Concordant Dizygotic Twins Research Articles

The Role of Genetic Testing Among Autistic Individuals.

Autism is estimated to have a heritability component of ∼90%.1 This estimate is based on the reported concordance rates of 70% to 90% between monozygotic twins compared with 10% concordance in dizygotic twins.2,3 Furthermore, siblings of autistic individuals carry a >17 times higher likelihood of being on the autism spectrum compared with the general population.3 Although a significant proportion of genetic and molecular mechanisms related to autism remain unclear, researchers have reported findings that suggest both rare Mendelian and polygenic, multifactorial patterns of inheritance. For example, chromosomal microarray testing may identify a genetic etiology in up to 20% of autistic individuals.4,5Given this extent of genetic heritability, large-scale genetic testing and tracking within databases are beneficial in informing both research and clinical practice. The developers of these datasets aim to identify specific gene interactions and assess individual gene contributions while advancing the diagnostic yield of genetic testing.6 The Autism Intervention Research Network on Physical Health genetics research node is poised to help to facilitate the creation of registries for rare and orphan diseases that commonly co-occur with autism. An aim of the Autism Intervention Research Network on Physical Health data repository is to collect this information through the use of data-gathering materials designed to ease the burden on families and support groups wanting to initiate new registries.An important distinction to note is that genetic testing is not used to diagnose autism. An autism diagnosis is based on the presence of defined clinical characteristics. Although genetic test results may reveal the origin of autism in an individual or provide information about the statistical likelihood of being on the autism spectrum, they can also be used to improve the physical health and well-being of autistic individuals by identifying co-occurring medical conditions. Genetic testing may inform a specific diagnosis (eg, fragile X syndrome, Rett syndrome) that could ultimately establish a personalized roadmap for identifying syndrome-associated co-occurring conditions, instituting surveillance, and developing interventions or treatments specific to the genetic etiology. Furthermore, the individual diagnosis may lead to diagnosis-specific community support and help to guide family planning efforts.Despite the American College of Medical Genetics and Genomics establishing fragile X and chromosomal microarray testing as standard-of-care, first-tier tests in the genetic evaluation of autistic individuals,7,8 a surprisingly low number of autistic individuals receive these recommended genetics tests. One recent study with 1280 participants revealed that although 16.5% of participants had some genetic testing done, only 3% had received both recommended tests.9 Moreover, well-documented racial and ethnic disparities exist in the timely identification and genetic screening of autistic individuals. Black, Hispanic/Latinx, and other children of color, particularly those with co-occurring intellectual disabilities, are more likely to have a missed or delayed diagnosis of autism.10–12 Unfortunately, this inequality in the care of autistic individuals, and particularly for Black children, is also observed in the context of genetic screening and counseling.13 Overall, approximately two-thirds of autistic children receive some form of genetic screening and/or counseling; however, Black children are much less likely than their White peers to be offered these services.13 The majority of parents of autistic children actually favor the use of genetic screening and counseling because they believe that the increased knowledge empowers and helps them to intervene earlier than they might have otherwise.14Our goal is to increase awareness regarding the importance and utility of genetic screening and counseling in the lives of autistic individuals and their families. Novel intervention strategies need to be implemented to improve access to such services so that autistic people can be empowered to make informed decisions surrounding the lifestyle interventions and care they wish to pursue.

Concordance for Parkinson's disease in twins: A 20-year update.

During the 1990s, we estimated the genetic contribution to Parkinson's disease risk in a large, population-based twin registry. Because many unaffected twins were still alive, previous concordance estimates were based on incomplete information. Ninety-five percent of twins are now deceased. Here, we update concordance and heritability through 2015 using National Death Index data. In total, we identified 30 concordant and 193 discordant pairs. Proband-wise concordance was 0.20 in monozygotic and 0.13 in dizygotic pairs. Heritability was 0.27 overall, 0.83 in pairs diagnosed ≤50, and 0.19 in pairs diagnosed >50. High concordance in dizygotic twins suggests shared effects of early childhood environment. Ann Neurol 2019;85:600-605.

