Analyzing the etiology of benign rolandic epilepsy: a multicenter twin collaboration

PURPOSE: Benign rolandic epilepsy (BRE) is considered a genetically determined idiopathic partial epilepsy. We analyzed a large sample of twins from four international twin registers to probe the genetics of BRE. We also aim to synthesize the apparently conflicting family and twin data into a model of BRE etiology. METHODS: Large population-based twin registries of epilepsies from Odense (Denmark), Richmond, Virginia (United States), and Oslo (Norway) were reviewed for BRE cases and added to our Australian twin data. Diagnosis of classic BRE was based on electroclinical criteria with normal neurologic development. Cases with a compatible electroclinical picture but abnormal neurologic development were termed non-classic BRE. RESULTS: Eighteen twin pairs were identified (10 monozygous; eight dizygous) of whom at least one twin was diagnosed with classic BRE among a total sample of 1,952 twin pairs validated for seizures, and all were discordant for BRE. The estimated monozygous pairwise concordance for BRE in this sample was 0.0 [95% confidence interval (CI), 0.0-0.3). Four twin pairs (one monozygous, three dizygous) had non-classic BRE, and all co-twins had seizures. CONCLUSIONS: The twin data showing an absence of any concordant twin pairs with classic BRE suggest that noninherited factors are of major importance in BRE. Modelling the data shows that the familial occurrence of centrotemporal spikes makes only a minor contribution to the familial aggregation of BRE. Genetic factors are probably more important in non-classic BRE. The etiology and mode(s) of inheritance of BRE are much more complicated than initially conceptualized.     

Concordance for multiple sclerosis in Danish twins: an update of a nationwide study

The occurrence of multiple sclerosis (MS) in twins has not previously been studied in complete nationwide data sets. The existence of almost complete MS and twin registries in Denmark ensures that essentially unbiased samples of MS cases among twins can be obtained. In this population-based study, virtually all Danish MS cases among twins born before 1983 with onset of MS after 1948 and diagnosis before I January 1997 were identified. Of 13 286 MS cases, 178 were twins and, of these 164 twin pairs were discordant and seven were concordant. We found significantly higher proband-wise concordance among monozygotic twins than dizygotic twins, with estimated proband-wise concordances of 24% (95% confidence interval (CI): 5-39%) for monozygotic and 3% (95% CI: 0-8%) for dizygotic twins. Thus, a monozygotic twin whose co-twin has MS has a 24% risk of developing the disease, while the corresponding risk for a dizygotic twin is only 3%. Our results largely confirm previously published concordance estimates and indicate that genetic factors are of importance in susceptibility to MS.     

Epilepsies in twins: Genetics of the major epilepsy syndromes

We studied twins to examine the genetics of epilepsy syndromes. We ascertained 358 twin pairs in whom one or both reported seizures. After evaluation, 253 of 358 (71%) had seizure disorders and 105 pairs were false positives. Among the monozygous (MZ) pairs, more were concordant for seizures (48 of 108; casewise concordance = 0.62 ± 0.05) than among the dizygous (DZ) pairs (14 of 145; casewise concordance = 0.18 ± 0.04). In 94% of concordant MZ pairs, and 71% of concordant DZ pairs, both twins had the same major epilepsy syndrome. When analyzed according to major epilepsy syndrome, the casewise concordances for generalized (MZ = 0.82; DZ = 0.26), both idiopathic (MZ = 0.76; DZ = 0.33) and symptomatic (MZ = 0.83; DZ = 0), were greater than those for partial epilepsies (MZ = 0.36; DZ = 0.05), with intermediate values seen for febrile seizures (MZ = 0.58; DZ = 0.14) an dunclassified epilepsies (MZ = 0.53; DZ = 0.18). We conclude that genetic factors are particularly important in the generalized epilepsies but also play a role in the partial epilepsies. The high frequency of concordant MZ pairs with the same major syndrome strongly suggets there are syndrome-specific genetic determinants rather than a broad genetic predisposition to seizures.     

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.     

