Genetic and environmental influences on cortical surface area and cortical thickness in bipolar disorder.

BACKGROUND: The risk of developing bipolar disorder (BD) has been linked to structural brain abnormalities. The degree to which genes and environment influence the association of BD with cortical surface area remains to be elucidated. In this twin study, genetic and environmental contributions to the association between liability to develop BD and surface area, thickness and volume of the cortex were examined. METHOD: The study cohort included 44 affected monozygotic (nine concordant, 12 discordant) and dizygotic (four concordant, 19 discordant) twin pairs, and seven twins from incomplete discordant monozygotic and dizygotic discordant twin pairs. In addition, 37 monozygotic and 24 dizygotic healthy control twin pairs, and six twins from incomplete monozygotic and dizygotic control pairs were included. RESULTS: Genetic liability to develop BD was associated with a larger cortical surface in limbic and parietal regions, and a thicker cortex in central and parietal regions. Environmental factors related to BD were associated with larger medial frontal, parietal and limbic, and smaller orbitofrontal surfaces. Furthermore, thinner frontal, limbic and occipital cortex, and larger frontal and parietal, and smaller orbitofrontal volumes were also associated with environmental factors related to BD. CONCLUSIONS: Our results suggest that unique environmental factors play a prominent role in driving the associations between liability to develop BD and cortical measures, particularly those involving cortical thickness. Further evaluation of their influence on the surface and thickness of the cortical mantle is recommended. In addition, cortical volume appeared to be primarily dependent on surface and not thickness.

Dermatoglyphics in relation to brain volumes in twins concordant and discordant for bipolar disorder.

Palmar and finger dermatoglyphics are formed between the 10th and the 17th weeks of gestation and their morphology can be influenced by genetic or environmental factors, interfering with normal intrauterine development. As both the skin and the brain develop from the same embryonal ectoderm, dermatoglyphic alterations may be informative for early abnormal neurodevelopmental processes in the brain. We investigated whether dermatoglyphic alterations are related to structural brain abnormalities in bipolar disorder and to what extent they are of a genetic and of an environmental origin. Dermatoglyphics and volumetric data from structural MRI were obtained in 53 twin pairs concordant or discordant for bipolar disorder and 51 healthy matched control twin pairs. Structural equation modeling was used. Bipolar disorder was significantly positively associated with palmar a-b ridge count (ABRC), indicating higher ABRC in bipolar patients (rph=.17 (CI .04-.30)). Common genes appear to be involved because the genetic correlation with ABRC was significant (rph-A=.21 (CI .05-.36). Irrespective of disease, ABRC showed a genetically mediated association with brain volume, indicated by a significant genetic correlation rph-A of respectively -.36 (CI -.52 to -.22) for total brain, -.34 (CI -.51 to -.16) total cortical volume, -.27 (CI -.43 to -.08) cortical gray matter and -.23 (CI -.41 to -.04) cortical white matter. In conclusion, a genetically determined abnormal development of the foetal ectoderm between the 10th and 15th week of gestation appears related to smaller brain volumes in (subjects at risk for) bipolar disorder.

Longitudinal study of hormonal and physical development in young twins.

CONTEXT AND OBJECTIVE: Information on the correlation of normative reproductive hormone levels with physical development (Tanner stages) during puberty and on the influences of genes and environment on variation in these hormones and Tanner stages is limited. DESIGN, SETTING, AND PARTICIPANTS: One hundred twelve healthy 9-year-old twin pairs (n = 224) took part in a longitudinal study, of which 89 pairs participated again at age 12 years (n = 178). MAIN OUTCOME MEASURES: Morning urinary LH, FSH, estradiol, and salivary testosterone levels, determined by competitive immunoassays, were measured. Tanner stages were determined through physical examination. RESULTS: Over the 3-year interval, all hormone levels showed a 2- to 9-fold increase. LH and FSH at age 9 years predicted sex-specific Tanner stages at age 12 years in both boys and girls. Most of the associations between hormone levels at age 9 years and physical development at 12 years were explained by genetic influences. FSH in 9-year-old boys correlated with all hormone levels and Tanner stages at age 12 years. Moderate to high heritability estimates were found for hormone levels at both ages and in both sexes. In girls a shift from environmental (age 9 years) to genetic influences (age 12 years) was found for estradiol and pubic hair development, and for breast development a shift in the opposite direction was seen. CONCLUSIONS: During development LH and FSH (and testosterone in boys) levels predict secondary sexual characteristics in boys and girls 3 years later. These correlations are largely due to genes that are involved in both early pubertal hormone levels and subsequent physical development.

