Concordance In Monozygotic Twins Research Articles

A 'sticky' interhemispheric switch in bipolar disorder?

Despite years of research into bipolar disorder (manic depression), its underlying pathophysiology remains elusive. It is widely acknowledged that the disorder is strongly heritable, but the genetics are complex with less than full concordance in monozygotic twins and at least four susceptibility loci identified. We propose that bipolar disorder is the result of a genetic propensity for slow interhemispheric switching mechanisms that become 'stuck' in one or the other state. Because slow switches are also 'sticky' when compared with fast switches, the clinical manifestations of bipolar disorder may be explained by hemispheric activation being 'stuck' on the left (mania) or on the right (depression). Support for this 'sticky' interhemispheric switching hypothesis stems from our recent observation that the rate of perceptual alternation in binocular rivalry is slow in euthymic subjects with bipolar disorder (n = 18, median = 0.27 Hz) compared with normal controls (n = 49, median = 0.60 Hz, p < 0.0005). We have presented evidence elsewhere that binocular rivalry is itself an interhemispheric switching phenomenon. The rivalry alternation rate (putative interhemispheric switch rate) is robust in a given individual, with a test-retest correlation of more than 0.8, making it suitable for genetic studies. The interhemispheric switch rate may provide a trait-dependent biological marker for bipolar disorder.

Identical twins discordant for Sotos syndrome

The cause of Sotos syndrome is unknown but it usually occurs sporadically. Recent studies have shown no evidence of uniparental disomy. One set of concordant monozygotic twins has been reported. We have identified the Sotos syndrome in one of two 5-year-old male monozygotic twins. Our finding of discordance in these identical twins suggests that a postconceptual mutation, or epigenetic change and/or an environmental factor may be involved in the cause of Sotos syndrome.

Typology of common psychiatric syndromes. An empirical study.

Diagnostic comorbidity is prevalent in psychiatry and may be inadequately captured by the DSM-III/III-R nosology. The lifetime presence of II psychiatric diagnoses was determined by structured personal interviews of a population-based sample of 1898 female twins. We used latent class analysis to derive an empirical typology. Six classes provided the best fit to the data. Their mnemonics were: minimal disorder (60% of the sample), major depression-generalised anxiety disorder (19%), alcohol-nicotine (7%), highly comorbid major depression (5%) and eating disorders (3%). The validity of this typology was strongly supported by demographic, health, personality and attitudinal validators along with the significant monozygotic twin concordance for class membership. The typology superficially resembled DSM-III-R, but contained many differences. Major depression appeared in three forms (alone, with generalised anxiety disorder and with considerable comorbidity). Alcoholism-nicotine dependence and the various anxiety disorders formed discrete classes, but were also prominent in other classes. Bulimia and anorexia were exceptional in their appearance in a single class. The DSM-III-R and closely related DSM-IV nosology did not capture the natural tendency of these disorders to co-occur. Fundamental assumptions of the dominant diagnostic schemata may be incorrect.

Destiny rides again

Destiny rides again

Genetic epidemiology of schizophrenia: review and reassessment.

When a rigorous methodological approach is utilized, a substantial majority of recent studies provide evidence for the familial transmission of schizophrenia. Although the absolute rates of schizophrenia among relatives of schizophrenics tend to be lower than those reported in the earlier studies due to the restrictiveness of contemporary definitions of schizophrenia, the risk to relatives compared to that of controls has remained quite consistent. This observation that relatives of schizophrenics have an elevated risk for schizophrenia compared to controls is consistent with theories of both genetic and environmental transmission. Twin studies of schizophrenia have consistently reported greater concordance rates for monozygotic than dizygotic twins. Although this indicates the importance of genetic factors, the less than 100% concordance for monozygotic twins observed in every study indicates that nongenetic factors also play a role in the etiology of schizophrenia. Further, adoption studies offer an opportunity to unconfound genes and environment. The findings of adoption studies confirm that there are genetic components for schizophrenia. Even though we have shown that family, twin, and adoption studies have provided strong evidence for the role of genetic factors in schizophrenia, the mode of transmission remains unclear. The results of mathematical modeling studies do not support the single gene model. There is somewhat more support for the multifactorial polygenic model, but the model has also been rejected in several studies. Thus, the pattern of inheritance of schizophrenia has eluded an unambiguous characterization. Genetic linkage analysis promised to clarify the mechanisms of transmission, but early positive reports were subsequently overturned and, to date, there are no consistently replicated positive linkage findings for schizophrenia. There is now a world-wide search for the location of the genes on specific chromosomes which are responsible for schizophrenia. The clinical implications of current work to the future of locating a schizophrenic gene or genes will be discussed.