Epileptic seizures and syndromes in twins: the importance of genetic factors

The role of genetic factors in the occurrence of epilepsy syndromes was studied in twins recruited from the population-based Danish Twin Registry. A total of 34,076 twins were screened for epilepsy. Cases were confirmed and classified by two neurologists according to the classification systems of the International League Against Epilepsy (ILAE). A total of 214 twin pairs with epileptic seizures and 190 pairs with epilepsy were ascertained. Significantly higher concordance rates were found for monozygotic (MZ) compared to dizygotic (DZ) twins for both epileptic seizures (0.56 for MZ and 0.21 for DZ pairs, P<0.001) and for epilepsy (0.49 for MZ and 0.16 for DZ pairs, P<0.001). Concordance rates were also higher for MZ twins compared to DZ twins for both generalized epilepsy (0.65 for MZ and 0.12 for DZ) and for localization-related epilepsy (0.30 for MZ and 0.10 for DZ). In twin pairs where both members had seizures, 83% of MZ and 65% of DZ pairs had the same major epilepsy syndrome. Genetic factors were found to account for 80% of the liability to both epileptic seizures and epilepsy. In conclusion, analysis of this neurologist-verified epilepsy twin data set has confirmed that genetic factors have a substantial impact on the etiology of epileptic seizures as well as on the occurrence of both generalized and partial epilepsies.     

Monozygotic twins with seizures. Shared characteristics

Eleven sets of monozygotic twins with idiopathic seizure disorders seen at Children's Hospital, Boston, Mass, were reviewed Nine twin pairs were concordant for seizures. A marked correlation in the precise timing of onset of seizures was found; three sets of twins had their first clinical seizures within a 24-hour period of one another. The clinical features of the seizures and the electroencephalographic patterns, including the location of focal discharges, were strikingly similar in the twin pairs. The significance of these findings in suggesting aberrant processes that may contribute to epileptic syndromes is discussed.     

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.     

British motor neuron disease twin study.

OBJECTIVES: To investigate the cause of sporadic motor neuron disease (MND) by twin study, so allowing (1) estimation of the genetic contribution, and (2) collection of matched pairs for a case-control study of possible environmental factors. METHODS: 10872 death certificates bearing the diagnosis MND were collected from 1979 to 1989 inclusive. Inspection of individual birth entries allowed identification of potential twins. The status of each co-twin was determined and contact made through the National Health Service Central Register (NHS-CR) and their general practitioner (GP). The diagnosis of MND was verified via the co-twin and relatives, and medical records where available. Zygosity was assessed using a recognised questionnaire. Details concerning environmental exposures and health were gathered by interview of cotwin and relatives using a semistructured questionnaire. Heritability (h2) of MND was estimated, and the environmental information was analysed by conditional logistic regression modelling. RESULTS: Seventy seven probands were identified, of whom 26 were monozygotic and 51 dizygotic. Four monozygotic probands were concordant, but two probands came from a family known to have familial MND. The estimated heritability was between 0.38 and 0.85. Most environmental risk factors were not significant. Regular vehicle maintenance (odds ratio (OR) = 7.0; 95% confidence interval (95% CI) 1.3-89.9) and occupational paint usage (OR = 3.75; 95% CI 1.0-17.1), however, occurred significantly more often in the affected cases. CONCLUSIONS: This "death discordant" method for twin collection has proved to be viable, and has allowed the ascertainment of a large population sample in a rare disease. The genetic role in sporadic MND is substantial, and higher than expected. Exposure to industrial chemicals, particularly constituents of petrochemicals and paints, may contribute to the aetiology of MND.     

Genetic factors in epileptic seizures: evidence from a large twin population

The Finnish Twin Cohort study (27776 individuals; all twins of the same sex born before 1958 and alive in 1967) detected 316 cases of epileptic seizures occurring in 310 twin pairs: 89 monozygotic pairs and 221 dizygotic pairs, including three concordant monozygotic pairs and three concordant dizygotic pairs. The ratio of the observed to expected number of concordant pairs for epileptic seizures was 5.48 (90% CL 1.5–14.2) in monozygotic and 2.12 (90% CL 0.6–5.5) in dizygotic pairs. The results suggest that 8% to 27% of the incidence of epileptic seizures is related to genetic variability. The study of environmental differences in discordant monozygotic pairs should provide insights into the etiology of this group of disorders.     

