Genetic and environmental factors in epilepsy: a population-based study of 11900 Danish twin pairs

The contribution of genetic and environmental factors to the occurrence of epilepsy was examined in an unselected sample of twins recruited from the population-based Danish Twin Registry. Information on the occurrence of epilepsy in both members of a twin pair was obtained from 11900 pairs whose ages ranged from 12 to 41 years. Concordance rates, odds ratios and tetrachoric correlations were used to quantify the similarity of monozygotic (MZ) and dizygotic (DZ) twins. The sample was stratified by sex and separated into two age cohorts for analysis. Significantly higher probandwise concordance rates were found for MZ compared with DZ twins (0.37 and 0.08, P<0.01). Odds ratios and tetrachoric correlation showed similar pattern. An etiological model including additive genetic and individual specific environmental factors provided the best overall fit to the data, with 70 and 88% of the liability to develop epilepsy being accounted for by genetic factors in the younger and older cohorts, respectively. Individual specific environmental factors explained the remaining 30 and 12%, respectively. In conclusion, this study has confirmed the substantial impact, which genetic factors have in the etiology of epilepsy. The heritability of epilepsy is high and seems to increase with age.     

Incidence of febrile seizures in Finland: prospective population-based study

The objective was to study the incidence of febrile seizures prospectively determined through age 4 years. A standardized randomized cluster sample of nulliparous pregnant women from a geographically defined area were prospectively followed from the beginning of pregnancy through the child's age 4. Data on children eligible for the study (n = 1287), including febrile seizures, sociodemographic data, developmental milestones, and chronic diseases, were prospectively collected from families and health care staff. Data were available for 1033 children. Through age 4, the average annual incidence of febrile seizures was 14 per 1000 person-years (15 for girls and 13.5 for boys). The incidence rate through age 4 was 6.9% (7.3% for girls and 6.5% for boys). The incidence rate of febrile seizures in Finnish children is comparable to that reported previously. The higher figure, based on prospective rather than retrospective data, may give a more accurate picture of the clinical importance of febrile seizures.     

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.     

A Danish population-based twin study on autism spectrum disorders

Genetic epidemiological studies of Autism Spectrum Disorders (ASDs) based on twin pairs ascertained from the population and thoroughly assessed to obtain a high degree of diagnostic validity are few. All twin pairs aged 3–14 years in the nationwide Danish Twin Registry were approached. A three-step procedure was used. Five items from the “Child Behaviour Checklist” (CBCL) were used in the first screening phase, while screening in the second phase included the “Social and Communication Questionnaire” and the “Autism Spectrum Screening Questionnaire”. The final clinical assessment was based on “gold standard” diagnostic research procedures including diagnostic interview, observation and cognitive examination. Classification was based on DSM-IV-TR criteria. The initial sample included 7,296 same-sexed twin pairs and, after two phases of screening and clinical assessment, the final calculations were based on 36 pairs. The probandwise concordance rate for ASD was 95.2 % in monozygotic (MZ) twins (n = 13 pairs) and 4.3 % in dizygotic (DZ) twins (n = 23 pairs). The high MZ and low DZ concordance rate support a genetic aetiology to ASDs.     

Evidence of a genetic factor in migraine with aura: A population-based Danish twin study

We studied the genetic influence on cause of migraine with aura (MA) by analyzing a twin population. The twin sample consisted of 2,026 monozygotic (MZ) twins and 3,334 same-sex dizygotic (DZ) twins, born from 1953 to 1960, from the population-based New Danish Twin Register. A validated questionnaire was used to screen for migraine, the response rate being 87%, and similar among MZ and DZ twins. All twin pairs with at least 1 twin with possible MA were interviewed by a physician experienced in headache diagnoses. The answers from the questionnaire as well as the zygosity of the twins were blinded for the interviewer. A total of 211 twin pairs were identified, of whom 77 pairs were MZ and 134 pairs were DZ. The lifetime prevalence of MA was 7% and with a male-to-female ratio of 1:1.1. The pairwise concordance rates were significantly higher in MZ (34%) than in DZ twin pairs (12%), emphasizing the importance of genetic factors in MA. However, environmental factors are also important, as the pairwise concordance rate was less than 100% in MZ twin pairs. The recurrence risk of MA was 50% in MZ and 21% in DZ twin pairs. In nontwin siblings, the recurrence risk of MA is 27%, which is similar to the recurrence risk in DZ twins. This indicates that MA is not developed due to specific environmental factors shared by the twins. Ann Neurol 1999;45:242–246     

