Twin studies of affective illness.

In a summary of the major twin studies of affective illness, there are significant differences between monozygotic (MZ) and dizygotic (DZ) concordance rates for both unipolar and bipolar illness, indicating the importance of genetic factors in the etiology of affective illness. However, since 28% of MZ twins are discordant for bipolar illness and 60% of MZ twins are discordant for unipolar illness, environmental factors are important as well. In addition, there is a significant difference between unipolar and bipolar concordance for MZ twins (although not for DZ twins). This supports other evidence that unipolar and bipolar illness are separate entities, and it suggests the possibility that genetic factors are more important in the occurrence of bipolar illness than in unipolar illness.     

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.     

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.     

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.     

Is autoimmune thyroiditis part of the genetic vulnerability (or an endophenotype) for bipolar disorder?

BACKGROUND: Both genetic and environmental factors are involved in the etiology of bipolar disorder; however, biological markers for the transmission of the bipolar genotype ("endophenotypes") have not been found. Autoimmune thyroiditis with raised levels of thyroperoxidase antibodies (TPO-Abs) is related to bipolar disorder and may be such an endophenotype. This study was intended to examine whether autoimmune thyroiditis is related to the disease itself, to the (genetic) vulnerability to develop bipolar disorder, or both. METHOD: Blood was collected from 22 monozygotic (MZ) and 29 dizygotic (DZ) bipolar twins and 35 healthy matched control twins to determine TPO-Abs. RESULTS: The TPO-Abs were positive in 27% of the bipolar index twins, 29% of the monozygotic bipolar cotwins, 27% of the monozygotic nonbipolar cotwins, 25% of the dizygotic bipolar cotwins, 17% of the dizygotic nonbipolar cotwins, and in 16% of the control twins. Repeated measures analysis of covariance on log-transformed absolute TPO-Abs values revealed significantly increased mean TPO-Abs levels in discordant twin pairs as compared with healthy twin pairs, whereas no difference was found between bipolar patients and their (discordant) nonbipolar cotwins. CONCLUSIONS: This study shows that autoimmune thyroiditis is related not only to bipolar disorder itself but also to the genetic vulnerability to develop the disorder. Autoimmune thyroiditis, with TPO-Abs as marker, is a possible endophenotype for bipolar disorder.     

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.     

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.     

Neuropsychological performance of monozygotic twins discordant for bipolar disorder.

BACKGROUND: A paradigm that involves cognitive assessment of monozygotic (MZ) twins discordant for a neuropsychiatric disorder (here bipolar illness) allows for the examination of both disease-specific impairments (in the comparison of affected to unaffected twins) and risk factors (in the comparison of unaffected twins to normal twins). METHODS: Neuropsychological functions were evaluated in seven MZ twin pairs discordant for bipolar illness and seven pairs of normal MZ twins in an attempt to highlight cognitive abilities associated with manifestations of disease and genetic risk factors. At the time of testing, 3 of the affected twins were euthymic, 2 had depressive symptoms, and 2 had manic symptoms; all were receiving medication. All twins receive neuropsychological tests to evaluate intelligence, attention, visuospatial skills, language, learning and memory, and problem solving. RESULTS: Statistical analyses revealed that the affected twins were significantly impaired as compared to the unaffected (and normal) twins on some measures of visuospatial functioning and some verbal memory measures. In contrast to a sample of MZ twins discordant for schizophrenia studied previously, the cognitive impairments we observed in bipolar twins were mild in nature and fairly circumscribed. The unaffected twins performed significantly worse than normal controls on a Brown-Petersen memory task, verbal list learning, and overall Wechsler Memory Quotient. CONCLUSIONS: These data suggest that while some visuospatial deficits and verbal memory deficits may be features of bipolar disorder related to disease parameters, mild attenuations in overall memory or retrieval function may be related to genetic factors associated with the illness.     

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.     

Language lateralization in monozygotic twins discordant and concordant for schizophrenia. A functional MRI pilot study.

AIM: Previous studies have suggested altered structural and functional asymmetry of the brain in schizophrenia. METHODS: Functional MRI was used to assess differences in cortical activation during a verbal task in Broca's area and its contralateral homologue in four pairs of right-handed monozygotic (MZ) twins discordant and concordant for schizophrenia with low and high familial loading for the illness and four healthy control MZ twin pairs. RESULTS: Pooled data from all subjects with schizophrenia showed increased activation in the right homologue of Broca's area in contrast to healthy individuals. Concordant twins (i.e. high familial loading group) showed prominent between co-twin differences in lateralization index within given region of interest. Intra-pair differences in lateralization index were significantly higher in concordant twins compared to the controls (0.69+/-0.4 vs. 0.13+/-0.13, P<0.03), albeit no significant differences in the variable were shown between the discordant and control groups. CONCLUSION: This study provides evidence of reduced cerebral dominance for language processing in patients with schizophrenia. The findings further suggest the need for additional research on relative proportion of genetic and environmental factors underlying deviations of functional asymmetry in schizophrenia.     

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.     

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.     

