Monozygotic twins discordant for schizophrenia: A review.

Describes 3 approaches using monozygotic twins discordant for schizophrenia. It is noted that comparisons of discordant with concordant pairs have yielded conflicting results concerning the possibility of both genetic and environmentally induced forms of schizophrenia. Life history comparisons of schizophrenics with their nonschizophrenic co-twins have revealed consistent early differences in personality and parental treatment; investigators disagree, however, on the relationship of birth weight to schizophrenic development. Relatively few studies have been done of concordance for personality or performance traits among monozygotic twins discordant for schizophrenic diagnosis. It is suggested that this 3rd type of research holds great promise for identifying fundamental manifestations of the schizophrenic genotype, that higher female concordance rates make female discordance worthy of greater attention, and that investigations of environmental influences on the development of schizophrenia neglect less the possible positive influences which may buffer against schizophrenic breakdown. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The genetic susceptibility to Graves' disease

Graves' disease (GD) develops as a result of a complex interaction between genetic susceptibility genes and likely environmental factors. Most epidemiological data support an important genetic contribution to the development of GD. The concordance rate of GD in monozygotic twins is 30-60% and in dizygotic twins 3-9%, and thyroid autoantibodies have been reported in up to 50% of the siblings of patients with GD. For many years now, HLA studies have consistently shown an increased frequency of HLA-DR3 in Caucasian patients with GD; but with only a risk ratio of 3-5. However, recent advances in human genome mapping techniques have enabled the study of many other candidate genes. Of these additional, non-HLA genes, only CTLA-4 has been consistently found to be associated with GD. Using a linkage based approach which only detects highly significant susceptibility genes we have recently reported preliminary results which demonstrated that a marker located approximately 25 cM from the TSH receptor gene on chromosome 14q31 is linked to GD and in the same vicinity as the IDDM-11 locus. Such results, if confirmed, may signal the presence of a gene family related to endocrine autoimmunity on chromosome 14q31.     

Attempts to develop an efficient speech test in fully modulated noise

We have estimated how much of the total genetic predisposition to SLE may be attributable to genes outside the HLA region by comparing figures for concordance of SLE in monozygotic twins with those for concordance in HLA identical siblings in Australia. None of six dizygotic co-twins of white Australian SLE probands was concordant for SLE. One of four (25%) monozygotic co-twins of white Australian SLE probands was concordant for SLE which when added to previously published figures for Caucasoid populations gives an overall concordance rate for SLE in monozygotic twins of 25%. None of 18 HLA identical, same sex siblings of SLE probands, had definite SLE by the study criteria (i.e. less than 6%). The comparison of these figures shows that most of the genetic predisposition to SLE is attributable to genes outside the HLA region.     

Modified intra-arterial calcium stimulation with venous sampling test for preoperative localization of insulinomas

BACKGROUND: Both genetic and environmental factors are thought to contribute to specific IgE responses, however, the relative contribution of each in the responses to individual ryegrass pollen allergens is largely unknown even though some responses to allergens have been linked to certain HLA complexes. OBJECTIVE: Using a large group of monozygotic and dizygotic twins, this study was designed to investigate the IgE binding profiles of individual ryegrass pollen (Lolium perenne) components to assess the relative contribution of genetic and environmental factors in determining IgE responses to specific allergens. METHODS: Ryegrass pollen proteins were separated by electrophoresis and immunoblotted with sera from 191 pairs of twins where at least one sibling had a SPT > 2 mm to perennial ryegrass. Concordance levels for individual ryegrass pollen components were compared between monozygotic and dizygotic twins in a subset group where both twins had SPT > 3 mm to perennial ryegrass. RESULTS: Immunoblotting revealed 23 individual IgE-binding components from ryegrass pollen. Although there was a significantly greater proportion of monozygotic twins with SPT wheals greater than 3 mm when compared with the dizygotic twins, the mean case-wise concordance for the immunoblot components was similar for both groups of twins. The mean case-wise concordance when at least four pairs of sera were involved was 44% for the MZ twins (n=11 components) and 45% for the DZ twins (n=12 components). We found no significant differences in concordance levels for any of the 23 individual components including allergens previously associated with HLA. CONCLUSION: Evidence for genetic control of allergen-specific IgE responses in a large population sample of twins to individual ryegrass allergens is limited, indicating that the IgE responses to specific ryegrass pollen allergens are determined largely by environmental factors.     

