Congenital dermatoglyphic malformations and psychosis: a twin study

OBJECTIVE: In a previous twin study, congenital dermatoglyphic abnormalities, such as ridge dissociations and abnormalities of palmar flexion creases, were more prevalent in twins with psychotic and related disorders than in comparison twins. This study was an attempt to replicate that finding in an independent study group. METHOD: Ridge dissociations and abnormal palmar flexion creases were assessed in monozygotic pairs concordant (19 pairs) and discordant (31 pairs) for psychosis and related disorders. RESULTS: The presence of either ridge dissociations or abnormal palmar flexion creases was higher in the combined group of affected concordant and discordant twins (37.7%), than in the nonaffected discordant twins (20.0%; odds ratio=2.4). In the discordant pairs, the presence of either abnormality was strongly associated with psychotic disorder (odds ratio=3.0). CONCLUSIONS: Factors affecting early fetal development may increase the risk for psychotic disorder. Differential exposure to such early risk factors may contribute to twin discordance for psychotic disorder.     

Smoking and Parkinson's disease in twins

OBJECTIVE: To test the hypothesis that cigarette smoking protects against the development of PD. BACKGROUND: Smoking has been inversely associated with PD in many studies, but whether this reflects a biologic effect on the underlying disease process or merely confounding or selection bias remains uncertain. METHODS: The authors compared smoking histories in male twin pairs identified from the National Academy of Sciences--National Research Council World War II Veteran Twins Cohort. The amount of cigarettes smoked (in pack-years) was collected until the time of PD onset in the affected twin or until the time of death for the unaffected twin, whichever came first. Differences in pack-years smoked until PD onset and until 10 and 20 years before onset were compared using paired t-tests. Comparisons were made overall and stratified by zygosity and concordance for PD. To assess the role of shared environment, correlation for smoking behaviors was compared between pairs concordant and discordant for PD. RESULTS: Detailed smoking histories were available for 113 twin pairs in which at least one twin had PD (discordant pairs: 43 monozygotic [MZ], 50 dizygotic [DZ]; concordant pairs: 10 MZ, 10 DZ). Within-pair correlation for ever smoking was high in MZ pairs (phi = 0.47, p = 0.001) but not in DZ pairs (phi = 0.007, p = 0.96). In 33 discordant MZ pairs and 39 discordant DZ pairs in which at least one twin had smoked, the twins without PD smoked more than their brothers smoked (32.5 vs. 22.7 pack-years, p = 0.026). This was more marked in the MZ pairs (37.1 vs. 25.3 pack-years, p = 0.077) than in the DZ pairs (28.6 vs. 20.5 pack-years, p = 0.17). A similar relationship was seen when smoking dose was calculated only until 10 years before PD onset, suggesting that the lower dose of smoking in the twin with PD was not the result of early, undiagnosed disease. CONCLUSION: Within twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.     

Monozygotic twins discordant for attention-deficit/hyperactivity disorder: ascertainment and clinical characteristics

OBJECTIVE: Nongenetic factors and phenomenology of attention-deficit/hyperactivity disorder (ADHD) were examined in monozygotic (MZ) twin pairs discordant for ADHD. METHOD: Recruitment included telephone screening (n = 297 pairs), behavioral ratings obtained from parents and teachers (n = 59 pairs), and, finally, in-person assessment (n = 25 pairs; structured classroom observation, diagnostic interview, psychoeducational evaluation, birth record review, establishment of monozygosity, and anatomic brain imaging). Affected twins were further contrasted with previously studied affected singletons. RESULTS: Of the 25 MZ twin pairs qualifying for in-person evaluation, only 10 proved discordant for ADHD. Affected twins were mostly comparable with affected singletons on clinical measures, although fathers' self-ratings of childhood ADHD status were significantly lower in twins than in singletons. CONCLUSIONS: Discordance for ADHD in MZ twins appears to be ascribable to greater environmental discordance and decreased familiality. Despite these differences, affected twins were phenotypically comparable with affected singletons. Thus MZ twins discordant for ADHD, while rare, can inform research on the etiology and pathophysiology of this disorder.     