Multiple sclerosis in twins from continental Italy and Sardinia: a nationwide study

Knowledge about the balance between heritable and nonheritable risk in multiple sclerosis (MS) is based on twin studies in high-prevalence areas. In a study that avoided ascertainment limitations and directly compared continental Italy (medium-prevalence) and Sardinia (high-prevalence), we ascertained 216 pairs from 34,549 patients. This gives a twinning rate of 0.62% among MS patients, significantly less than that of the general population. In continental Italy, probandwise concordance was 14.5% (95% confidence interval, 5.1-23.8) for monozygotic and 4.0% (95% confidence interval, 0.8-7.1) for dizygotic twins. Results in Sardinia resemble those in northern populations but in limited numbers. Monozygotic concordance was 22.2% (95% confidence interval, 0-49.3) probandwise, but no concordant dizygotic pairs were identified. A questionnaire on 80 items possibly related to disease cause was administered to 70 twin pairs, 135 sporadic patients, and 135 healthy volunteers. Variables positively (7) or negatively (2) associated with predisposition and concordance in twins largely overlapped and were mainly linked to infection. If compared with previous studies, our data demonstrate that penetrance in twins appears to correlate with MS prevalence. They highlight the relevance of nonheritable variables in Mediterranean areas. The apparent underrepresentation of MS among Italian twins draws attention to protective factors, shared by twins, that may influence susceptibility.     

High concordance of bipolar I disorder in a nationwide sample of twins

OBJECTIVE: The few studies of bipolar I disorder in twins have consistently emphasized the genetic contribution to disease liability. The authors report what appears to be the first twin study of bipolar I disorder involving a population-based twin sample, in which the diagnoses were made by using structured, personal interviews. METHOD: All Finnish same-sex twins (N=19,124) born from 1940 to 1957 were screened for a diagnosis of bipolar I disorder as recorded in the National Hospital Discharge Register between 1969 and 1991 or self-reported in surveys of the Finnish Twin Cohort in 1975, 1981, and 1990. Thirty-eight pairs were thereby identified and invited to participate in the study; the participation rate was 68%. Lifetime diagnoses were made by using the Structured Clinical Interview for DSM-IV. The authors calculated probandwise and pairwise concordances and correlations in liability and applied biometrical model fitting. RESULTS: The probandwise concordance rates were 0.43 (95% CI=0.10 to 0.82) for monozygotic twins and 0.06 (95% CI=0.00 to 0.27) for dizygotic twins. The correlations in liability were 0.85 and 0.41, respectively. The model with no familial transmission was rejected. The best-fitting model was the one in which genetic and specific environmental factors explained the variance in liability, with a heritability estimate of 0.93 (95% CI=0.69 to 1.00). CONCLUSIONS: The high heritability of bipolar disorder was demonstrated in a nationwide population-based twin sample assessed with structured personal interviews.     

Migraine without aura: a population-based twin study.

To investigate the importance of genetic and environmental factors to the etiology of migraine without aura and to compare the symptomatology of migraine without aura in monozygotic and dizygotic twins, 2,680 twin pairs were recruited from the population-based Danish Twin Registry. Monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs, where at least one twin had self-reported migraine or self-reported severe headache with accompanying symptoms, were telephone interviewed by a physician. The participation rate in the telephone interview was 90%. The pairwise concordance rate was significantly higher in MZ than in DZ twin pairs (28% vs 18%). The probandwise concordance rate was 40% (95% CI, 33-48%) in MZ and 28% (95% CI, 23-33%) in DZ twin pairs. The pairwise concordance rates for the different pain characteristics and accompanying symptoms were not significantly different in MZ and DZ twin pairs. However, comparing all of the pairwise concordance rates of pain characteristics and accompanying symptoms together, MZ twin pairs were significantly more concordant than DZ twin pairs. Our data demonstrate a significant genetic factor in migraine without aura. The size of this factor is modest and the demonstration of susceptibility genes is predicted to be laborious and difficult.     