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.     

Genetic and environmental factors in relative body weight and human adiposity

We review the literature on the familial resemblance of body mass index (BMI) and other adiposity measures and find strikingly convergent results for a variety of relationships. Results from twin studies suggest that genetic factors explain 50 to 90% of the variance in BMI. Family studies generally report estimates of parent-offspring and sibling correlations in agreement with heritabilities of 20 to 80%. Data from adoption studies are consistent with genetic factors accounting for 20 to 60% of the variation in BMI. Based on data from more than 25,000 twin pairs and 50,000 biological and adoptive family members, the weighted mean correlations are .74 for MZ twins, .32 for DZ twins, .25 for siblings, .19 for parent-offspring pairs, .06 for adoptive relatives, and .12 for spouses. Advantages and disadvantages of twin, family, and adoption studies are reviewed. Data from the Virginia 30,000, including twins and their parents, siblings, spouses, and children, were analyzed using a structural equation model (Stealth) which estimates additive and dominance genetic variance, cultural transmission, assortative mating, nonparental shared environment, and special twin and MZ twin environmental variance. Genetic factors explained 67% of the variance in males and females, of which half is due to dominance. A small proportion of the genetic variance was attributed to the consequences of assortative mating. The remainder of the variance is accounted for by unique environmental factors, of which 7% is correlated across twins. No evidence was found for a special MZ twin environment, thereby supporting the equal environment assumption. These results are consistent with other studies in suggesting that genetic factors play a significant role in the causes of individual differences in relative body weight and human adiposity.     

Genetic loadings in schizophrenia: a dermatoglyphic study

Finger and palmar dermatoglyphics of 120 male and 120 female schizophrenics with and without a family history of schizophrenia in first-degree relatives were studied in the northwestern part of India. Patients were selected according to specific diagnostic criteria. Significant dermatoglyphic differences were observed for fingerprint patterns, total finger ridge counts and 'atd' angle between the schizophrenics with and those without a positive family history of schizophrenia, suggesting a strong "genetic loading" (i.e., hereditary factors) in familial cases of schizophrenia. Dermatoglyphic features of isolated schizophrenics also significantly differed from those of controls, thus indicating the involvement of genetic factors in the etiology of schizophrenia.     

Modification of pentasaccharide core of surface N-glycans during differentiation of HL-60 cells

Graves' disease (GD) is generally thought of as a multifactorial disorder in which genetic susceptibility interacts with environmental and endogenous factors to cause disease. The importance of genetic factors is suggested by the clustering of GD within families and by a higher concordance rate for disease in monozygotic than dizygotic twins. This has, however, recently been shown to be less pronounced than previously thought. During the last decade, much effort has been put into characterization of the genetic background of GD. Until recently most studies have examined associations between GD and the human leukocyte antigen (HLA) region, but recent advances in molecular techniques have opened the way for whole-genome screening. A number of HLA and non-HLA candidate genes have been proposed, but despite several large investigations within multiplex families no major susceptibility genes have been identified. This brief review discusses relevant articles published from 1940 through 1997 regarding the influence of genetic factors in the etiology of GD. Ongoing studies will focus on whole genome screening in multiplex families as well as population based twin studies. However, the possibility of GD being a heterogeneous disease without a single well-defined genotype and phenotype should be left open.     

Genetics of coeliac disease

Coeliac disease is one of the most common gastrointestinal disorders. The clinical features of the disease are protean, possibly due to heterogeneity. A familial basis for coeliac disease is well recognized, and although a strong HLA association is seen, this cannot entirely account for the increased risk seen in relatives of affected cases. A gene (or genes) at an HLA-unlinked locus also participates in causing coeliac disease and is likely to be a stronger determinant of disease susceptibility than the HLA locus. Such a gene (or genes) could theoretically act either additively or multiplicatively in conjunction with HLA. However, the familial risks seen in siblings and monozygotic twins are most parsimonious with a multiplicative model. Without evidence for a particular HLA-unlinked gene, and because no genetic model can be reliably ascribed to the non-HLA-linked locus, identifying causative non-linked HLA genes is likely to be through a genome-wide linkage search using non-parametric methods.     

