Concordance Rate In Monozygotic Twins Research Articles

Genetics of insulin-dependent diabetes mellitus.

IDDM is caused by autoimmune destruction of insulin-producing beta cells of the pancreas in genetically susceptible individuals. Although the incidence and prevalence if IDDM in Japan are much lower than those in Caucasian countries, the recurrence risk in siblings of IDDM probands is much higher than the population prevalence, indicating that IDDM is clustered in families even in Japan, where the incidence of the disease is the lowest in the world. The higher concordance rate in monozygotic twins than in dizygotic twins indicates that genetic factors contribute to the familial clustering of IDDM in Japan. Analysis of the HLA region revealed that susceptibility genes (IDDM1) consist of multiple components, those in class II DR and DQ regions and another in the class I region. Analysis in NOD mice, an animal model of IDDM, supports this observation: susceptibility genes (Idd1) are mapped to class II A and E regions, but the incidence of the disease is strongly affected by a gene or genes outside of this segment (Idd16). Studies in both humans and an animal model will clarify the genetic components of IDDM, facilitating prediction of the disease and the development of effective strategies for its prevention.

Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7.

Insulin-dependent diabetes mellitus (IDDM) is characterized by autoimmune destruction of the insulin secreting beta-cells of the pancreas and subsequent disruption of glucose metabolism. The tendency of IDDM to cluster in families and the modest (36%) concordance rate in monozygotic twins indicates that both genetic and environmental factors contribute to IDDM susceptibility. Recent genome-wide searches using the affected sib-pair (ASP) approach have provided evidence for novel loci, in addition to HLA (IDDM1) and insulin (IDDM2), which show evidence of linkage to IDDM (P < 0.05). We have evaluated 35 microsatellite marker loci on human chromosome 7 for linkage to IDDM in 339 affected sib-pair families. Increased sharing of parental haplotypes in affected sib-pairs was detected for two microsatellite markers flanking glucokinase (GCK). Preferential transmission of alleles to affected offspring was observed at one of these marker loci, GCK3, indicating linkage disequilibrium between the marker and a disease susceptibility locus. This combination of linkage and disease association suggests that glucokinase, or a gene in the vicinity, plays an important part in IDDM susceptibility.

Reply to 'A Genetic Study of Male Sexual Orientation'

To the Editor.— I am surprised that the article by Bailey and Pillard 1 was carried out, written, and published in the December 1991 edition of the ARCHIVES with so little regard for the problems in the numerous studies of the genetics of schizophrenia based on the comparison of incidence in monozygotic (MZ) and dizygotic (DZ) twins as well as the various adoption studies that have caused so much misunderstanding and confusion in the field. Are we now to go through the same misapplications of methodology and statistics to homosexuality? Kallmann 2 misled psychiatrists into the belief that schizophrenic disorders were almost entirely genetically determined. His very high concordance rate for MZ twins appears to have been due to his sampling of twins hospitalized for schizophrenia where concordance was generally only noted when both twins were schizophrenic. Further, the fact that DZ twin sisters were almost as concordant as MZ

HLA class II genes in primary sclerosing cholangitis and chronic inflammatory bowel disease: no HLA-DRw52a association in Swedish patients with sclerosing cholangitis.

The familial predisposition to chronic inflammatory bowel disease and the increased concordance rate in monozygotic twins with Crohn's disease, suggest that genetic factors influence disease susceptibility. A 100% association with the supertypic HLA class II specificity DRw52a was recently described in white North American patients with primary sclerosing cholangitis, with or without concurrent ulcerative colitis. HLA class II alleles of the DR, DQ, and DP subregions were determined by genomic typing techniques in a large group of Swedish patients with ulcerative colitis or Crohn's disease as well as in a series of patients with primary sclerosing cholangitis. No statistically significant HLA class II association was observed in any of the investigated diseases or when the patients were subgrouped according to disease site or occurrence of extraintestinal manifestations, except an insignificant increase of the DRw17, DQw2 haplotype in patients with primary sclerosing cholangitis. The failure to confirm the well established DRw17 association in Swedish patients with sclerosing cholangitis probably represents a statistical type II error. Furthermore, this study did not verify the recently described strong DRw52a association in sclerosing cholangitis--52% of the patients were DRw52a positive compared with 28% of the controls (p less than 0.05, pc NS). This discrepancy was probably caused by different typing techniques. The DRw52a specificity was determined directly by hybridising HLA-DRB3 genes, group specifically amplified by the polymerase chain reaction, with an allele specific oligonucleotide probe, whereas in the previously mentioned study DRw52a was assigned by indirect serological criteria, which overestimate the frequency of this allele.