Is there change in intelligence quotient in chronically ill schizophrenia patients? A longitudinal study in twins discordant for schizophrenia.

BACKGROUND: Intellectual deficits are commonly found in schizophrenia patients. These intellectual deficits have been found to be heritable. However, whether the intellectual deficits change over time and, if so, whether the change is related with an increased genetic risk for the disease are not known. METHOD: We investigated change of intelligence quotient (IQ) in a twin sample of chronically ill schizophrenia patients, the discordant co-twins and healthy controls during a follow-up period of 5 years. A total of 52 twins completed two IQ assessments: nine patients [three monozygotic (MZ) and six dizygotic (DZ)], 10 unaffected co-twins (three MZ and seven DZ) and 33 healthy control twins (21 MZ and 12 DZ). RESULTS: A significant interaction effect over time was found between IQ measurement and illness (F=4.22, df=1, p<0.05), indicating that change in IQ over time is significantly different between the groups. A stable course in IQ over time was found in the patients with schizophrenia (mean IQ from 109.78 at baseline to 108.44 at follow-up) relative to both the healthy control twins who showed a small increase (from 114.61 at baseline to 119.18 at follow-up) (t=2.06, p<0.05) and the unaffected co-twins (from 111.60 to 117.60, t=-2.32, p<0.05). IQ change in the unaffected co-twins of schizophrenia patients was comparable with that in healthy control twins (t=-0.49, p=0.63). CONCLUSIONS: Patients with schizophrenia in the chronic phase of the disease, but not the discordant co-twins, show a lack of increase in IQ, which is probably due to environmental (non-genetic) factors related to the disease.

Genetic influences on thinning of the cerebral cortex during development.

During development from childhood to adulthood the human brain undergoes considerable thinning of the cerebral cortex. Whether developmental cortical thinning is influenced by genes and if independent genetic factors influence different parts of the cortex is not known. Magnetic resonance brain imaging was done in twins at age 9 (N = 190) and again at age 12 (N = 125; 113 repeated measures) to assess genetic influences on changes in cortical thinning. We find considerable thinning of the cortex between over this three year interval (on average 0.05 mm; 1.5%), particularly in the frontal poles, and orbitofrontal, paracentral, and occipital cortices. Cortical thinning was highly heritable at age 9 and age 12, and the degree of genetic influence differed for the various areas of the brain. One genetic factor affected left inferior frontal (Broca's area), and left parietal (Wernicke's area) thinning; a second factor influenced left anterior paracentral (sensory-motor) thinning. Two factors influenced cortical thinning in the frontal poles: one of decreasing influence over time, and another independent genetic factor emerging at age 12 in left and right frontal poles. Thus, thinning of the cerebral cortex is heritable in children between the ages 9 and 12. Furthermore, different genetic factors are responsible for variation in cortical thickness at ages 9 and 12, with independent genetic factors acting on cortical thickness across time and between various brain areas during childhood brain development.

Premorbid school performance in twins concordant and discordant for bipolar disorder.