Clinical features and genetic characterization of two dizygotic twins with C9orf72 expansion.

The objective of the study was to present a detailed clinical, genetic, and epigenetic characterization of 2 amyotrophic lateral sclerosis (ALS) concordant dizygotic twins. The described cases underwent clinical and paraclinical examinations according to the motor neuron disease protocol of our referral center. Mutation analysis of the major causative genes related to ALS was performed. The methylation profile of the CpG island located in the promoter region of C9orf72 and in the repeat region itself was investigated by bisulfite sequencing of C9orf72 expansion carriers. The described cases presented an overlapping phenotype. Genetic analysis revealed the presence of an abnormal (>50 repeats) G4C2-repeat expansion in C9orf72. Both the direct bisulfite sequencing-sensitive and the methylation-sensitive HhaI assays did not reveal any DNA methylation at the CpG island 5' of the G4C2 repeat in C9orf72. The (G4C2)n methylation assay indicated that also the expansion itself was not methylated in both twins, suggesting a probably intermediate allele expansion. This is the first report of ALS-concordant dizygotic twins carrying a C9orf72 expansion probably of intermediate length, and with a detailed clinical and genetic characterization. Twin studies add significant information about the mechanisms of C9orf72 expansion pleiotropism, probably driven by genetic, epigenetic, and environmental factors.

The Role of Host Genetics (and Genomics) in Tuberculosis.

Familial risk of tuberculosis (TB) has been recognized for centuries. Largely through studies of mono- and dizygotic twin concordance rates, studies of families with Mendelian susceptibility to mycobacterial disease, and candidate gene studies performed in the 20th century, it was recognized that susceptibility to TB disease has a substantial host genetic component. Limitations in candidate gene studies and early linkage studies made the robust identification of specific loci associated with disease challenging, and few loci have been convincingly associated across multiple populations. Genome-wide and transcriptome-wide association studies, based on microarray (commonly known as genechip) technologies, conducted in the past decade have helped shed some light on pathogenesis but only a handful of new pathways have been identified. This apparent paradox, of high heritability but few replicable associations, has spurred a new wave of collaborative global studies. This review aims to comprehensively review the heritability of TB, critically review the host genetic and transcriptomic correlates of disease, and highlight current studies and future prospects in the study of host genomics in TB. An implicit goal of elucidating host genetic correlates of susceptibility to Mycobacterium tuberculosis infection or TB disease is to identify pathophysiological features amenable to translation to new preventive, diagnostic, or therapeutic interventions. The translation of genomic insights into new clinical tools is therefore also discussed.

Increased frequency of Mediterranean fever gene variants in multiple myeloma.

High frequencies of inherited variants in the Mediterranean fever (MEFV) gene have been identified in patients with multiple myeloma (MM). The sample size of the present pilot study was small, therefore, the actual frequency of inherited variants in the MEFV gene could be investigated in patients with MM. Twenty-eight patients with MM and 65 healthy controls were included in the study. Six heterozygous and one homozygous (E148Q/E148Q) variant was identified in patients with MM. None of the patients had a family history compatible with familial Mediterranean fever. In the healthy control group, 11 heterozygous variants were identified. The difference in the overall frequency of the inherited variants in the MEFV gene between the MM patients and the controls was statistically significant (χ2=4.905; P=0.027). In conclusion, a high frequency of inherited variants in the MEFV gene was identified in patients with MM. Based on the current data, it is hypothesized that the MEFV gene is a cancer susceptibility gene. Additional evidence, such as familial aggregation, monozygotic versus dizygotic twin concordance, and tumors in genetically engineered model organisms, is required in order to support this hypothesis.

The equal environments assumption in schizophrenia genetics

It is widely stated that schizophrenia is “genetic”. The main basis for this claim is the literature on twin concordance for schizophrenia in monozygotic (MZ) and dizygotic (DZ) twins. The validity of twin studies depends on the equal environments assumption. However, the low concordance rates in MZ and DZ twins prove two things: (1) schizophrenia can be at most only a little bit genetic, and (2) the equal environments assumption cannot hold. Proponents of the genetic contribution to schizophrenia must deal with a logical bind: the greater they make the gap between MZ and DZ twin concordance rates, the more they undermine the equal environments assumption; the smaller they make it, the more they undermine the genetic contribution to schizophrenia.