Genetic factors in the etiology and pathogenesis of autoimmunity.

Family and population studies indicate that several different genes can increase susceptibility to autoimmune diseases. Established genetic risk factors include genes encoding histocompatibility molecules, complement proteins, immunoglobulins, peptide transporter proteins, and genes controlling the production of sex hormones. Each factor may independently enhance the immunogenicity of autoantigens, either by increasing their processing and presentation by B lymphocytes and macrophages or by increasing the chance for recognition by autoreactive T and B lymphocytes. Genetic factors may also influence immune responses to infectious agents that can trigger autoimmunity. Because of the somatic generation of immune diversity, genetically identical individuals have different immune systems. The ability of genetic diagnosis to predict autoimmune disease in outbred populations cannot easily exceed the disease concordance rates in monozygotic twins, which usually are less than 50%. However, genetic diagnosis can target populations that should be monitored for serologic evidence of autoimmunity, which may precede clinical signs and symptoms. In the future, it may be possible to match different forms of immunotherapy with specific genetic defects.

HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus

The analysis of HLA class II sequence variation in IDDM patients and controls, made possible by the PCR, has revealed that specific alleles are associated with IDDM. The HLA-DQ beta chain appears to play a role in determining genetic susceptibility and resistance, although polymorphisms in the DRB1, the DQ alpha, and the DP beta chain may also contribute. Although there is a correlation between susceptibility and the charge of DQ beta residue 57, the complex genetic epidemiology of IDDM cannot be accounted for by polymorphism at this position. As we have discussed previously (Horn et al, 1988a, 1988b; Erlich et al, 1990b), there are no unique class II sequences associated with IDDM, consistent with the view that 'normal' class II alleles confer susceptibility. Given the estimates of concordance of under 50% for monozygotic twins and approximately 15% (Tattersall and Pyke, 1972; Thomson, 1988) for HLA-identical sibs--it is not surprising that some unaffected individuals contain putative susceptibility alleles. Perhaps some environmental 'triggering' agent, such as viral infection, is required for the disease to develop in susceptible individuals. Other non-MHC-linked genes which contribute to susceptibility may account for the difference in concordance rates for monozygotic twins and for HLA-identical sibs. In the NOD (non-obese diabetic) mouse and the BB rat models for IDDM, non-MHC susceptibility loci have been identified and mapped (Colle et al, 1981; Hattori et al, 1986) but, in humans, the analysis of non-MHC candidate loci (i.e. the T cell receptor) has, thus far, failed to reveal any other susceptibility loci. In general, the HLA-linked genetic susceptibility to IDDM, as well as to other autoimmune diseases, appears to be associated with specific combinations of class II epitopes (e.g. alleles, haplotypes or genotypes) rather than with specific individual residues or epitopes. Understanding the role of these predisposing sequences will require structural analysis of the class II molecules as well as in vitro and in vivo functional studies of interactions with putative autoantigens and T cell receptors. In the meantime, DNA typing offers the potential for identifying individuals at high risk. These susceptible individuals could be monitored by immunological (e.g. anti-islet cell antibody) or by metabolic tests to detect the preclinical phase of IDDM.

The genetics of neurotic-reactive depression: a reanalysis of Shapiro's (1970) twin study using diagnostic criteria

The present study explored the role of genetic factors in the development of neurotic depression. Case studies of 16 monozygotic (MZ) and 14 same-sex dizygotic (DZ) twins from Robert Shapiro's 1970 study of non-endogenous depression were rediagnosed by two raters blind to the zygosity and identity of each twin. Diagnoses were made using Research Diagnostic Criteria (RDC) and George Winokur's 1985 criteria for neurotic-reactive depression. When neurotic depression was operationally defined using Winokur's criteria plus RDC major or definite minor depression, the concordance rate for MZ twins was significantly greater than that for DZ twins. Our results contrast with Shapiro's negative findings, probably due to our use of formal diagnostic criteria and Shapiro's requirement that cotwins be hospitalized to be considered concordant. The present results suggest that genetic factors play a role in the etiology of at least some forms of neurotic depression.