An update on the genetic basis of type 2 diabetes

A striking familial aggregation, high concordance in monozygotic twins, and segregation analyses all support the notion of a major genetic susceptibility for type 2 diabetes. Several genetic loci that result in autosomal dominant insulin secretion defects and onset of type 2 diabetes before 25 years of age have been identified. These discoveries have uncovered a new pathway, the transcription factors hepatocyte nuclear factor 1α and 4α, and possibly other genes in these regulatory pathways. However, these genes play at most a small role in the more typical late-onset type 2 diabetes. Studies of candidate genes for insulin secretion and insulin sensitivity have likewise explained little about diabetes susceptibility. Common amino acid variants of the insulin receptor substrate 1 gene appear to have a small role, as does a common variant of the intestinal fatty acid binding protein and the β3-adrenergic receptor gene, but inconsistent findings argue that these polymorphisms do not explain most cases of diabetes susceptibility. Likewise, an unexplained association of the sulfonylurea receptor gene with type 2 diabetes seems unlikely to represent a major locus. Genome-wide scans remain in their infancy, but several promising findings may lead to new genes. These include the NIDDM1 locus on chromosome 2q, evidence for a locus somewhere on chromosome 20, and evidence in both Pima Indians and a US population of Northern European descent for a locus near the apolipoprotein A-2 locus on chromosome 1. Future studies, particularly combined analyses of groups currently working independently, will better define new diabetes genes.

Extreme Th1 bias of invariant Vα24JαQ T cells in type 1 diabetes

Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) is a disease controlled by the major histocompatibility complex (MHC) which results from T-cell-mediated destruction of pancreatic beta-cells. The incomplete concordance in identical twins and the presence of autoreactive T cells and autoantibodies in individuals who do not develop diabetes suggest that other abnormalities must occur in the immune system for disease to result. We therefore investigated a series of at-risk non-progressors and type 1 diabetic patients (including five identical twin/triplet sets discordant for disease). The diabetic siblings had lower frequencies of CD4-CD8- Valpha24JalphaQ+ T cells compared with their non-diabetic sibling. All 56 Valpha24JalphaQ+ clones isolated from the diabetic twins/triplets secreted only interferon (IFN)-gamma upon stimulation; in contrast, 76 of 79 clones from the at-risk non-progressors and normals secreted both interleukin (IL)-4 and IFN-gamma. Half of the at-risk non-progressors had high serum levels of IL-4 and IFN-gamma. These results support a model for IDDM in which Thl-cell-mediated tissue damage is initially regulated by Valpha24JalphaQ+ T cells producing both cytokines; the loss of their capacity to secrete IL-4 is correlated with IDDM.

Classical Rett syndrome in sisters: variability of clinical expression

Familial cases of Rett syndrome (RS) are rare. No significant differences have been reported in the clinical courses of concordant monozygotic twins with RS. We present the variability of clinical expression in two Japanese sisters with classic RS. The younger sister, currently 6 years and 6 months old, never stood or walked alone, showed severe spasticity, growth retardation, and microcephaly and developed sleep-wake rhythm disturbance from age 4 years and seizures from age 5 years. The elder, currently 7 years and 9 months old, walked alone and had mild spasticity, no growth retardation, normal sleep-wakefulness rhythm and no seizures. RS is most likely to be transmitted as an X-linked dominant, male-lethal (XDML) disorder, although this is still contested. If RS is an XDML disorder, lyonization may account for variability of expression in the sisters.