APOE and AD concordance in twin pairs as predictors of AD in first-degree relatives

OBJECTIVE: To examine the independent effects of the APOE genotype (APOE) and concordance for AD in twin pairs on the occurrence of AD in first-degree relatives. BACKGROUND: Studies of twins have been undertaken to investigate the influence of genes in a variety of conditions, including AD. A previous study, performed before reports linking APOE to AD, demonstrated an increase in AD among first-degree relatives of twins concordant for AD compared with relatives of discordant twins. METHODS: In a sample of 94 twin pairs the authors examined the association between concordance for AD within the twin pair and family history of AD among first-degree relatives of twins. They then examined the extent to which the presence of the APOE epsilon4 allele in the twin pair explains the association between concordance for AD within the twin pair and family history of AD. RESULTS: Concordance among twins was associated with increased risk of AD among relatives (logrank test, chi2 = 12.558; p = 0.0004), and the presence of at least one APOE epsilon4 allele in each member of the twin pair is also associated with increased risk of AD among family members (logrank test, chi2 = 7.712; p = 0.0055). CONCLUSIONS: APOE genotype explains much but not all of the association between concordance among twins and increased familial risk of AD.     

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.     

Epilepsy and seizure occurrence in a population-based sample of Virginian twins and their families

Epilepsy and seizure occurrence was assessed in a large, population-based sample of Virginian twins and their families. Medical history information on twins and their relatives was collected by questionnaire and used to estimate prevalence of seizures and epilepsy for this sample. Health history information was available on 16,634 twins and their families. Lifetime prevalence of a history of seizures ranged from < 1 to 5%. Concordance rates were larger in monozygotic (MZ) than dizygotic (DZ) pairs overall, however, significant differences between the zygosities were only noted for Caucasian twins. To facilitate interpretation of results, the sample was partitioned into two age groups: 16-35 years and > 35 years of age. In the first age category of twins, significant differences were observed for the following seizure types; epilepsy (0.30 and 0.13, p <0.03), febrile seizures (0.39 and 0.12, p <0.001), and other convulsions/seizures (0.28 and 0.01, p < 0.001). While for twins in the second age category, only the comparison for febrile seizures (0.42 and 0.14, p < 0.001) resulted in a significant difference between zygosities. A family history of seizures was reported in 215 (35.1%) of the 613 seizure positive probands. Increased risk of seizures (1.88-4.64) among relatives of affected versus unaffected individuals was also observed.     

Concordance and heritability of multiple sclerosis in Finland: study on a nationwide series of twins

Objectives: To evaluate the changes in the multiple sclerosis (MS) concordance in twins, and the contribution of genetic and environmental factors to the aetiology of MS in Finland. Background: Both genes and the environment contribute to the development of MS. A well‐conducted twin study is an excellent means to assess the relative contribution of heritability and environmental factors. Methods: Multiple sclerosis concordance was assessed for 10 Monozygotic and 14 dizygotic twin pairs using pairwise and probandwise concordance rates. The tetrachoric correlations in liability to disease for twin pairs were computed and a polygenic multifactorial model was used to estimate heritability. Results: The pairwise concordance for MZ twins was 30% and for the DZ twins 14.3%, compared with 30% for MZ and 0% for DZ 20 years ago. The corresponding probandwise concordance rates were 46.2% and 25%. The genetic variance (heritability) was 15.3% (95% Cl 0.0–77.6), the common environmental variance 73.7% (95% Cl 14.1–93.9) and the unique environmental variance 11.1% (95% Cl 2.3–30.0). Conclusions: As the concordance of MS in DZ twins has increased during the past two decades and the heritability estimate is low, it seems that the reported increase in MS incidence in Finland is mainly caused by environmental factors.     

Genetic and environmental factors in febrile seizures: a Danish population-based twin study

The relative importance of genetic and environmental factors in the etiology of febrile seizures was estimated using a large, unselected population-based twin sample. A total of 34,076 twins (aged 12-41 years), recruited from the Danish Twin Registry, were screened for febrile seizures by questionnaire. Information was obtained from 11,872 complete pairs. Concordance rates, odds ratios and correlations were used to assess the degree of similarity in monozygotic (MZ) and dizygotic (DZ) twins. Model fitting and estimation of heritability (proportion of the population variance attributable to genetic variation) were performed using standard biometrical methods. Significantly higher probandwise concordance rates were found for MZ compared with DZ twins (0.36 and 0.12, P < 0.01). Odds ratios and correlations showed a similar pattern. An etiological model including additive genetic effects and individual-specific environmental factors provided the best fit to the data with a heritability for febrile seizures of 70% (95% CI: 61-77%). The remaining 30% of the variation could be attributed to individual-specific environmental factors. In conclusion, this study has confirmed a major impact of genetic factors in the etiology of febrile seizures. Future studies aimed at identifying the specific genetic factors and environmental exposures involved in determining febrile seizure risk are clearly warranted.     