Hippocampal volumes in schizophrenic twins

CONTEXT: The effects of genes and environment on brain abnormalities in schizophrenia remain unclear. OBJECTIVE: To examine the contributions of genes and environment to hippocampal volume reduction in schizophrenia. DESIGN: Population-based twin cohort study. SETTING: Finland. PARTICIPANTS: Seven monozygotic (MZ) twin pairs concordant for schizophrenia and 16 MZ and 32 dizygotic (DZ) twin pairs discordant for schizophrenia, ascertained so as to be representative of all such probands in a Finnish birth cohort, along with 28 MZ and 26 DZ healthy comparison twin pairs without a family history of psychosis. MAIN OUTCOME MEASURES: Hippocampal volume measurements taken from high-resolution magnetic resonance images. RESULTS: Hippocampal volumes of probands were smaller than those of their nonschizophrenic MZ and DZ co-twins and healthy twins. Hippocampal volumes of probands' non-ill co-twins were smaller than those of healthy twins, but those of non-ill MZ and DZ co-twins of schizophrenic patients were similar. The intraclass correlations for hippocampal volumes among healthy and discordant MZ pairs were larger than those among the respective DZ pairs. The intraclass correlation for healthy MZ pairs was larger than that for discordant MZ pairs, and the variance component estimate for additive genetic effects was lower in discordant twins than in healthy twins. CONCLUSIONS: Although hippocampal volume in healthy individuals is largely affected by genetic factors, it is subject to substantially greater modulation by environmental factors in schizophrenic patients and their relatives. The results are discussed in view of assumptions underlying classic twin methods.     

Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?

The goal of this pilot study was to explore the putative molecular mechanisms underlying the phenotypic discordance of monozygotic (MZ) twins. Thus, patterns of epigenetic DNA modification were investigated in the 5'-regulatory region of the dopamine D2 receptor gene (DRD2) in two pairs of monozygotic twins, one concordant and one discordant for schizophrenia. The bisulfite DNA modification-based approach was used to fine-map methylated cytosines in DRD2 in genomic DNA extracted from lymphocytes. Numerous DNA methylation differences were identified in the analyzed region both within and between the pairs of MZ twins. "Epigenetic distances" between MZ twins were calculated and used for the comparison of twin DRD2 methylation profiles. It was detected that the affected twin from the pair discordant for schizophrenia was epigenetically "closer" to the affected concordant twins than to his unaffected MZ co-twin. Although the epigenetic analysis was conducted for only several hundred base pairs of DRD2, the fact that numerous studies identified nonuniform methylation patterns across the clones of bisulfite-modified DNA from the same individual, as well as nonuniform patterns across different individuals, argues for the universality of intra- and interindividual epigenetic variation. Epigenetic studies should provide insight into the molecular causes of differential susceptibility to a disease in genetically identical organisms that may generalize to singletons.     

Magnetic resonance imaging of the thalamus and adhesio interthalamica in twins with schizophrenia

CONTEXT: Abnormalities of the thalamus are thought to be central to the pathophysiology of schizophrenia. These abnormalities include altered structure and shape of the thalamus itself and possibly changes to the adhesio interthalamica (or massa intermedia), the gray matter bridge connecting the 2 thalamic lobes. However, it is not clear to what extent these abnormalities are determined by the genetic liability for schizophrenia. OBJECTIVE: To investigate thalamic volume and the presence of the adhesio interthalamica in monozygotic (MZ) twins concordant or discordant for schizophrenia. DESIGN: Study of MZ twins. SETTING: Patients were drawn from inpatient and outpatient clinics. Twin controls were recruited from a volunteer twin register and through media advertisements. PARTICIPANTS: A total of 123 twins participated: 19 MZ twin pairs concordant for schizophrenia, 15 MZ schizophrenic twins and 16 MZ nonschizophrenic twins drawn from 17 pairs discordant for schizophrenia, and 27 MZ twin pairs without schizophrenia. Groups were matched for age, sex, handedness, level of education, parental socioeconomic status, and ethnicity. MAIN OUTCOME MEASURES: The volume of the thalamus (including right and left hemispheres) was measured (in cubic centimeters) and the presence of the adhesio interthalamica was ascertained from structural magnetic resonance images. RESULTS: Concordant twin pairs displayed significantly reduced thalamic volume compared with control twins, even when covarying for effects of whole-brain volume, age, and sex. There was a significant linear decrease in thalamic volume (control greater than discordant nonschizophrenic greater than discordant schizophrenic greater than concordant). In all groups, right thalamus was larger than left thalamus. There was no difference across groups in the frequency of the adhesio interthalamica. CONCLUSIONS: Volumetric thalamic abnormalities in schizophrenia occur in twin pairs concordant for schizophrenia. These abnormalities may mark the substantial genetic contribution to the illness seen in concordant twin pairs, whereas the adhesio interthalamica is unlikely to be affected in schizophrenia.     