The Genetics of Human Noninsulin-Dependent (Type 2) Diabetes Mellitus

Familial aggregation and concordance in monozygotic and dizygotic twins argue strongly for a genetic etiology to noninsulin-dependent diabetes (NIDDM). Nonetheless, studies of pathways implicated by the known physiology have failed to identify gene defects that can explain the genetic susceptibility. In contrast, studies of early onset dominant diabetes have revealed three major loci resulting in diminished insulin secretion. Recently, studies have taken a new approach to map the genes causing typical NIDDM using large numbers of families or sibling pairs. The first reports of these studies have suggested possible loci on chromosomes 1, 2 and 12, but no report has been confirmed. Other studies have examined the quantitative defects that may be precursors of clinical NIDDM such as hyperinsulinemia, hyperglycemia, insulin response to glucose and obesity. These studies have suggested additional loci that may contribute to NIDDM susceptibility, but the genes responsible for most of these loci remain unknown. Studies of NIDDM susceptibility and the role of obesity genes in that susceptibility have entered an exciting new phase, but the challenges of complex disease genetics in humans will have to be conquered to translate this research into preventive or therapeutic benefits.

Evidence that a locus for familial psoriasis maps to chromosome 4q.

Psoriasis is an inflammatory skin disease that affects 2% of the population. It is characterised by red, scaly skin patches which are usually found on the scalp, elbows and knees, and may be associated with severe arthropathy. The lesions are caused by abnormal keratinocyte proliferation, and infiltration of inflammatory cells into the dermis and epidermis. The usual age of onset of psoriasis is between 15 and 30 years, although it can present at any age. Psoriasis is recognised to have a large genetic component. Twin studies show the concordance in monozygotic twins to be between 65-70%, compared to between 15-20% in dizygotic twins. Family studies estimate the risk to first degree relatives at between 8-23%. However, there are also several environmental factors, including streptococcal infection and stress, that affect the onset and presentation of the disease. The mode of inheritance of psoriasis is unclear. We conducted a genome-wide scan to search for psoriasis susceptibility loci in a single large multiplex family. Parametric linkage analysis indicated that a susceptibility locus for familial psoriasis was located on chromosome 4q. Investigation of this locus in five further multiplex families using both parametric and non-parametric methods gave significant localisation to chromosome 4q. The maximum total pairwise lod score obtained was 3.03 with the microsatellite marker D4S1535 at theta = 0.08. Non-parametric multipoint analysis with GENEHUNTER- demonstrated significant excess allele sharing, with a P value of 0.0026, at the same locus.

Familial Temporal Lobe Epilepsy in Twins

A new syndrome of familial temporal lobe epilepsy is described in 38 subjects from 13 unrelated families and was first identified in 5 concordant monozygotic twin pairs at the Australian National Health and Medical Research Council Twin Registry, University of Melbourne, Parkville, Australia.

Familial temporal lobe epilepsy: a common disorder identified in twins.

We describe a new syndrome of familial temporal lobe epilepsy in 38 individuals from 13 unrelated white families. The disorder was first identified in 5 concordant monozygotic twin pairs as part of a large-scale twin study of epilepsy. When idiopathic partial epilepsy syndromes were excluded, the 5 pairs accounted for 23% of monozygotic pairs with partial epilepsies, and 38% of monozygotic pairs with partial epilepsy and no known etiology. Seizure onset for twin and nontwin subjects usually occurred during adolescence or early adult life. Seizure types were simple partial seizures with psychic or autonomic symptoms, infrequent complex partial seizures, and rare secondarily generalized seizures. Electroencephalograms revealed sparse focal temporal interictal epileptiform discharges in 22% of subjects. Magnetic resonance images appeared normal. Nine affected family members (24%) had not been diagnosed prior to the study. Pedigree analysis suggested autosomal dominant inheritance with age-dependent penetrance. The estimated segregation ratio was 0.3, indicating an overall penetrance of 60% assuming autosomal dominant inheritance. The mild and often subtle nature of the symptoms in some family members may account for lack of prior recognition of this common familial partial epilepsy. This disorder has similarities to the El mouse, a genetic model of temporal lobe epilepsy with a major gene on mouse chromosome 9, which is homologous with a region on human chromosome 3.

