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.

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 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.

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.