Psoriasis Epidemiology: The Interplay of Genes and the Environment

Psoriasis is a common chronic dermatological disease whose prevalence varies among different populations worldwide. In epidemiological studies, the factors that potentially account for this variability include climate, genetic susceptibility, and environmental antigen exposure. In this issue, Parisi et al. performed a systematic review to explore the global prevalence and incidence of psoriasis.

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness1 and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them2. This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia3. The male-to-female ratio of mutation rate is estimated at about 4–6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males4. A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia

There are several lines of evidence supporting the role of de novo mutations as a mechanism for common disorders, such as autism and schizophrenia. First, the de novo mutation rate in humans is relatively high, so new mutations are generated at a high frequency in the population. However, de novo mutations have not been reported in most common diseases. Mutations in genes leading to severe diseases where there is a strong negative selection against the phenotype, such as lethality in embryonic stages or reduced reproductive fitness, will not be transmitted to multiple family members, and therefore will not be detected by linkage gene mapping or association studies. The observation of very high concordance in monozygotic twins and very low concordance in dizygotic twins also strongly supports the hypothesis that a significant fraction of cases may result from new mutations. Such is the case for diseases such as autism and schizophrenia. Second, despite reduced reproductive fitness1 and extremely variable environmental factors, the incidence of some diseases is maintained worldwide at a relatively high and constant rate. This is the case for autism and schizophrenia, with an incidence of approximately 1% worldwide. Mutational load can be thought of as a balance between selection for or against a deleterious mutation and its production by de novo mutation. Lower rates of reproduction constitute a negative selection factor that should reduce the number of mutant alleles in the population, ultimately leading to decreased disease prevalence. These selective pressures tend to be of different intensity in different environments. Nonetheless, these severe mental disorders have been maintained at a constant relatively high prevalence in the worldwide population across a wide range of cultures and countries despite a strong negative selection against them2. This is not what one would predict in diseases with reduced reproductive fitness, unless there was a high new mutation rate. Finally, the effects of paternal age: there is a significantly increased risk of the disease with increasing paternal age, which could result from the age related increase in paternal de novo mutations. This is the case for autism and schizophrenia3. The male-to-female ratio of mutation rate is estimated at about 4–6:1, presumably due to a higher number of germ-cell divisions with age in males. Therefore, one would predict that de novo mutations would more frequently come from males, particularly older males4. A high rate of new mutations may in part explain why genetic studies have so far failed to identify many genes predisposing to complexes diseases genes, such as autism and schizophrenia, and why diseases have been identified for a mere 3% of genes in the human genome. Identification for de novo mutations as a cause of a disease requires a targeted molecular approach, which includes studying parents and affected subjects. The process for determining if the genetic basis of a disease may result in part from de novo mutations and the molecular approach to establish this link will be illustrated, using autism and schizophrenia as examples.

Utilizing Twins Concordance Rates to Infer the Predisposition to Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disorder in which patients experience muscular fatigability due to the presence of anti-acetylcholine receptor (AChR) antibodies which inhibit signal transduction across the neuro-muscular junction. Like all complex disorders, disease is caused by an interaction between genetic and environmental factors. Although several genes have been identified which appear to be associated with MG, both classic twin studies and current multi-gene models are insufficient to explain either disease pathogenesis or inheritance. We examined the literature on MG to determine both mono- and dizygotic twin concordance rates, and used this data to (1) estimate the proportion of the population with underlying genetic predisposition to MG and the frequency of the environmental component and (2) derive the number of inherited genetic regions that are required to confer predisposition to MG. Using a MZ twin concordance rate of 35.5%, and a dizygotic rate of approximately 4-5% (based on family data), the probability of encountering environmental components necessary to develop MG in an individual with genetic predisposition is approximately 52.4%, making the frequency of predisposition (1:5240) roughly twice the rate of incidence. Furthermore, the number of genetic regions co-inherited between affected individuals is between two and four, which may be large haplotypes with interacting activity. Determining these haplotypes, by fully sequencing associated regions in cases and controls to identify mutations present, may therefore be a practically step toward the understanding of complex disease.