Genetic and environmental influences on schizotypy: a community-based twin study

This study investigated the factor structure and etiology of four self-report schizotypy questionnaires during young adulthood (age 18-27) in 98 monozygotic and 59 same-sex dizygotic twin pairs from the community. A single phenotypic factor was identified that was primarily associated with Perceptual Aberration, Magical Ideation, and the Rust Inventory of Schizotypal Cognitions scales, and less so with Social Anhedonia. Univariate etiologic models suggested that in addition to nonshared environmental influences, Perceptual Aberration and Social Anhedonia were significantly influenced by either genes or shared family environment, whereas Magical Ideation and the Rust Inventory were influenced by shared family environment, but not genes. Multivariate twin analyses detected a common schizotypy factor, primarily defined by Perceptual Aberration, Magical Ideation, and the Rust Inventory scales, that was influenced by genes or shared environment as well as nonshared environment. Contrary to expectations, these results suggest that, at least in community-based samples, these "positive" schizotypy questionnaires are not strongly genetically influenced.     

Risk factors for complex partial seizures: a population-based case-control study

This investigation is to our knowledge the first population-based case-control study of risk factors for complex partial seizures (CPS). Included in the study were all patients with onset of complex partial seizures before age 35, who were residents of Rochester, Minnesota, at the time of diagnosis between 1935 and 1979, and who were also born in Rochester (n = 82). Two control subjects were matched to each patient, and for both patients and control subjects, the unique records-linkage system for residents of Rochester was used to obtain information about possible risk factors. A history of epilepsy or febrile seizures in the mother, febrile seizures, neonatal convulsions, cerebral palsy, head trauma, and viral encephalitis were significantly more common in patients than in control subjects (p less than 0.05). None of the prenatal or perinatal factors investigated were found to be associated with complex partial seizures, except for being small for gestational age at birth. This factor lost significance after adjustment for cerebral palsy.     

Genetic and environmental influences on the fibrinolytic system: a twin study

The determination of heritability is a key issue to assess the predictive power of polymorphisms for disease in clinical studies. The aim of this study was to determine the heritability of proteins and activation markers of the fibrinolytic system in a large cohort of healthy twins. Heritability was calculated as 0.76 for thrombin activatable fibrinolysis inhibitor (TAFI), 0.44 for plasminogen activator inhibitor-1 (PAI-1), and 0.43 for tissue plasminogen activator. No significant genetic influence was observed for alpha2-antiplasmin-plasmin-complex and D-dimer. Heritability explained by single gene polymorphisms was 25.2% for TAFI 505G>A, 31.5% for 1542C>G, and 50.0% for combination of both. The influence on TAFI levels of 1542C>G (CC-->GG, median: -80.5%) was considerably stronger than that of 505G>A (GG-->AA, median: +49.3%) and in both cases there seems to be a dose-response relationship. Significant environmental influences on TAFI levels were observed for combined interaction terms (age*sex and bmi*sex). The PAI-1 4G/5G polymorphism explained 56.4% of the calculated heritability. The genetic variables accounting for the 43% heritability of tPA remain unknown. Our data show that the production of several key components of the fibrinolytic system is strongly genetically determined. This genetic influence is accounted for in large part but not completely by a limited number of polymorphisms within the respective genes associated with plasma levels of the gene products.     

