maximum crown dimensions) was examined using 58 pairs of twins (23 MZ and 35 DZ) from Chandigarh, India. The t'-test for equality of means by zygosity showed only one variable significantly different among 56: this is ascribable to Type 1 error. Heterogeneity of MZ-DZ total variance was observed in 42.9% of traits of the two types (fluctuating and directional) of bilateral asymmetry. In general, MZ twins showed higher total variance than DZ pairs. MZ twins also showed stronger environmental covariance for a majority of the traits. Dental asymmetry measures thus yielded consistently low genetic variance ratios and indicated predominantly complex environmental determinism. Since fluctuating asymmetry is widely believed to be an environmental stress indicator, this data set allows confirmation of methods for detecting unequal environmental influences on the zygosities which bias estimates of genetic variance and heritability.     

The behaviors of some heritability estimators in the complete absence of genetic factors.

Heritability is an important concept in quantitative genetics and is widely used in human genetics. A high or even a moderate value of heritability estimate is usually taken as evidence for a genetic component for a quantitative trait. In this paper, the behaviors of some correlation-based heritability estimators are reexamined under the assumption of complete absence of any genetic factors. It turns out that when monozygotic (MZ) twins (or full sibs) are environmentally more similar than dizygotic twins (or half sibs), or when there is placement bias in MZ twins reared apart, those correlation-based heritability estimates can lead to nonnegligible or even high heritability values, even when genetic factors are completely absent. These alarming results suggest that extreme care should be exercised when using these heritability estimators.     

Genetic and environmental influences on pupil performances.

The results presented in this paper are part of a current comparative study of genetic and environmental influences in three educational settings: Stockholm, Jerusalem and the Israeli kibbutz. We specifically wanted to investigate whether a more restrictive educational setting would decrease genetic influences. Here we report on comparisons of cognitive performance measures at several time points for twins/controls, boys/girls and within-pair similarity in MZ, DZ and controls. The tests used were the Raven Progressive Matrices, verbal, reading comprehension and arithmetic. The results show no differences between twins and controls, whilst gender differences seem to be smallest in the Stockholm sample and largest in Jerusalem. A pattern of genetic influences on cognitive performance was also clearly visible in Jerusalem. In Stockholm shared environmental influences at home and at school seemed even stronger than in the kibbutz. No consistent differences were found between tests or occasions.     

Contribution of genetic and environmental effects to postural balance in older female twins.

The aim of the present study was to determine the relative roles of genetic and environmental influences on postural balance in older women. The participants were 97 monozygotic (MZ) and 102 dizygotic (DZ) female twins, aged 64-76 yr. Postural sway was measured during side-by-side stance with eyes open and eyes closed, and during semitandem stance with eyes open on a force platform. Sway data were condensed into four first-order and one second-order latent factors. The second-order factor, named balance, incorporates sway data from multiple tests and thus best describes the phenotype of postural balance. The contribution of genetic and environmental influences on the variability of the latent factors was assessed by using structural equation modeling. Additive genetic influences accounted for 35% and shared environmental influences accounted for 24% of the total variance in the balance factor. In the present study, postural balance in older women had a moderate genetic component. Genetic influences on postural balance may be mediated through gene variation in the systems that control posture. The finding that individual environmental influences accounted for almost one-half of the variance in postural balance points to the potential of targeted interventions to maintain and improve balance control in older persons.     

The influence of zygosity and chorion type on fat distribution in young adult twins consequences for twin studies.

An adverse intra-uterine environment has been associated with abdominal fat distribution in singletons. Twins often have a low birth weight and a short gestation. Therefore, they may have an increased risk to develop abdominal obesity. Furthermore, monozygotic monochorionic twins (MZ MC) have a larger intra-pair birth weight difference compared to monozygotic dichorionic twins (MZ DC). If adult anthropometry is programmed in utero, this may affect the intra-pair correlations in adulthood and, consequently, also the results from the classic twin method to estimate genetic and environmental influences. In the present study, we compared the absolute values, the intra-pair differences, and the intra-pair correlations of body mass, height, BMI, and abdominal fat distribution of 424 MZ MC, MZ DC and dizygotic (DZ) twin pairs (aged 18-34 yrs). DZ, MZ DC and MZ MC twins did not differ for most anthropometric characteristics. Only MZ women tended (p = 0.03) to accumulate more abdominal fat compared to DZ twins. Overall, the contribution of zygosity and chorion type to adult anthropometry was rather low (< or = 1.7%). Although the intra-pair birth weight difference of MZ MC pairs (10.5% in men, 12.3% in women) was significantly larger compared to that of MZ DC pairs (6.9% and 9.2% resp.), the intra-pair differences in adult anthropometry were similar for both MZ twin types. Also the intra-pair correlations of MZ MC and MZ DC pairs were strikingly alike, suggesting no significant influence of the prenatal environment on adult concordance. In conclusion, the substantial difference in the prenatal environment of MZ MC and MZ DC twins did not result in a difference in intra-pair concordance of adult anthropometry and fat distribution. Therefore, we suggest that the chorion type of MZ twins does not bias the twin design and the estimation of the genetic contribution to adult anthropometry.     