The contribution of HLA to rheumatoid arthritis.

The contribution of genes within the major histocompatibility complex to rheumatoid arthritis has been calculated (Rotter & Landaw 1984). Separate data from hospital- and population-based studies of monozygotic twin concordance rates and sibling recurrence risks have been used, along with material from published haplotype-sharing studies. Using either source of information gives the same result, a contribution of 37%.

Candidate for inherited neurobiological dysfunction in schizophrenia.

Schizophrenia is a mental illness that affects approximately 1% of the population. It generally begins in early adulthood and continues as a chronic illness for the individual's lifetime. It is characterized by hallucinations, which are unreal sensory sensations such as hearing voices that converse about oneself, and by delusions, which are unreal beliefs. The delusions are often paranoid; e.g., one is being spied on by the police. These symptoms are called positive symptoms and may show fluctuation over time. The periods of exacerbation are called acute psychotic episodes. While they can be partly treated with tranquilizing medication, the effects are generally not complete. In addition, the patient suffers negative symptoms, so called because they are an absence of normal behavior, rather than a clearly abnormal behavior like the hallucinations and delusions. The most common negative behavior is social isolation or reclusiveness. The combination of negative and positive symptoms generally results in severe mental disability. The inheritance of schizophrenia has been long hypothesized, but the evidence for a particular genetic mechanism has not been forthcoming.Epidemiologic studies show clustering of the illness in families (1), and twin adoption studies demonstrate that inherited biological elements are likely to be important in the pathophysiology of the illness (2). However, monozygotic twin concordance rates are rarely higher than 70%. Frequently, relatives show some signs reminiscent of the illness, such as severe shyness, suspiciousness, or magical thinking, but the relationship of these symptoms to schizophrenia is not clear. This state is termed schizotypy. It has been proposed that there must be an inherited schizotaxic factor which predisposes persons to either schizotypy or, in the presence of other genetic or environmental factors, to schizophrenia (3). However, this schizotaxic factor has not yet been identified. Were it to be identified, however, it might be a better candidate for genetic analysis than schizophrenia itself. Such a factor would be a basic element in the pathophysiology of schizophrenia and would be present in some form in relatives of schizophrenics as well. Among basic elements in the pathophysiology of schizophrenia, attention has been directed to problems in the regulation of responsiveness to sensory stimuli. These problems are apparent in first-person accounts of the illness, in which patients describe being unable to filter out extraneous sensory stimuli. They find noises around them very difficult to ignore. Consequently, they seem unable to pay attention to the important parts of their environment. For example, while talking to a

Symptoms and the genetics of schizophrenia: implications for diagnosis.

To determine whether genetic influences in schizophrenia are related to the symptoms specified by diagnostic criteria, the case histories of 151 pairs of monozygotic twins from five twin studies of schizophrenia were rated for positive and negative symptoms. Concordance rates in monozygotic twins were significantly higher when probands had a greater number of negative symptoms; no evidence of a similar relationship was found for positive symptoms. The data indicate that negative symptoms may be characteristic of schizophrenia in which there is a greater genetic component. The results have important implications for determining diagnostic criteria and understanding the pathogenesis of schizophrenia.

Genetic models of affective disorder: application to twin data.

Twin data on bipolar and unipolar affective disorders are analyzed by multiple threshold models of inheritance. The two illness types are represented in the models on a continuum of genetic–environmental liability in which bipolar illness has a higher liability threshold than unipolar disorder. Autosomal single major locus model provides an acceptable fit to observed concordance rates in monozygotic twins. The multifactorial-polygenic model is rejected.

Conditional concordance in monozygotic twins.