Genetic and environmental influences on multiple dimensions of religiosity: a twin study

In recent years there has been a renewed scientific interest in the study of religiosity, including research on genetic and environmental contributions to religiosity. In this article, we investigate genetic and environmental effects on 7 religiosity factors and explore how genetic and environmental effects covary across these factors. Seven religiosity factors estimated from 78 items were examined in a sample of adult male and female twins. The 7 religiosity factors were largely influenced by additive genetic and unique environmental effects, with relatively little influence from common environmental effects. Multivariate genetic analyses found the 7 religiosity factors were influenced by 1 common additive genetic factor, 3 common unique environmental factors, and unique environmental effects specific to each religiosity factor. The results suggest that for the population studied, additive genetic and unique environmental effects largely account for the variance across the religiosity construct.     

Gender differences in binge-eating: a population-based twin study

OBJECTIVE: To assess whether genetic and environmental effects on liability to binge-eating (BE) are of equal importance for males and females and whether the same genetic risk factors predispose to BE in the two sexes. METHOD: Questionnaire data on 8045 same sex and opposite sex twins, aged 19-31 years, from a population-based Norwegian registry, was used to estimate the relative contribution of genetic and environmental factors to liability for BE utilizing structural equation modeling. RESULTS: In the best-fitting model, the magnitude of genetic and environmental effects on BE was the same for males and females. Heritability was 51%. The correlation between genetic risk factors in men and women was estimated to be +0.57. CONCLUSION: Binge-eating appears to be equally heritable in males and females. Although the majority of the genetic risk factors are shared between the sexes, there may exist gender-specific genetic effects on liability.     

Risk factors for absence seizures: a population-based case-control study in Rochester, Minnesota

To our knowledge, this is the first population-based case-control study of risk factors for absence seizures (AS). Diagnosis of AS was based on clinical criteria. The complete medical history of potential cases, available through the records-linkage system for residents of Rochester, MN, was independently reviewed by three neurologists who agreed upon the diagnosis. All AS patients who were residents of Rochester at time of diagnosis between 1935 and 1979, and who were born in this community, were included (N = 30). Two population controls (born in Rochester) were matched to each patient, and for both patients and controls, the records-linkage system was used to obtain information about possible risk factors. The only factor significantly more common in cases than in controls was a history of febrile seizures (odds ratio = 12; p less than 0.01). We suggest that these febrile seizures represent either an early manifestation of the convulsive diathesis or the symptom of a preexisting brain dysfunction. None of the other factors investigated reached statistical significance, including those that have been previously suggested such as twin pregnancy, breech presentation at delivery, being first-born, and perinatal asphyxia. Sample size limitations should be considered in interpreting these findings.     

Genetic susceptibility to febrile seizures: Case-control association studies

Objective: A genetic predisposition to febrile seizures (FS) has long been recognized. The inheritance appears to be polygenic in small families or sporadic cases of FS encountered in daily clinical practice. To determine whether candidate genes are responsible for the susceptibility to FS, we have performed genetic association studies in FS patients and controls. Methods: The single-nucleotide polymorphisms (SNPs) of genes involved in immune response (interleukin (IL) 1B), endocannabinoid signaling (CNR1), acid–base balance (SLC4A3, SLC9A1, SLC9A3), gap junction channel (CX43), and GABA_A receptor trafficking (PRIP1) were examined in 249 FS patients (186 simple and 63 complex FS) and 225 controls. Results: There were no significant differences in the allele frequencies of the SNPs between controls and all FS, simple FS, and complex FS patients. When the simple FS patients were divided into two groups according to either having (familial) or not having a family history of FS in close relatives (sporadic), there was a significant association between IL1B −511 SNP and sporadic simple FS (p = 0.003). Conclusions: These data suggest that cytokine genes may act as enhancers or attenuators of FS susceptibility. Genetic association study may be an effective approach to understanding the molecular basis of FS at least in a subgroup of patients.     