Sexual victimization in adolescent girls (age 15-20 years) enrolled in post-mandatory schools or professional training programmes in Switzerland

We investigated 21 pairs of twins for zygosity and idiopathic scoliosis. DNA fingerprinting confirmed that 13 pairs were monozygotic and eight were dizygotic. There was concordance for idiopathic scoliosis in 92.3% of monozygotic and 62.5% of dizygotic twins. Of the 12 pairs of monozygotic twins concordant for idiopathic scoliosis, six showed discordant curve patterns but eight had differences in Cobb angle of less than 10 degrees. Seven of the ten pairs of monozygotic twins had similar back shapes. Our findings suggest that there is a genetic factor in the aetiology of idiopathic scoliosis; they also indicate that there is a genetic factor in both the severity of the curve and the general shape of the back.     

Parkinson disease in twins: an etiologic study

CONTEXT: The cause of Parkinson disease (PD) is unknown. Genetic linkages have been identified in families with PD, but whether most PD is inherited has not been determined. OBJECTIVE: To assess genetic inheritance of PD by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. DESIGN: Twin study comparing concordance rates of PD in MZ and DZ twin pairs. SETTING AND PARTICIPANTS: A total of 19842 white male twins enrolled in the National Academy of Sciences/National Research Council World War II Veteran Twins Registry were screened for PD and standard diagnostic criteria for PD were applied. Zygosity was determined by polymerase chain reaction or questionnaire. MAIN OUTCOME MEASURE: Parkinson disease concordance in twin pairs, stratified by zygosity and age at diagnosis. RESULTS: Of 268 twins with suspected parkinsonism and 250 presumed unaffected twin brothers, 193 twins with PD were identified (concordance-adjusted prevalence, 8.67/1000). In 71 MZ and 90 DZ pairs with complete diagnoses, pairwise concordance was similar (0.129 overall, 0.155 MZ, 0.111 DZ; relative risk, 1.39; 95% confidence interval, 0.63-3.1). In 16 pairs with diagnosis at or before age 50 years in at least 1 twin, MZ concordance was 1.0 (4 pairs), and DZ was 0.167 (relative risk, 6.0; 95% confidence interval, 1.69-21.26). CONCLUSIONS: The similarity in concordance overall indicates that genetic factors do not play a major role in causing typical PD. No genetic component is evident when the disease begins after age 50 years. However, genetic factors appear to be important when disease begins at or before age 50 years.     

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.     

The heritability of cognitive functioning in very old adults: Evidence from Danish twins aged 75 years and older.

Heritable influences on cognitive functioning were investigated in a sample of 403 pairs of like-sex Danish twins aged 75 years and older. Twins completed the Mini-Mental State Examination and 3 other cognitive tests. Genetic factors accounted for 26–54% of the variance on these measures, with the balance being due to environmental factors that create differences rather than similarities among reared-together relatives. Deleting twins with severe cognitive impairment had little effect on the results, indicating that the heritability of cognitive functioning was not due entirely to genes affecting dementia. Neither age nor gender moderated twin similarity, and differential social contact could not account for correlation differences between monozygotic and dizygotic twins. These results replicate G. E. McClearn et al.'s (1997) study in indicating substantial genetic influences on late-life cognitive functioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alopecia areata and cytomegalovirus infection in twins: genes versus environment?

BACKGROUND: Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease mediated by T cells directed to the hair follicle. Genetic susceptibility may be conferred by HLA, and an environmental trigger, such as a viral infection, is suspected. The incidence of AA in the population is estimated to be 1.7%, with an average of one in four patients having a positive family history. OBJECTIVE: Our purpose was to examine the concordance rate of AA among identical versus fraternal twins and the correlation between stress, cytomegalovirus (CMV) infection, and disease. METHODS: Families with AA were solicited from dermatologists in the United States and through a Website on the Internet. HLA class 2 typing and identification of CMV early and late genes were performed by polymerase chain reaction (PCR) on genomic peripheral blood DNA. Serum antibodies for CMV were determined by enzyme-linked immunosorbent assay. RESULTS: From 114 families, we identified 11 sets of monozygotic twins and 3 sets of dizygotic twins. The concordance rate was 55% for monozygotic twins and 0% for fraternal twins. Most identical twins were male. The severity of the AA phenotype varied and appeared most severe in the first affected twin. Five of 24 twins were CMV seropositive but CMV DNA was not detected in blood lymphocytes of any of the subjects when studied after the onset of AA. The presence of AA in twins was not correlated with evidence of CMV. CONCLUSION: A 55% concordance rate in identical twins and AA occurring in families support a genetic component as well as possible environmental triggers that remain unknown.     