Twin concordance rates are usually reported without reference to the number of parents affected, apparently because the simple demonstration that monozygotic (MZ) twins are more concordant than are dizygotic (DZ) twins is the goal of most twin studies. Depending on the underlying mechanism, however, twin concordance rates can vary widely when conditioned on the number of parents affected. For the generalized single-locus model it is shown that conditional concordance rates in monozygotic twins, along with an estimate of the disorder's prevalence in the population, uniquely specify the underlying parameters of this important model. Knowledge of the exact parameter set is essential for competent genetic counseling.

Is Juvenile Diabetes Determined by a Single Gene Closely Linked to HLA?

The transmission behavior of insulin-dependent juvenile diabetes mellitus (JDM) has been studied with respect to its frequency in the relatives of JDM probands and its possible linkage to the HLA complex. Mathematical analysis shows that under a single locus hypothesis a very restricted range of incidence rates is possible in the full siblings of probands once the concordance rate in monozygotic (MZ) twins is specified. Specifically, for a given population prevalence of the disease, high concordance rates in MZ twins require high incidence rates in siblings, and low rates require low incidence rates, if a single locus model is th be valid. Moreover, if these rates do conform to a single locus model, then they give additional information about possible linkage between the purported JDM susceptibility gene and the HLA complex. By using observations on the identity by descent scores at the HLA locus of sibling pairs, both of whom are affected with JDM, it is shown that tight linkage of a disease susceptibility locus is possible only when the MZ twin and sibling incidence rates are low, whereas high rates support loose linkage. If the single locus model is rejected, then an alternative hypothesis, involving epistasis between a JDM susceptibility locus and genes in (or close to) the HLA complex can be suggested as a mechanism whereby JDM would appear to be linked to HLA within families while maintaining an association with HLA at the population level.

CONGENITAL CARDIAC MALFORMATIONS IN 109 SETS OF TWINS AND TRIPLETS

The distribution of specific defects among 107 sets of twins and 2 sets of triplets with cardiac malformations was found to be similar to that in the general population, but there were no cases of associated Down's syndrome. The mean age for mothers of twins, 27.49 years, was slightly higher than for mothers of all children with cardiac malformations because of the somewhat older age of mothers of dizygotic twins. The mean birth weight of affected twins, 2,198 g, was lower than for twins in general, and was lower for monozygotic than for dizygotic twins, and for affected twins than for their normal monozygotic or dizygotic cotwins. There was a disproportionately high percentage of monozygotic twins (58 percent), same-sex twins (81 percent) and females (62 percent). The concordance rate in monozygotic twins was 6.8 percent (8.2 percent if triplet couplets are included), approximating the 5 to 10 percent rate theoretically expetted on the basis of population and sibship data. For dizygotic twins the concordance rate was 2.3 percent (2.2 percent if triplet couplets are included), essentially the same as for siblings of children with cardiac malformations. Concordance for specificity of cardiac defect was very high in the few monozygotic twins who were concordant for cardiac malformation. A low concordance rate in monozygotic twins does not exclude. a significant role for genetic factors in the etiology of cardiac malformations.

Congenital Cardiac Malformations in 109 Sets of Twins and Triplets

The distribution of specific defects among 107 sets of twins and 2 sets of triplets with cardiac malformations was found to be similar to that in the general population, but there were no cases of associated Down's syndrome. The mean age for mothers of twins, 27.49 years, was slightly higher than for mothers of all children with cardiac malformations because of the somewhat older age of mothers of dizygotic twins. The mean birth weight of affected twins, 2,198 g, was lower than for twins in general, and was lower for monozygotic than for dizygotic twins, and for affected twins than for their normal monozygotic or dizygotic cotwins. There was a disproportionately high percentage of monozygotic twins (58 percent), same-sex twins (81 percent) and females (62 percent). The concordance rate in monozygotic twins was 6.8 percent (8.2 percent if triplet couplets are included), approximating the 5 to 10 percent rate theoretically expetted on the basis of population and sibship data. For dizygotic twins the concordance rate was 2.3 percent (2.2 percent if triplet couplets are included), essentially the same as for siblings of children with cardiac malformations. Concordance for specificity of cardiac defect was very high in the few monozygotic twins who were concordant for cardiac malformation. A low concordance rate in monozygotic twins does not exclude. a significant role for genetic factors in the etiology of cardiac malformations.