Motor disorder and anxious and depressive symptomatology: a monozygotic co-twin control approach

The aim of this study was to investigate the relationship between poor motor ability and anxious and depressive symptomatology in child and adolescent monozygotic twins. The co-twin control design was used to explore these mental health issues in MZ twins concordant and discordant for a motor disorder, and controls. This methodology offers the unique opportunity to control for genetic effects and shared environmental influences, and permits the investigation of non-shared environmental influences. The Developmental Coordination Disorder Questionnaire was used to identify 23 sets of twins discordant for a motor disorder, 23 sets concordant for a motor disorder, and 773 sets of twins with no motor disorder from a total sample of 2122 Australian sets of twins. The Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour questionnaire was used to exclude participants with high Attention Deficit Hyperactivity Disorder symptomatology. Anxious and depressive symptomatology were assessed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) based questionnaires on Generalised Anxiety Disorder and Sad Affect. Results indicated significantly higher levels of anxious and depressive symptomatology in twins with a motor disorder in discordant pairs compared to their co-twins without a motor disorder, and controls. There were significantly higher levels of anxious symptomatology in twins with a motor disorder in discordant sets than in sets of twins concordant for a motor disorder. There were significantly higher levels of anxious symptomatology in concordant twins than in controls. Implications of these findings are discussed with emphasis on understanding and recognising the relationship between a motor disorder and anxious and depressive symptomatology in clinical practice for children and adolescents with these disorders.     

Salivary cortisol in unaffected twins discordant for affective disorder

Dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a biological endophenotype for affective disorders. In the present study the hypothesis that a high genetic liability to affective disorder is associated with higher cortisol levels was tested in a cross-sectional high-risk study. Healthy monozygotic (MZ) and dizygotic (DZ) twins with (High-Risk twins) and without (Low-Risk twins) a co-twin history of affective disorder were identified through nationwide registers. Awakening and evening salivary cortisol levels were compared between the 190 High- and Low-Risk twins. The 109 High-Risk twins had significantly higher evening cortisol levels than the 81 Low-Risk MZ twins, also after adjustment for age, sex, and the level of subclinical depressive symptoms. No significant difference was found in awakening cortisol levels between High-Risk and Low-Risk twins. In conclusion, a high genetic liability to affective disorder was associated with a higher evening cortisol level, but not with awakening cortisol level. Future prospective family, high-risk and twin studies are needed to decide whether abnormalities in the HPA axis can be identified as an endophenotype of affective disorder.     

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 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.     

Genome-wide methylation study on depression: differential methylation and variable methylation in monozygotic twins

Depressive disorders have been shown to be highly influenced by environmental pathogenic factors, some of which are believed to exert stress on human brain functioning via epigenetic modifications. Previous genome-wide methylomic studies on depression have suggested that, along with differential DNA methylation, affected co-twins of monozygotic (MZ) pairs have increased DNA methylation variability, probably in line with theories of epigenetic stochasticity. Nevertheless, the potential biological roots of this variability remain largely unexplored. The current study aimed to evaluate whether DNA methylation differences within MZ twin pairs were related to differences in their psychopathological status. Data from the Illumina Infinium HumanMethylation450 Beadchip was used to evaluate peripheral blood DNA methylation of 34 twins (17 MZ pairs). Two analytical strategies were used to identify (a) differentially methylated probes (DMPs) and (b) variably methylated probes (VMPs). Most DMPs were located in genes previously related to neuropsychiatric phenotypes. Remarkably, one of these DMPs (cg01122889) was located in the WDR26 gene, the DNA sequence of which has been implicated in major depressive disorder from genome-wide association studies. Expression of WDR26 has also been proposed as a biomarker of depression in human blood. Complementarily, VMPs were located in genes such as CACNA1C, IGF2 and the p38 MAP kinase MAPK11, showing enrichment for biological processes such as glucocorticoid signaling. These results expand on previous research to indicate that both differential methylation and differential variability have a role in the etiology and clinical manifestation of depression, and provide clues on specific genomic loci of potential interest in the epigenetics of depression.     

Orbitofrontal dysfunction in a monozygotic twin discordant for postpartum affective psychosis: a functional magnetic resonance imaging study

BACKGROUND: Incomplete concordance for psychosis in monozygotic (MZ) twins has been interpreted as indicative of non-genetic cofactors in transmission of the illness. In this case study, we consider childbirth a landmark in the onset of psychotic symptoms, leading to the diagnosis of puerperal psychosis and then to bipolar/schizoaffective disorder. At the end of the third trimester, there is a sudden drop in estrogen, which exerts prominent effects on the serotonergic system in the orbitofrontal cortex (OFC). OBJECTIVES: The purpose of the present study was to investigate OFC activation during emotional processing in MZ twins discordant for affective psychosis. METHODS: Blood-oxygen-level-dependent activation using functional magnetic resonance imaging was measured during the passive viewing of emotional film excerpts. RESULTS: Consistent with our hypothesis, a significant locus of activation was found in the left OFC in the normal MZ twin, but not in the psychosis MZ twin. CONCLUSIONS: The personality changes noted in the psychosis MZ twin (postpartum psychosis) may be related to dysfunctional OFC. Ms J's childbirth may have triggered the onset of psychotic symptoms, leading to the diagnosis of bipolar or schizoaffective disorder.     

Fluctuating dermatoglyphic asymmetry in psychotic twins

Fluctuating asymmetry of bilateral morphological traits is the result of prenatal developmental instability and has been shown to be greater in organisms having more homozygous genotypes (aabb vs. AaBb, for example). This expected increase in fluctuating asymmetry has been found among individuals having a high degree of liability for schizophrenia, as this disorder appears to have a polygenic basis. We tested the additional prediction that the greater genetic liability for schizophrenia necessary for concordance between twins should be associated with greater fluctuating asymmetry in twin pairs in which both twins are mentally ill compared to twin pairs in which one individual is normal. Our analysis of asymmetry for finger ridge counts from fingerprints of concordant and discordant pairs of twins supports this prediction and provides additional indirect support for the roles of polygenic transmission and prenatal epigenetic vulnerability in schizophrenia.     

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.