Familial resemblance in infant mental development.

Compared the scores on a scale of mental development (N. Bayley) of 151 sets of 8-mo-old twins and 2,481 other sibling pairs in the Collaborative Perinatal Project. Intraclass correlation coefficients between scores of twins were high (.84, monozygotic; .55, dizygotic), suggesting a substantial genetic influence; however, the average correlation between scores of other siblings was only .22. The discrepancy between the values for dizygotic twins and other sibling pairs may have resulted from the twins' greater environmental similarity. The high heritability estimate derived from the difference between monozygotic and dizygotic correlations was due to the higher concordance for severe retardation in monozygotic pairs. It is noted that since infant twins are a unique sample in terms of retardation frequency as well as birth weight and gestational age, it may be inappropriate to generalize infant twin study results to singleton populations. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Minireview: Molecular genetics in affective illness

Genetic transmission in manic depressive illness (MDI) has been explored in twins, adoption, association, and linkage studies. The X-linked transmission hypothesis has been tested by using several markers on chromosome X: Xg blood group, colour blindness, glucose-6-phosphate dehydrogenase (G6PD), factor IX (haemophilia B), and DNA probes such as DXS15, DXS52, F8C, ST14. The hypothesis of autosomal transmission has been tested by association studies with the O blood group located on chromosome 9, as well as linkage studies on chromosome 6 with the Human Leucocyte Antigens (HLA) haplotypes and on Chromosome 11 with DNA markers for the following genes: D2 dopamine receptor, tyrosinase, C-Harvey-Ras-A (HRAS) oncogene, insuline (ins), and tyrosine hydroxylase (TH). Although linkage studies support the hypothesis of a major locus for the transmission of MDI in the Xq27-28 region, several factors are limiting the results, and are discussed in the present review.     

Genetics, the Big Five, and the tendency to be self-employed.

We applied multivariate genetics techniques to a sample of 3,412 monozygotic and dizygotic twins from the United Kingdom and 1,300 monozygotic and dizygotic twins from the United States to examine whether genetic factors account for part of the covariance between the Big Five personality characteristics and the tendency to be an entrepreneur. We found that common genes influenced the phenotypic correlations between only Extraversion and Openness to Experience and the tendency to be an entrepreneur. Although the phenotypic correlations between the personality characteristics and the tendency to be an entrepreneur were small in size, genetic factors accounted for most of them. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Emergenesis: Genetic traits that may not run in families.

Traits that are influenced by a configuration, rather than by a simple sum, of polymorphic genes may not be seen to be genetic unless one studies monozygotic twins (who share all their genes and thus all gene configurations) because such "emergenic" traits will tend not to run in families. Personal idiosyncrasies that have been found to be surprisingly concordant among monozygotic twins separated in infancy and reared apart may be emergenic traits. More speculatively, important human traits like leadership, genius in its many manifestations, being an effective therapist or parent, as well as certain psychopathological syndromes may also be emergenic. These ideas reemphasize the importance of the role played in human affairs by genetic variation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inheritance of general intelligence.

Describes the author's extensive research of the relative influence of hereditary factors on general cognitive ability. Analysis of measures of intelligence for family members related by varying degrees of kinship identified 4 types of factors: common and specific genetic and environmental influences. A model was then developed to represent the mode of mental inheritance, based on the theory of polygenic inheritance of bodily characteristics. The total phenotypic variance was divided into 4 mathematical components, represented by correlations between (a) monozygotic twins reared apart (genetic factor), (b) children and 1 of their parents (dominance factor), (c) fathers and mothers (assortative mating factor), and (d) monozygotic twins reared together and those reared apart (environmental factor). Application of the equation to actual data indicates that intelligence and bodily characteristics are influenced to much the same extent by very similar genetic characteristics. It is concluded that there is a general factor which enters into every type of cognitive process and differs according to the individual's genetic constitution. (40 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)