Discordance and concordance of dementia of the Alzheimer type (DAT) in monozygotic twins indicate heritable and sporadic forms of Alzheimer's disease

Monozygotic (MZ) twin pairs concordant for dementia of the Alzheimer type (DAT) or for proven Alzheimer's disease (AD) have a significantly higher frequency of a positive family history (DAT or AD in at least one first-degree relative, p less than 0.002) than do discordant MZ twin pairs, consistent with a lesser predicted distribution of proportions of surviving first-degree relatives without DAT (or AD) (p less than 0.001). The results suggest that concordant MZ twin pairs with DAT (or AD) have a heritable form of disease. AD in discordant twins may result from environmental influences or from a somatic chromosomal change following zygotic division.     

Birthweight and obstetric complications in schizophrenic twins.

Birthweight and obstetric complications were registered retrospectively in 24 monozygotic (MZ) twin pairs. Sixteen pairs were discordant and 8 pairs were concordant for DSM-III-R schizophrenia. There was no significant intrapair difference in birthweight between the 2 groups of MZ twins. Prematurity was more often observed in the discordant pairs, but neither differences in prematurity nor differences in obstetric complications between the concordant and discordant twins reached significance. No difference in respect of family history of schizophrenia between the 2 groups of MZ twins was found. In the discordant pairs, no significant difference between the schizophrenic twin and the nonschizophrenic co-twin was observed regarding birth order, birthweight or physical condition at birth.     

A twin study of Tourette syndrome

In 43 pairs of same-sex twins, in which at least one co-twin had Tourette syndrome (TS), 30 pairs were probably monozygotic (MZ) and 13 were probably dizygotic (DZ). Concordances for TS were 53% and 8% for MZ and DZ pairs, respectively. When diagnostic criteria were broadened to include any tics in co-twins, concordance rates were 77% and 23% for MZ and DZ pairs, respectively. These concordances are consistent with genetic etiology. However, the fact that only 53% of MZ twins were fully concordant indicates nongenetic factors affect expression of TS. Presence of tics in discordant co-twins and timing of onset in partially concordant co-twins support an association between TS and tics in families with TS present. The data are inconclusive on whether some MZ twins with discordant co-twins are etiologically different from those who are concordant.     

Gene expression analysis in absence epilepsy using a monozygotic twin design

Purpose: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design. Methods: Genome‐wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT‐PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls. Results: Sixty‐five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT‐PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium‐binding protein Reticulocalbin 2) were reconfirmed by qRT‐PCR in the independent sample. Discussion: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy.     

Dementia of the Alzheimer type: clinical and family study of 22 twin pairs

We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.     

Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population‐based family twin study of migraine without aura

Migraine without aura (MO) is a multifactorial disorder. Expression of a disorder with multifactorial inheritance depends on the genetic liability and on environmental factors. A high liability is reflected by a high frequency of affected relatives. We have previously shown that monozygotic (MZ) twin pairs have a significant higher concordance of MO than dizygotic twin pairs. The incomplete concordance among MZ twin pairs may be due to a lower genetic liability among discordant than concordant MZ twin pairs. The present study analysed the genetic liability in MZ twin pairs concordant and discordant for MO by the population-relative risk of MO among parents and siblings. The twin pairs were from the population-based Danish Twin Register. First-degree relatives of 29 concordant and 34 discordant MZ twin pairs were blindly telephone interviewed by a physician. The participation rate of the eligible first-degree relatives was 96%. The population-relative risk of MO among parents and siblings was 2.73 (2.39-3.06) in concordant and 2.37 (2.03-2.71) in discordant MZ twin pairs. The relative risk of MO was significantly higher in female first-degree relatives of concordant than of discordant MZ male and female twin pairs. An opposite effect was observed in male first-degree relatives, although this was not significant for male first-degree relatives of female MZ twin pairs. The present study found no statistically significant difference in genetic liability to MO among concordant and discordant MZ twin pairs. However, a difference in genetic liability among MZ and DZ twin pairs is anticipated to be small. Thus, it may be possible to show the effect in a larger study population or by investigating a more frequent trait than MO.     