A gerontological cohort study of aged twins: the Osaka University Aged Twin Registry.

We describe subject recruitment and research results from the Osaka University Aged Twin Registry (OUATR). The research focus of OUATR is the genetic and environmental contributions to physical-cognitive-mental aging which we examined in Japanese twins in later adulthood. Within this large-scale registry (12,000 pairs) of oriental twins born between 1900 and 1935, approximately 10% of participants are MZ twins reared apart from early childhood. Two hundred and fifty pairs have had comprehensive medical examinations, including various blood chemical panels, lymphocyte subtests, WAIS (Wechsler Adult Intelligence Scale), and urine analysis. The future foci of this study are primarily on longevity, decline of cognitive functions with aging, bio-physiological functions, lifestyle and behavior genetics, and psycho-spiritual functions.     

Chorion type as a possible influence on the results and interpretation of twin study data.

The estimation of genetic effects from twin studies usually relies upon the equal environment assumption--that monozygous (MZ) and dizygous (DZ) twin pairs experience equal similarity of their environments from prenatal experiences through adulthood. However, the sharing of a chorion may make a subset of identical twins more similar, or in some cases, more different, than twins that do not share a chorion. Recent studies suggest monochorionic MZ twins resemble one another more than dichorionic MZ twins in cognitive abilities, personality, and risk for psychiatric disorder. To the extent that prenatal environment affects these characteristics, the traditional twin method will yield biased estimates of genetic and environmental influences. We develop models for quantifying this bias and estimating the influence of chorion type on estimates of heritability.     

Does higher concordance in monozygotic twins than in dizygotic twins suggest a genetic component?

It is widely regarded that twins can be used as a natural experiment to subject hypotheses to empirical testing regarding the contributions of genetic factors to phenotypic variability in human traits, especially behavioral traits. In genetic epidemiology, a higher concordance rate in monozygotic (MZ) twins than in dizygotic (DZ) twins is often taken as prima facie evidence for a genetic component. While twins studies have been used to estimate the contributions of genetic factors to phenotypic variability in human traits, the corresponding methodology that allows the estimation entails several crucial assumptions. The most critical is that MZ and DZ twins are equally similar environmentally. Although MZ twins are genetically more similar than DZ twins, they are often environmentally more similar. This paper demonstrates that, even in the complete absence of any genetic factor and of any biases, the greater environmental similarity alone in MZ twins can result in higher concordance rate in MZ twins than in DZ twins. This is especially true when there are multiple environmental factors, which may have multiple exposure levels and/or interact strongly, although each of them may be of low risk. This may serve as a sobering antidote to the uncritical reliance on twin studies without examining the validity of the underlying assumptions.     

A study in twins of the urinary excretion of vanilmandelic acid, 17-keto-steroids, 17-hydroxycorticosteroids, and creatinine]

The 24-hour urinary excretion rates of creatinine, vanilmandelic acid (VMA), 17-hydroxycorticosteroids, 17-ketosteroids were analysed in 30 female twin pairs. For each of these variables, a comparative study based on the breakdown of total variance into interpair and intrapair variance was undertaken, first on identical (MZ) and fraternal (DZ) twins and then on twins who live together or separately. The comparison of test results shows a strong likeness in the MZ group and in the living together group with respect to the urinary excretion of 17-OH. The variability of VMA excretion can be explained by genetic factors while the variability of 17-ketosteroids and creatinine can be explained with reference to environmental factors.     