Risk factors for generalized tonic-clonic seizures: a population-based case-control study in Rochester, Minnesota

This investigation is, to our knowledge, the first population-based case-control study of prenatal, perinatal, and postnatal risk factors for generalized tonic-clonic seizures (GTCS). The clinical diagnosis of GTCS was confirmed through the independent review of the complete medical history of potential cases by three neurologists. All subjects with onset of GTCS before age 30 who were residents of Rochester, Minnesota at time of diagnosis between 1935 and 1979, and who were born in this community, were included (N = 53). Two controls were matched to each patient, and for both patients and controls, the unique records-linkage system for residents of Rochester was used to obtain information about possible risk factors. A history of convulsions in the mother, febrile seizures, and head trauma were significantly more common in cases than in controls. However, factors previously suggested such as: advanced age of the mother, previous miscarriages, gestational toxemia or eclampsia, bleeding during the index pregnancy, low birth weight, asphyxia, or postmaturity were not confirmed. Based on the present and previous studies, we suggest that different types of seizures have different risk factors and should, therefore, be investigated separately.     

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.     

Genetic and environmental contributions to neonatal brain structure: A twin study

Twin studies have found that global brain volumes, including total intracranial volume (ICV), total gray matter, and total white matter volumes are highly heritable in adults and older children. Very little is known about genetic and environmental contributions to brain structure in very young children and whether these contributions change over the course of development. We performed structural imaging on a 3T MR scanner of 217 neonatal twins, 41 same‐sex monozygotic, 50 same‐sex dizygotic pairs, and 35 “single” twins—neonates with brain scans unavailable for their co‐twins. Tissue segmentation and parcellation was performed, and structural equation modeling was used to estimate additive genetic, common environmental, and unique environmental effects on brain structure. Heritability of ICV (0.73) and total white matter volume (0.85) was high and similar to that described in older children and adults; the heritability of total gray matter (0.56) was somewhat lower. Heritability of lateral ventricle volume was high (0.71), whereas the heritability of cerebellar volume was low (0.17). Comparison with previous twin studies in older children and adults reveal that three general patterns of how heritability can change during postnatal brain development: (1) for global white matter volumes, heritability is comparable to reported heritability in adults, (2) for global gray matter volume and cerebellar volume, heritability increases with age, and (3) for lateral ventricle volume, heritability decreases with age. More detailed studies of the changes in the relative genetic and environmental effects on brain structure throughout early childhood development are needed. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Genetic epilepsy with febrile seizures plus: definite and borderline phenotypes

Generalised epilepsy with febrile seizures plus (GEFS+) is the most studied familial epilepsy syndrome. However, characteristics of UK families have not previously been reported. Among the first 80 families recruited to our families study, four broad subphenotypes were identified: families with classical GEFS+; families with borderline GEFS+; families with unclassified epilepsy; and families with an alternative syndromal diagnosis. Borderline GEFS+ families shared many characteristics of classical GEFS+ families-such as prominent febrile seizures plus and early onset febrile seizures-but included more adults with focal epilepsies (rather than the idiopathic generalised epilepsies predominating in GEFS+) and double the prevalence of migraine. Thus the authors believe that a novel and robust familial epilepsy phenotype has been identified. Subcategorising families with epilepsy is helpful in targeting both clinical and research resources. Most families with GEFS+ have no identified causal mutation, and so predicting genetic homogeneity by identifying endophenotypes becomes more important.     

Genetic literacy series: genetic epilepsy with febrile seizures plus

Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which affected individuals within a family typically have a variety of epilepsy phenotypes, varying from simple febrile seizures and febrile seizures plus with a good outcome to severe epileptic encephalopathies. Here, we review the spectrum of epilepsy phenotypes, the genetic architecture of GEFS+, and the implicated genes. Using an illustrative clinical case study, we describe important steps in managing patients with GEFS+: making the diagnosis of GEFS+, appropriate genetic testing, and counselling.