Magnetic resonance relaxometry in monozygotic twins discordant and concordant for schizophrenia.

T1 and T2 relaxation times were examined in four pairs of monozygotic (MZ) twins discordant and concordant for schizophrenia with low and high genetic loading for the illness and five healthy control MZ twin pairs. Patients with schizophrenia (n = 11) showed significant prolongation in T1 relaxation times in the globus pallidus (GP) bilaterally (P < 0.005, Bonferroni corrected) when compared to 14 healthy MZ twins.     

Primary degenerative dementia of the Alzheimer type in twins: Initial findings from the Maudsley Hospital Twin Register

In detailed published accounts to date of 40 twin pairs one or both of whom were said to have Alzheimer's disease (AD), 16 of 35 monozygotic (MZ) pairs were described as concordant for the disease and the remaining 19 pairs as discordant, while of the five pairs of dizygotic (DZ) twins two pairs were designated as concordant. However, these data have emerged almost exclusively from selective case reports and volunteer samples, resulting in an over-representation of MZ twins that complicates the overall interpretation of the data. In an effort to reduce such ascertainment bias, we screened for diagnoses consistent with AD in the Maudsley Hospital Twin Register, which consists of twins registered at the Bethlem Royal and the Maudsley Hospitals (London, UK) since 1948. Seven twins were identified who met criteria for primary degenerative dementia of the Alzheimer type. Available details of their affected status as well as of the status of their co-twins are presented and discussed.     

Prefrontal and Striatal Volumes in Monozygotic Twins Concordant and Discordant for Schizophrenia

Frontostriatal networks mediating important cognitive and motor functions have been shown to be abnormal structurally and functionally in schizophrenia. However, the influence of genetic risk for schizophrenia on structural abnormalities in these areas is not well established. This study therefore aimed to investigate prefrontal and striatal volume alterations in schizophrenia and to define the extent to which they are dependent on genetic vulnerability for the condition. We employed structural magnetic resonance imaging (sMRI) in monozygotic (MZ) twins with or without schizophrenia. A sample of 129 twins completed sMRI, consisting of 21 MZ twin pairs concordant for schizophrenia, 17 MZ schizophrenic twins and 18 MZ nonschizophrenic twins drawn from 19 pairs discordant for schizophrenia, and 26 MZ control twin pairs without schizophrenia. Groups did not significantly differ in age, gender, handedness, height, level of education, parental socioeconomic status, and ethnicity. Using a region-of-interest approach, we measured the gray matter volumes (in cm³) of superior, middle, inferior, and orbital frontal cortices (SFC, MFC, IFC, and OFC, respectively); the caudate; and putamen. Covarying for whole-brain volume, age, and gender, we found that concordant but not discordant twins with schizophrenia had significantly lower volumes of MFC and OFC than control twins. In contrast, both patient groups had significantly lower SFC volumes than both groups of nonschizophrenic twins. There were no significant group differences in IFC and the striatum. We conclude that the prefrontal cortex shows a heterogeneous pattern of genetic influences on volumetric reductions in schizophrenia.     

Neurological soft signs and dermatoglyphic anomalies in twins with schizophrenia.

Schizophrenia is associated with altered neural development. We assessed neurological soft signs (NSS) and dermatoglyphic anomalies (total a-b ridge count (TABRC) and total finger ridge count) in 15 pairs of twins concordant and discordant for schizophrenia. Within-pair differences in both NSS and TABRC scores were significantly greater in discordant compared to concordant monozygotic pairs. There was no significant difference in NSS and TABRC scores between subjects with schizophrenia and their co-twins without the illness. However, monozygotic discordant twins with schizophrenia had higher ABRCs on their right hands compared to their co-twins without the illness. These findings suggest that an unidentified environmental event acting between weeks 6 and 15 of gestation affects the development of monozygotic twins who go on to develop schizophrenia but does not have a corresponding effect on their co-twins who do not develop the illness. The effect of such an event on dermatoglyphic profiles appears lateralised to the right hand in affected twins.     

Neurological abnormalities in schizophrenic twins.