Reduced left hemispheric white matter volume in twins with bipolar I disorder.

BACKGROUND: Although the heritability of bipolar I disorder (BPI) is high, few magnetic resonance imaging (MRI) studies of siblings of bipolar patients exist. We performed MRI brain scans on a nationwide sample of twins with BPI, as well as on their co-twins and a demographically balanced sample of control twin subjects, to detect any structural alterations related to the disorder and to the increased genetic risk. METHODS: The National Hospital Discharge Register, National Population Register, and Finnish Twin Cohorts were used to identify bipolar twins. Structured diagnostic interviews and MRI scans were obtained for 24 twins with BPI, 15 healthy co-twins, and 27 control twin subjects. RESULTS: Patients and co-twins showed a significant decrease in left hemispheric white matter volume. The disparity in patients was -16.1 cm(3) (95% confidence interval [CI] -26.6, -5.6) and in co-twins -11.3 cm(3) (95% CI -22.1, -0.4) compared with control twin subjects. No gray matter decrease was seen in patients or co-twins. CONCLUSIONS: The results of this first large-scale MRI study of twins with BPI, their co-twins, and appropriate control twin subjects, suggest that alterations of the left hemisphere white matter in BPI may reflect genetic factors predisposing to the disorder.     

Familial influences on the clinical characteristics of major depression: a twin study.

We sought in this study to clarify the role that familial factors play in influencing the clinical presentation of major depression (MD). We examined the similarity of the historical and symptomatic features of MD in 176 pairs of female-female monozygotic (MZ) and dizygotic (DZ) twins from a population-based registry, where both members reported a history of MD defined by DSM-III-R criteria. The age at onset and treatment-seeking were significantly correlated in all twin pairs and the correlation in concordant DZ pairs was actually somewhat higher than in concordant MZ twins. The degree of impairment was modestly correlated in all twin pairs with substantially higher correlations in MZ vs DZ twins. No twin resemblance was observed for number of episodes or longest duration of an episode. Twin resemblance for the clinical features of MD was modest, but so was their consistency for the same individual over successive 1-year periods. However, in 5 of the 6 neurovegetative symptoms involving changes in appetite, weight and sleep, MZ twins were significantly correlated and correlations were significantly greater in concordant MZ vs DZ twins. Although the familial factors that cause twin resemblance for the age at onset and treatment seeking appear to be largely environmental, twin resemblance for the degree of impairment and neurovegetative symptoms are probably due largely to genetic factors. Our results suggest that familial factors influence the predisposition to some clinical features of MD.     

Further evidence that congenital dermatoglyphic abnormalities are associated with psychosis: a twin study

The presence of abnormal palmar flexion creases (APFC) and dermatoglyphic ridge dissociation (RD) may constitute enduring evidence of a prenatal insult that occurred before the third trimester of intrauterine life. We examined these dermatoglyphic abnormalities in a twin study of psychotic disorders. RD and APFC were analyzed in a monozygotic (MZ) twin sample from the Maudsley Hospital in London (11 normal control pairs, 16 pairs concordant for psychosis, 9 pairs discordant for psychosis, 1 concordant triplet, and 1 triplet with one affected member). The risk of either RD or APFC was 44 percent in affected twins and 20 percent in nonaffected twins (odds ratio = 3.25, 95% confidence interval: 1.03-10.31; one-sided p = 0.023). In the group of MZ twins discordant for psychosis, discordance for RD or APFC always paralleled discordance for psychosis (one-sided p = 0.078), suggesting the operation of nongenetic factors. The results confirm previous work suggesting the possibility that nongenetic factors early in pregnancy contribute to the liability to develop psychosis in later life.