Inheritance of randomness

The mouse mutant iv is characterized by ‘a random determination of a developmental process‘ in that 50 rather than 100% of the homozygotes have situs inversus. The same explanation is given to the inheritance of situs inversus in the human immotile-cilia syndrome. There are probably two alleles of the responsible gene, one for control of the proper asymmetry and one without control and hence resulting in equal numbers of situs solitus and situs inversus in the homozygote. Left-handedness may be similarly inherited; furthermore, because of its high prevalence (around 10–12%) it has been assumed that there is an advantage of carrying both alleles (‘balanced polymorphism’). With these two assumptions, a prevalence of left-handedness of 12.5% is expected, a 50% chance of left-handedness in matings between two left-handed persons, and equal numbers of discordant and left-handed concordant monozygotic twins. These values are close to those actually found. As the values for (female) homosexuality are similar to those of left-handedness a similar inheritance is proposed.

Genetic factors in the presence, severity, and triggers of asthma.

The role of heredity in the presence of asthma, severity of the condition, and impact of 12 specific triggers of attacks was investigated. Health surveys containing questions about children's asthma characteristics were completed by 325 families with twin children across the United States. Data for 39 monozygotic twin pairs and 55 same sex dizygotic twin pairs who were between 2 and 20 years of age and had asthma present in at least one member of each pair were received and analysed. Results revealed higher concordance for the presence of asthma among monozygotic (58.97%; n = 23) than dizygotic twins (23.64%; n = 13). Further analyses were restricted to data from the concordant monozygotic and dizygotic twin pairs. Asthma severity (the product of attack frequency and intensity ratings) was significantly correlated for monozygotic pairs but not for dizygotic pairs, and this difference in monozygotic and dizygotic severity correlations was significant. Also, monozygotic twins showed significantly higher correlations than dizygotic twins for the impacts of two asthma triggers: respiratory infection and physical activity. These results indicate a role of heredity in the presence of asthma and suggest that genetic factors may also affect the severity of children's asthma condition and the impact of respiratory infection and physical exertion as asthma triggers.

Genetic epidemiology of rheumatoid disease.

The aetiology of rheumatoid arthritis (RA) has both genetic and environmental origins. However, the relationship of these with each other and with RA disease is complicated as both genes and environment may be protective or render individuals susceptible. Diagnostic certainty and disease heterogeneity have posed serious hurdles for investigating RA. Patients with similar disease phenotypes may have different aetiologies and it may now be more appropriate to investigate genetic susceptibility with respect to disease process or characteristic immunopathology. Disease concordance studies have been a classical approach to estimating the upper threshold of the genetic contribution to RA and recent studies have approximately halved the much quoted figure of 32% reported by Lawrence for RA concordance in monozygotic twins. However, the interpretation of twin data has to be treated with caution as MZ twins can differ in terms of somatic rearrangement/mutation of immunoglobulin and T cell receptor genes, X chromosome inactivation in females, genomic imprinting and in utero immune relationship. Calculations based on heritability put the genetic component in RA much higher. HLA is an important genetic factor in RA and risk is thought to be associated with a consensus sequence of amino acids within the third hypervariable region of certain DRB1 alleles. It is now clear that HLA is not particularly associated with onset of synovitis but is more associated with progression and severity of the disease process. The HLA-DRB1*0401/0404 genotype is particularly associated with severe, erosive and seropositive RA. Clear differences in RA susceptibility exist between males and females and this may be attributed to hormonal status. Males have a higher threshold requirement for developing RA and this may explain why RA in males is more associated with HLA risk alleles. We have now reached a critical time for the investigation of RA aetio-pathology. Recent advances in molecular biology and automated microsatellite gene scanning technology are making it possible to map disease susceptibility genes over the whole genome in common disorders such as RA. This will require large numbers of well characterised multiplex affected families. It is anticipated that some of the genes identified will fit in with our current concepts of which inflammatory and immune processes are pathologically important in RA. However others may be a major surprise.

Twins With Schizophrenia: Genes or Germs?