BACKGROUND: Neurological abnormalities (NAs) are well recognized in schizophrenia, though their genetic and environmental determinants, and pathophysiological significance, are poorly understood. METHODS: Sixty-three twin pairs, varying in their zygosity and concordance for schizophrenia, and 73 unaffected control twin pairs were examined for total, primary and integrative NAs using the Neurological Evaluation Scale. RESULTS: NAs were increased in probands with schizophrenia compared to nonschizophrenic co-twins and to healthy control twins but there were no significant differences between patients from the concordant and discordant pairs. NAs in the nonpsychotic co-twins from discordant pairs were increased compared to control twins. There were no significant differences in NAs between the nonschizophrenic co-twins from monozygotic (MZ) and dizygotic (DZ) discordant pairs, but the within pair correlations were greater in the MZ compared to DZ pairs. NAs were modified in all groups by pre-morbid schizotypal traits, and in patients by anti-psychotic medication. CONCLUSIONS: NAs in schizophrenia are determined in part by genetic risk for the illness but the presence of premorbid schizotypal traits, and anti-psychotic medication confer additional risk for NAs.     

Subtle signs of prenatal maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygotic twin study

Genes that predispose to psychosis may act by making individuals more vulnerable to the disruptive effects of various prenatal insults. Fetal organogenesis is mostly completed in the first prenatal trimester. The second trimester is a critical period of massive neuronal migration from the periventricular germinal matrix to the cortex. A peripheral appendage developing simultaneously with this neural migration to the cortex is the distal upper limb. The ectodermal cells of the fetal upper limb migrate to form the hand skin during the fourth and fifth months of gestation (first two-thirds of the second prenatal trimester). Discrepancies in hand morphology between two identical (monozygotic [MZ]) co-twins may be temporal markers, that is, the "fossilized" evidence of various ischemic and other nongenetic insults that may have affected one fetus more than his MZ co-twin during that early part of the second trimester. In twins, prenatal insults (e.g., ischemia) frequently do not affect both co-twins to the same extent, so we examined seven putative markers of prenatal injury to the hand in 24 MZ twin pairs discordant for schizophrenia or delusional disorder. Compared with well co-twins, the affected co-twins had significantly higher total scores of fourth- and fifth-month dysmorphological hand anomalies.     

A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder

Six monozygotic (MZ) twin pairs discordant for bipolar disorder were compared with normal MZ twins with magnetic resonance imaging (MRI) on volumes of basal ganglia (BG), amygdala-hippocampus (AH), and cerebral hemisphere. Caudate nuclei were larger in both affected and unaffected bipolar twins than in normal MZ twins. The right hippocampus was smaller in the sick vs. well bipolar twins. The hippocampus was also less asymmetric in the affected bipolar twins than in the well cotwins and the normal MZ twins. These anatomical structures continue to be of interest in bipolar disorder research.     

Does a shift in the T-cell receptor repertoire precede the onset of MS?

BACKGROUND: Utz et al., in a study of identical twins discordant for MS, showed that antigen-stimulated T cells from the MS twins have a major shift in their T-cell receptor (TCR) repertoires when compared with the healthy twins. We hypothesized that a shift in the TCR repertoire precedes the onset of MS and tested this hypothesis by studying unstimulated naive T cells because the TCR repertoires of these cells are largely unaffected by disease. OBJECTIVE: To investigate whether unstimulated naive T cells from MS patients have a detectable shift in their TCR repertoires. METHODS: We analyzed the TCR J beta (TCRBJ) repertoires of naive T cells from identical twin pairs discordant for MS, healthy identical twin pairs, healthy unrelated pairs, and unrelated MS patient pairs. The correlation coefficient (r value) was used as a measure of similarity of TCRBJ repertoires in each pair of individuals. Fisher's z transformation was then used to test for the significance of the difference between the r values from different pairs. RESULTS: The TCRBJ repertoires of the discordant MS twin pairs were significantly different from those of the healthy identical twin pairs, whereas MS patient pairs had TCRBJ repertoires similar to those of the healthy unrelated pairs formed from healthy twin pairs and discordant MS twin pairs. CONCLUSIONS: MS patients have a major shift in their naive T-cell TCRBJ repertoires compared with healthy individuals, implying that this shift precedes the disease onset. This shift could represent the nongenetic factor that explains MS discordance in genetically identical individuals.