Twin studies in behavioral research: a skeptical view

We review in detail two major ongoing research projects that employ samples of twins reared apart (and in one case, twins reared together). The studies attempt, via model fitting, to estimate proportions of genetic and environmental variance for many human traits. We discuss problems concerning the representativeness of samples, the accuracy and reliability of the data, the extent of contact of nominally separated twins, the measurement of selective placement effects, and the particular model-fitting procedures. The two studies agree in their conclusions, but we do not find the conclusions to be convincing. We suggest that no scientific purpose is served by the flood of heritability estimates generated by these studies.     

Skin testing versus radioallergosorbent testing for indoor allergens

BACKGROUND: Skin testing (ST) is the most common screening method for allergy evaluation. Measurement of serum specific IgE is also commonly used, but less so by allergists than by other practitioners. The sensitivity and specificity of these testing methods may vary by type of causative allergen and type of allergic manifestation. We compared ST reactivity with serum specific IgE antibodies to common indoor allergens in patients with respiratory allergies. METHODS: 118 patients (3 mo-58 yr, mean 12 yr) with allergic rhinitis and/or bronchial asthma had percutaneous skin testing (PST) supplemented by intradermal testing (ID) with those allergens suspected by history but showed negative PST. The sera were tested blindly for specific IgE antibodies by the radioallergosorbent test (Phadebas RAST). The allergens were D. farinae (118), cockroach (60), cat epithelium (90), and dog epidermal (90). Test results were scored 0-4; ST >/= 2 + and RAST >/= 1 + were considered positive. RESULTS: The two tests were in agreement (i.e., either both positive or both negative) in 52.2% (dog epidermal) to 62.2% (cat epithelium). When RAST was positive, ST was positive in 80% (dog epidermal) to 100% (cockroach mix). When ST was positive, RAST was positive in 16.3% (dog epidermal) to 50.0% (D. farinae). When RAST was negative, ST was positive in 48.5% (cat epithelium) to 69.6% (D. farinae). When ST was negative, RAST was positive in 0% (cockroach) to 5.6% (cat epithelium). The scores of ST and RAST showed weak to moderate correlation (r = 0.24 to 0.54). Regardless of history of symptoms on exposure, ST was superior to RAST in detecting sensitization to cat epithelium and dog epidermal. CONCLUSION: For all four indoor allergens tested, ST was more sensitive than RAST. When both tests were positive, their scores showed poor correlation. Sensitizations to cat epithelium and dog epidermal are common, even in subjects who claimed no direct exposure.     

A twin study of structural chromosome aberrations in lymphocytes

Structural chromosome aberrations were analyzed in peripheral lymphocytes of eight monozygotic (MZ) and seven dizygotic (DZ) pairs of male twins. There was no significant intrapair difference in the variance of aberration frequencies among the MZ and DZ twins. Thus, there was no evidence of a major genetic influence on the development of structural chromosome aberrations. Although a genetic component could not be excluded, it was concluded that any chromosome aberrations observed were probably due mainly to environmental influences.     

Effect of Genome and Environment on Metabolic and Inflammatory Profiles

Twin and family studies have established the contribution of genetic factors to variation in metabolic, hematologic and immunological parameters. The majority of these studies analyzed single or combined traits into pre-defined syndromes. In the present study, we explore an alternative multivariate approach in which a broad range of metabolic, hematologic, and immunological traits are analyzed simultaneously to determine the resemblance of monozygotic (MZ) twin pairs, twin-spouse pairs and unrelated, non-cohabiting individuals. A total of 517 participants from the Netherlands Twin Register, including 210 MZ twin pairs and 64 twin-spouse pairs, took part in the study. Data were collected on body composition, blood pressure, heart rate, and multiple biomarkers assessed in fasting blood samples, including lipid levels, glucose, insulin, liver enzymes, hematological measurements and cytokine levels. For all 51 measured traits, pair-wise Pearson correlations, correcting for family relatedness, were calculated across all the individuals in the cohort. Hierarchical clustering techniques were applied to group the measured traits into sub-clusters based on similarity. Sub-clusters were observed among metabolic traits and among inflammatory markers. We defined a phenotypic profile as the collection of all the traits measured for a given individual. Average within-pair similarity of phenotypic profiles was determined for the groups of MZ twin pairs, spouse pairs and pairs of unrelated individuals. The average similarity across the full phenotypic profile was higher for MZ twin pairs than for spouse pairs, and lowest for pairs of unrelated individuals. Cohabiting MZ twins were more similar in their phenotypic profile compared to MZ twins who no longer lived together. The correspondence in the phenotypic profile is therefore determined to a large degree by familial, mostly genetic, factors, while household factors contribute to a lesser degree to profile similarity.     

Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects--a monozygotic twin study

Both genetic and environmental factors are involved in the etiology of obesity and the associated lipid disturbances. We determined whether acquired obesity is associated with changes in global serum lipid profiles independent of genetic factors in young adult monozygotic (MZ) twins. 14 healthy MZ pairs discordant for obesity (10 to 25 kg weight difference) and ten weight concordant control pairs aged 24-27 years were identified from a large population-based study. Insulin sensitivity was assessed by the euglycemic clamp technique, and body composition by DEXA (% body fat) and by MRI (subcutaneous and intra-abdominal fat). Global characterization of lipid molecular species in serum was performed by a lipidomics strategy using liquid chromatography coupled to mass spectrometry. Obesity, independent of genetic influences, was primarily related to increases in lysophosphatidylcholines, lipids found in proinflammatory and proatherogenic conditions and to decreases in ether phospholipids, which are known to have antioxidant properties. These lipid changes were associated with insulin resistance, a pathogonomic characteristic of acquired obesity in these young adult twins. Our results show that obesity, already in its early stages and independent of genetic influences, is associated with deleterious alterations in the lipid metabolism known to facilitate atherogenesis, inflammation and insulin resistance.     

Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study.

Sleep disorders, such as obstructive sleep apnoea (OSA) and restless legs syndrome (RLS), are very common. The relative importance of genetic and nongenetic (environmental) influences on the symptomatology of these conditions has not been well studied. This study uses the twin design to examine this by evaluating OSA and RLS symptoms in monozygotic (MZ) and dizygotic (DZ) twins. Six thousand six hundred unselected female twin pairs, identified from a national volunteer twin register, were asked to complete a medical questionnaire. This questionnaire included questions on OSA and RLS symptoms, as well as questions on subject demographics, past medical history, smoking history and menopausal status. Responses were obtained from 4503 individuals (68% response rate). A total of 1937 twin pairs were evaluable: 933 MZ pairs (mean [range] age 51 [20-76] years) and 1004 DZ pairs (age 51 [20-80] years). Concordance rates were higher for MZ than DZ twins for OSA and RLS symptoms. Multifactorial liability threshold modeling suggests that additive genetic effects combined with unique environmental factors provide the best model for OSA and RLS symptoms. Heritability was estimated to be 52% (95% confidence interval 36% to 68%) for disruptive snoring, 48% (37% to 58%) for daytime sleepiness, 54% (44% to 63%) for restless legs, and 60% (51% to 69%) for legs jerking. These estimates dropped only slightly after adjustment for potential confounding influences on the symptoms of snoring and daytime sleepiness. These results suggest a substantial genetic contribution to the symptomatology of OSA and RLS. More research is needed to identify the genes responsible, and may ultimately lead to new therapies.     

Genetic susceptibility to prostate, breast, and colorectal cancer among Nordic twins

To investigate the role of genetics in the development of cancer, we developed a new approach to analyze data on prostate, breast, and colorectal cancer from the Swedish, Danish, and Finnish twin registries on monozygotic (MZ) and same-sex dizygotic (DZ) twins. In the spirit of a sensitivity analysis, we modeled genetic inheritance as either an autosomal recessive or dominant cancer susceptibility (CS) genotype that involves either a single gene, many genes with equal allele frequencies, or three genes with a ninefold range of allele frequencies. We also modeled the joint probability of cancer incidence among five age categories, conditional on the presence or absence of the CS genotype. The main assumptions are: (1) The joint distribution of unobserved environmental effects in a twin pair conditional on the presence or absence of the CS genotype is the same for MZ and DZ twins, (2) the probability of cancer conditional on the presence or absence of the CS genotype and the unobserved environmental effects (i.e., the gene-environment interaction) is the same for MZ and DZ twins, and (3) the probability of cancer is independent between twins with the CS genotype. Estimation was maximum likelihood via a search over allele frequency and two levels of EM algorithms. Models had acceptable or good fits. Variability was estimated using a bootstrap approach, but only 50 replications were feasible. The 94th percentile of bootstrap replications for the estimated fraction of cancers with the CS genotype ranged, over the various genetic models, from 0.16 to 0.45 for prostate cancer, 0.12 to 0.30 for breast cancer, and 0.08 to 0.27 for colorectal cancer. We conclude that genetic susceptibility makes only a small to moderate contribution to the incidence of prostate, breast, and colorectal cancer.