BACKGROUND: Although the genetic risk to develop bipolar disorder is present from conception, the first frank symptoms of the illness generally become evident in late adolescence or early adulthood. However, except for pediatric bipolar disorder (PBD), it is still unclear when the first signs of the illness in adults become apparent and whether these are related to the genetic risk to develop bipolar disorder. This study examined whether underperformance at school precedes the onset of the illness and is a genetically related risk marker for developing bipolar disorder. METHODS: Information on school performance was obtained using objective archival data from 53 bipolar twin pairs (24 monozygotic (MZ), 29 dizygotic (DZ)) and 42 healthy matched control twin pairs (23 MZ, 19 DZ). RESULTS: Affected twin pairs completed significantly fewer years of education than did control twin pairs with no difference between bipolar patients and their non-bipolar cotwins. The underperformance at school in the affected twin pairs occurred in early adolescence at a significantly younger age than the control twin pairs and preceded the onset of the first frank episode of bipolar disorder by thirteen years. Median age at onset of underperformance was not different in the patients and their non-bipolar cotwins. The association between liability of bipolar disease and age of first underperformance was significant and could be explained by genetic factors. LIMITATIONS: The sample is not a population based twin sample. CONCLUSION: Underperformance at school during early adolescence may be a genetic marker for the vulnerability to develop bipolar disorder.

Genetic and environmental influences on self-reported and parent-reported behavior problems in young adult adoptees.

The aim of the present study was to estimate the genetic, shared and nonshared environmental contributions to self-reported and parent-reported internalizing and externalizing problems in a follow-up study of intercountry adopted young adults. Young Adult Self-Report ratings were obtained from 1475 adoptees aged 22-32 years and Young Adult Behavior Checklist ratings from 1115 adoptive parents. For the genetic analyses, a subset of 143 adopted biologically related and 295 unrelated siblings was used. The data were subjected to model fitting decomposing three sources of variance: genetic factors (A) shared environment (C) and nonshared environment (E). Genetic factors were of more importance in both self-reported (A(2)= 54%, C(2)= 0, and E(2)= 46%) and parent-reported (A(2)= 76%, C(2)= 15% and E(2)= 9%) internalizing problems. Environmental factors were of more importance in both self-reported (A(2)= 33%, C(2)= 17% and E(2)= 50%) and parent-reported (A(2)= 28%, C(2)= 27% and E(2)= 45%) externalizing problems. This was in contrast with findings from the first and second assessments in the same sample during adolescence when genetic factors were more important in explaining externalizing problems compared with internalizing problems. Our results suggest a developmental reversal in genetic and environmental influences on behavior problems from early adolescence into adulthood, which could be related to different underlying developmental trajectories.

A twin study of differentiation of cognitive abilities in childhood.

The differentiation hypothesis in cognitive development states that cognitive abilities become progressively more independent as children grow older. Studies of phenotypic development in children have generally failed to produce convincing support for this hypothesis. The aim of the present study is to investigate the issue of differentiation at the genetic and environmental level. Six psychometric measures assessing verbal and nonverbal cognitive abilities were administered to 209 Dutch twin pairs at ages 5, 7, and 10 years. Longitudinal results provided little evidence for the differentiation hypothesis. Stability in subtest performance is due mainly to genetic influences. The shared environment contribution to phenotypic stability is small. The unique environment contributes to age-specific variance only.

Twin and family studies of the human electroencephalogram: a review and a meta-analysis.

Electrophysiological measures may be useful markers of the genetic underpinnings of complex behavior and psychopathology. Twin and family studies have been used to estimate the genetic contribution to the individual differences in a variety of electrophysiological measures. These studies are briefly reviewed here and published twin correlations from a number of studies with comparable methodology were selected for structural equation meta-analyses. For electroencephalographic (EEG) alpha power (11 twin groups) the heritability estimates in each of the single studies were high (averaged 79%), but it was not possible to equate the twin correlations across studies in the meta-analysis. In contrast, combining the data on alpha peak frequency (five twin groups) revealed a 'meta'-heritability of 81% (95% CI: 76-84%). Aggregating the twin correlations of five twin studies on the P300, the estimated meta-heritability is 60% (95% CI: 54-65%) for P300 amplitude and 51% (95% CI: 43-58%) for P300 latency. It is concluded that genomic variation contributes significantly to individual differences in all EEG and event related potential (ERP) measures studied to date.