High concordance for schizophrenia in monozygotic (MZ) twins is often cited as evidence for the etiological influence of genetics; however, even if twins are separated at birth, MZ twin concordance is influenced by the shared prenatal environment. Study of the placentation status of MZ twins provides a way to investigate some prenatal influences, including the possible role of viral infections. The probability of shared infections is likely to be greater in monochorionic MZ twin pairs than in dichorionic pairs because of shared fetal circulation in the monochorionic pairs. We drew from published twin studies and used reported concordance for handedness as a retrospective marker of placentation status. We found that MZ twin pairs with opposite-hand preferences were concordant for psychosis in 9 of 15 cases (60%), while only 18 of 56 twin pairs (32%) with same-hand preferences were concordant for psychosis. These results suggest that shared prenatal viral infection may account for much of the high concordance for schizophrenia in identical twins.

Epidemiology of Psoriasis: Clinical Issues.

Psoriasis is a genetically inherited spectrum of skin diseases characterized by epidermal proliferation and inflammation, which are reversible. Although many have reported that psoriasis is triggered by trauma, infections, stress, drugs, etc., the epidemiology of psoriasis remains poorly understood. Linkage to human leukocyte antigen-(HLA)-Cw6 and DR7 is strong in people with early onset disease, but concordance in monozygotic twins is only 67%, emphasizing the importance of a triggering event. Other factors that have been reported to affect the course of psoriasis include upper respiratory infections, smoking, obesity, alcohol ingestion, regional enteritis, and human immunodeficiency virus infection. This manuscript reviews the clinical epidemiology of psoriasis and highlights some of the needs for further investigation into specific areas of the disease.

"Homozygosity" for the HLA-DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins.

To assess the contribution of HLA-DRB1 alleles in determining rheumatoid arthritis (RA) concordance in monozygotic twins. Ninety-one monozygotic twins pairs in which at least 1 twin was affected were typed for HLA-DRB1 using both serologic methods and polymerase chain reaction amplification with sequence-specific oligonucleotide hybridization. The role of DR4 and of the shared epitope in disease concordance was investigated. Relative risks (RR) with 95% confidence intervals were determined. Increased concordance for RA was observed in both DR4 positive and shared epitope positive pairs (RR 3.4 and 3.7, respectively). A 5-fold risk for RA concordance was seen in twins who were "homozygous" for the shared epitope, compared with those negative for the shared epitope. In the absence of the shared epitope, RA concordance in monozygotic twins is rare. In contrast, "homozygosity" for the shared epitope is the most important factor in determining RA concordance.

Genetics and multiple sclerosis: an overview.

There is evidence to support the view that multiple sclerosis is a complex trait determined by both genetic and environmental factors. The genetic component is reflected in the higher rate of concordance in monozygotic versus dizygotic twins and in familial recurrence risk data. These data fit best with oligogenic hypotheses encompassing epistatic interactions. However, confirmation will require comprehensive linkage studies using techniques that can rapidly screen the entire genome. The number of families required to demonstrate the effects of a locus such as the major histocompatibility complex is very large.

Skewed T-cell receptor repertoire in genetically identical twins correlates with multiple sclerosis.

Although the cause of multiple sclerosis (MS) is unknown, it is thought to involve a T cell-mediated autoimmune mechanism. Susceptibility to the disease is influenced by genetic factors such as genes of the HLA and T-cell receptor (TCR) complex. Other evidence for a genetic influence includes the low incidence in certain ethnic groups, the increased risk if there are affected family members and the increased concordance rate for disease in monozygotic twin pairs (26%), compared to dizygotic twins. Epidemiological studies indicate that there may be an additional role for environmental factors. Although the target antigen(s) are not yet identified, several myelin or myelin-associated proteins have been suspected, among them myelin basic protein. A lack of genetically comparable controls has impaired the analysis of the T-cell response in MS patients and caused disagreement on TCR usage in the disease. Here we analyse the role of TCR genes in MS by comparing TCR usage in discordant versus concordant monozygotic twins in response to self and foreign antigens. We find that after stimulation with myelin basic protein or tetanus toxoid, control twin sets as well as concordant twin sets select similar V alpha chains. Only the discordant twin sets select different TCRs after stimulation with antigens. Thus exogenous factors or the disease shape the TCR repertoire in MS patients, as seen by comparison with unaffected genetically identical individuals. This skewing of the TCR repertoire could contribute to the pathogenesis of MS and other T-cell-mediated diseases.