Electrodermal functioning in adopted-away offspring of schizophrenics

UNTIL recent years, the strongest evidence for the importance of genetic factors in the etiology of schizophrenia came from twin studies. Early investigations reported concordance rates for monozygotic twin pairs that, from a genetic point of view, were most encouraging, but encountered methodological problems concerning sample acquisition, diagnosis of cotwins, and determination of twinship.1-5 The recent investigations of Tienari,6 Kringlen, ’ Gottesman and Shields,* and Fischer et ~1.~ have taken care to avoid the problems of the earlier studies and have obtained concordance rates for monozygotic twins that are appreciably less than those of the earlier studies. More recently, new methods have been employed to unconfound the possible effects of rearing and genes. These studies, using an adoption strategy, have incontrovertibly demonstrated the importance of the role of genetics in the etiology of schizophrenia. HestonlO and Rosenthal et aZ.ll evaluated the personalities of individuals born to a schizophrenic parent and reared in foster (Heston) or adoptive homes (Rosenthal et al.). In both studies the offspring were compared to an appropriate control group of foster and/or adoptive offspring whose biological parents had no record of psychosis and who were matched to the index group for age, sex and type of placement. All subjects were evaluated by a psychiatric interview and psychological tests. Heston reports that 5 of the 47 offspring of schizophrenic mothers had been hospitalized with a diagnosis of schizophrenia, and 8 were diagnosed as “schizoid psychopath,” for a total of 28 per cent of the index sample. None of the 50 controls was so diagnosed. In a still preliminary report, Rosenthal et al. found 3 diagnosed schizophrenics, 9 borderline schizophrenics, and 10 schizoid or “doubtful borderline” index cases among their sample of 69 offspring for a total of 32 per cent with a “schizophrenia spectrum diagnosis.” None of the 67 matched controls exhibited process schziophrenia, while 12 were diagnosed as borderline or schizoid for a total of 18 per cent. In both studies combined, 7 per cent of the index cases were chronic schizophrenics and 23 per cent were borderline or schizoid. Kety et a1.,1= using the adoption method in a different way, examined the prevalence of

Childhood leukemia in California-born twins.

In a study of the childhood leukemia experience in a California twin birth cohort, there was an apparent deficit of leukemia in twins compared to the occurrence in single births. The rough estimate of the deficit of leukemia in monozygotic twins tends to confirm that found in 2 other studies. The concordance rate for monozygotic twins was estimated to be 25%, which is in agreement with that made by MacMahon and Levy. Relative to the comparison group, the leukemic twins and their unaffected co-twins had a significantly greater disparity in birth weights, and heavy leukemic females made the greatest contribution to this result. More first-born twins died of leukemia than second-born, but an independent twin birth order effect was not shown when birth weight and sex composition were controlled.

Chromosome studies in patients with affective disorder (manic-depressive illness).

CONSIDERABLE evidence points to a genetically determined predisposition to affective disorder. In Kallman's study, the concordance rate for monozygotic twins was 100%; for dizygotic twins, 25.5%; for full siblings, 22.7%; for half siblings, 16.7%; and for parents of probands, 23.4%.¹Winokur and Pitts^2,3have presented data showing that siblings and parents of affective disorder probands have a higher rate of affective disorder themselves than the siblings and parents of control subjects. Chromosome studies have been reported on schizophrenics^4,5and other groups of psychiatric patients,⁶but not on a group of manic-depressive patients. <h3>Materials and Methods</h3> All of the patients with affective disorder were adults and met the criteria of Cassidy et al⁷for the diagnosis of manic-depressive illness. During the first phase of this project, 13 patients with affective disorder were studied. Of these, ten patients had a positive family history

Factors precipitating and predisposing to R. A. as illustrated by studies on monozygotic twins.

SummaryAn attempt was made to elucidate the relative importance of heredity and exogenous factors in the etiology of rheumatoid arthritis by a study of the concordance rate in monozygotic twins. Four sets of such monozygotic twins are reported and discussed. Three of them were discordant and one concordant, but with an atypical syndrome. When added to previously published cases in monozygotic twins, these cases bring the number up to 50 sets of monozygotic twins with rheumatoid arthritis 32 or 64 % of whom have shown discordance. It is concluded that an exogenous factor must be operative.