Genetic and environmental influences on the development of intelligence.

Measures of intelligence were collected in 209 twin pairs at 5, 7, 10, and 12 years of age, as part of a longitudinal project on intelligence, brain function, and behavioral problems. Intelligence was measured at 5, 7, and 10 years of age with the RAKIT, a well-known Dutch intelligence test, consisting of 6 subscales. At 12 years of age, the complete WISC-R was administered (12 subscales). Both intelligence tests resulted in a measure of full-scale IQ (FSIQ). Participation rate is around 93% at age 12. Correlation coefficients over time are high: (r(5-7) = .65; r(5-10) = .65; r(5-12) = .64; r(7-10) = .72; r(7-12) = .69 and r(10-12) = .78). Genetic analyses show significant heritabilities at all ages, with the expected increase of genetic influences and decrease of shared environmental influences over the years. Genetic influences seem to be the main driving force behind continuity in general cognitive ability, represented by a common factor influencing FSIQ at all ages. Shared environmental influences are responsible for stability as well as change in the development of cognitive abilities, represented by a common factor influencing FSIQ at all ages and age-specific influences, respectively.

Stability of genetic and environmental influences on P300 amplitude: a longitudinal study in adolescent twins.

This study examined the stability of genetic and environmental influences on individual differences in P300 amplitude during adolescence. The P300 component is an event-related brain potential (ERP) that has attracted much attention as a biological marker for disturbed cognitive processing in psychopathology. Understanding the genetics of this biological marker may contribute to understanding the genetics of the associated psychopathologies. In a group of 213 adolescent twin pairs, the P300 component was measured twice, the first time at age 16 and the second time 18 months later. A large part of the variance of the P300 amplitude could be explained by familial factors, with estimates ranging from 30% to 81%. Whether the familial resemblance was due to genetic or shared environmental factors depended on sex. For males, genetic factors explained familial resemblance in P300 amplitude, but for females such resemblance was likely due to shared environmental factors. The phenotypic stability of the P300 amplitude from 16 to 18 years was high in both sexes, and stability could be attributed largely to the same familial factors. There was no evidence that new familial influences emerged at age 18.

Genetic correlation between the P300 event-related brain potential and the EEG power spectrum.

Previous studies have demonstrated moderate heritability of the P300 component of event-related brain potentials (ERPs) and high heritability of background electroencephalogram (EEG) power spectrum. However, it is unclear whether EEG and ERPs are influenced by common or independent genetic factors. This study examined phenotypic and genetic correlations between EEG spectral power and P300 amplitude using data from 206 Dutch twin pairs, age 16 years. Multivariate genetic models (Cholesky decomposition) were fitted to the observed twin covariances using Mx software. In males, genetic correlations between P300 and EEG power measures were high (0.54-0.74); 30% of the total P300 variance could be explained by genetic factors influencing EEG delta power and 26% by P300-specific genetic factors (total heritability 56%). In females, 45% of P300 variance could be attributed to familial influences that were shared with the EEG. However, it was not possible to distinguish between the genetic versus shared environmental factors, consistent with previous analysis of P300 in this sample (van Beijsterveldt et al., 1998). The results suggest that a substantial proportion of genetic influences on P300 amplitude can be explained by strong heritability of slow EEG rhythms contributing to P300.

Longitudinal genetic analysis of EEG coherence in young twins.

During middle childhood, continuous changes occur in electroencephalogram (EEG) coherence, an index of cortico-cortical connectivity of the brain. In the gradual development of EEG coher ence, occasional "growth spurts" are observed which coincide with periods of discontinuous development in cognition. Discontinuous development may reflect changes in the genetic architecture of a trait over time, for instance, by the emergence of new genetic factors. To examine stability and change in genetic and environmental influences on EEG coherence from ages 5 to 7 years, intrahemispheric EEG coherences from 14 connections were collected twice in 209 twin pairs. Overall, heritabilities (h2) were moderate to high for all EEG coherences at both ages (average: 58%). For occipito-cortical connections in the right hemisphere, h2 increased with age due to a decrease in environmental variance. For prefronto-cortical connections in the left hemisphere, h2 decreased with age due to a decrease in genetic variance. New genetic factors at age 7 were found for prefronto-parietal coherence, and centro-occipital and parieto-occipital EEG coherences in both hemispheres and, in the left hemisphere, for prefronto-frontal EEG coherences. Mean genetic correlation for these cortico-cortical connections over time was 0.72, indicating that at least part of the genetic influences is age-specific. We argue that this is convincing evidence for the existence of stage-wise brain maturation from years 5 to 7, and that growth spurts in EEG coherence may be part of the biological basis for discontinuous cognitive development at that age range.

Potential bias regarding birth weight in historical and contemporary twin data bases.

In this study we examine the hypothesis that monozygotic (MZ) twins in historical databases are less discordant for birth weight due to negative selection of severely discordant MZ twins. Furthermore, we test the hypothesis that MZ twins are less discordant for birth weight when comparing a volunteer based twin registry with a population based twin registry, due to selective registration. Data were available on 3927 twin pairs from the volunteer Australian Twin Registry born before 1964, 3059 volunteer twin pairs from the Netherlands Twin Register born 1987-1989 and 454 Belgian twin pairs from The East Flanders Prospective Twin Survey born 1987-1989. Intrapair relative birth weight differences (RBWD) were computed for MZ and dizygotic (DZ) twins from each twin registry. Comparing birth weight differences between MZ and DZ twins provides support for the hypothesis that MZ twins are subject to a negative selection in historical databases. Furthermore, Australian MZ twins have a lower RBWD compared to Dutch MZ twins when corrected for the RBWD of Australian and Dutch DZ twins, indicating circumstances which only affect MZ twins. Our hypothesis that MZ twins are less discordant for birth weight in a volunteer based twin registry compared to a population based twin registry had to be rejected. We suggest that investigators using historical databases to test the fetal origins hypothesis should be aware of this increased likelihood of selective exclusion of individuals with extreme morphometric parameters at time of birth.

Genetic factor analyses of specific cognitive abilities in 5-year-old Dutch children.

The genetic and environmental factor structures of intellectual abilities in 5-year-old Dutch twins were examined. Six subtests of the RAKIT, a Dutch intelligence test, were administered to 209 twin pairs. The subtests were categorized as either verbal or nonverbal. The genetic covariance structure displayed a two-common factor structure including specific factors to account for subtest residual variance. The correlation between the genetic Verbal and genetic Nonverbal factors did not differ significantly from zero. The shared environmental influence displayed a single-common factor structure. Unique environmental influences did not contribute to the covariance between subtests and were specific in origin. Estimates of heritability of the subtests ranged from 15% to 56%. Shared environmental influences were significantly present, but were modest in magnitude. The phenotypic data was best described by an oblique two-factor model. This model was not mirrored in the factor structures found for either the genetic or environmental covariances.

Y chromosomal and sex effects on the behavioral stress response in the defensive burying test in wild house mice.

Genetically selected short attack latency (SAL) and long attack latency (LAL) male wild house mice behave differently in the defensive burying test. When challenged, SAL males respond actively with more time spent on defensive burying, whereas LAL males are more passive with more time remaining immobile. The first aim of this study was to find out whether the nonpairing part of the Y chromosome (Y(NPAR)) affects the behavioral stress response in this paradigm. Second, to determine if the differential behavioral profile found in males is also present in females, SAL and LAL females were tested. Third, nonattacking and attacking LAL males were compared. Five behavioral elements were recorded: defensive burying, immobility, rearing, grooming, and exploration. Males were first tested for attack latency. The results show that the Y(NPAR) influences defensive burying. However, the size of this effect is overshadowed by the background of the mice. Furthermore, although females differed from males, they tended to demonstrate the same behavioral profile as males. Nongenetic factors may also play a role, as attacking LAL males showed more defensive burying than nonattacking LAL males.

A religious upbringing reduces the influence of genetic factors on disinhibition: evidence for interaction between genotype and environment on personality.

Information on personality, on anxiety and depression and on several aspects of religion was collected in 1974 Dutch families consisting of adolescent and young adult twins and their parents. Analyses of these data showed that differences between individuals in religious upbringing, in religious affiliation and in participation in church activities are not influenced by genetic factors. The familial resemblance for different aspects of religion is high, but can be explained entirely by environmental influences common to family members. Shared genes do not contribute to familial resemblances in religion. The absence of genetic influences on variation in several dimensions of religion is in contrast to findings of genetic influences on a large number of other traits that were studied in these twin families. Differences in religious background are associated with differences in personality, especially in Sensation Seeking. Subjects with a religious upbringing, who are currently religious and who engage in church activities score lower on the scales of the Sensation Seeking Questionnaire. The most pronounced effect is on the Disinhibition scale. The resemblances between twins for the Disinhibition scale differ according to their religious upbringing. Receiving a religious upbringing seems to reduce the influence of genetic factors on Disinhibition, especially in males.

The influence of religion on alcohol use initiation: evidence for genotype X environment interaction.

We examined the possible role of religious upbringing as a mediator of the shared environmental influences and as a moderator of the genetic influences on the risk of alcohol use initiation in a large population-based sample of Dutch adolescent and young adult twins (1967 twin pairs). There was not a significant association between religious participation and alcohol use initiation among Dutch adolescents and young adults. We also hypothesized that the relative magnitude of the genetic influences on the risk of alcohol use initiation would be greater for those adolescents and young adults who were raised in a less religious environment compared to those adolescents and young adults who were raised in a more religious environment. We indeed found higher heritabilities for females without a religious upbringing compared to females with a religious upbringing. Genetic influences accounted for 40% of the variance in alcohol use initiation in nonreligious females, compared to 0% in religiously raised females. Shared environmental influences accounted for 54% of the variance for nonreligious females and 88% of the variance in religious females. For males, the genetic variance was also higher in the nonreligious group compared to the religious group, but this difference was not statistically significant. Whether or not they were raised religiously, the liability to alcohol use initiation in males was moderately influenced by genetic factors (30%) and substantially influenced by shared environmental factors (60%).

Genetic influences on EEG coherence in 5-year-old twins.

Electroencephalographic (EEG) coherence has been suggested to be an index of the connectivity of the brain. It represents the coupling between two EEG signals from different brain areas and is mathematically analogous to a cross-correlation in the frequency domain. We obtained data from 167 pairs of 5-year-old twins to study genetic and environmental influences on individual differences in intrahemispheric coherences. Coherence was computed in the theta band (4.0 to 7.5 cycles/s) between prefrontal, frontal, central, parietal, and occipital regions during quiet rest. Univariate genetic analyses of the data showed moderate to strong genetic influences for all coherences. Broad heritabilities ranged from 30 to 71%, with a mean heritability of 49%. With one exception, no sex differences were found. Split-half reliabilities varied with interelectrode distances, ranging from .91 for the shortest distance to .62 for the longest distance. When split-half reliabilities are compared with heritabilities, the data suggest that for corticocortical connections between adjacent brain areas, a large part of the variance is explained by "true" environmental influences, whereas for longer connections, that is, sensory to frontal areas, the variance is mostly genetic in origin.