Heritability of Plasma Adiponectin Levels and Body Mass Index in Twins

Adiponectin is suspected to exert antiatherogenic, antiinflammatory, and insulin-sensitizing effects. However, the relative importance of the genetic and environmental factors in influencing plasma adiponectin levels (ADPN) remains unclear. The aim of the study was to investigate whether ADPN and body mass index (BMI) are genetically determined. In a series of 60 pairs of healthy twins, we estimated genetic variance and heritability of ADPN and BMI using both ANOVA and path analysis methods. Twins were genotyped at two biallelic single nucleotide polymorphisms (SNPs) at the gene encoding adiponectin: the +45 T/G (on exon 2) and the -11377 G/C (on the promoter). A total of 30 pairs of twins were Monozygotic (MZ), and 30 were dizygotic (DZ). The mean ADPN (+/-SD) was 10.6 +/- 5.7 in MZ and 11.1 +/- 4.5 in DZ twins (nonsignificant). Three tests of heritability (within pair = 1.13, P < 0.0001; among components = 1.62, P = 0.005; and intraclass correlation 1.34, P < 0.0001) consistently showed ADPN heritability. The preferred model of a likelihood-based analysis included an additive genetic influence and an individually unique environmental influence for ADPN, accounting for 88% and 12% of ADPN variance, respectively. We found a significantly higher within-pair difference of ADPN in DZ than in MZ pairs, and in +45 T/G SNP discordant compared with concordant DZ twins, indicating a significant effect of this adiponectin gene SNP on ADPN. ADPN shows significant genetic variance and heritability, which is independent of BMI and partly accounted for by the +45 T/G, but not the -11377 G/C adiponectin gene SNP.

Williams syndrome in twins

Two sets of identical twins with Williams syndrome have been reported previously. We report on 2 additional sets of presumed identical twins with Williams syndrome. All 4 patients had the typical Williams syndrome facial appearance, growth deficiency, and developmental delay. None of the patients had supravalvular aortic stenoses; however, all were diagnosed as having probable distal pulmonary artery stenosis. In the set of twins in which serum calcium was measured, one twin had an elevated serum ionized calcium level. These 2 sets of twins further document the occurrence of Williams syndrome in identical twins. To our knowledge, there are no reported cases of concordance in dizygotic twins. This adds further support to the likelihood that Williams syndrome is a genetic disorder.

Concordant Contralateral Lambdoidal Synostosis in Dizygotic Twins

Twin studies have been widely used to investigate genetic versus environmental causality of malformations. While there are numerous reports of concordant sutural fusions in syndromic twins, there are few cases in siblings with nonsyndromic single suture synostosis. Lambdoidal synostosis has no clear genetic etiology. Discordant synostosis has been reported in one monozygotic twin; there is also an unsubstantiated report of concordance in dizygotic twins. We describe dizygotic twins concordant for contralateral lambdoidal synostosis. Mutational analysis for FGFR 1,2,3 was negative. Given the low incidence, absence of reported inheritability, and lack of documented concordance in monozygotic twins, the pathogenesis of isolated lambdoidal fusion can only be ascribed to stochastic influences.

Twin concordance and sibling recurrence rates in multiple sclerosis.

Size and ascertainment constraints often limit twin studies to concordance comparisons between identical and fraternal twins. Here we report the final results of a longitudinal, population-based study of twins with multiple sclerosis (MS) in Canada. Bias was demonstrably minimized, and an estimated 75% of all Canadian MS twin pairs were ascertained, giving a sample sufficiently large (n = 370) to permit additional informative comparisons. Twinning was not found to affect prevalence, and twins with MS did not differ from nontwins for DR15 allele frequency nor for MS risk to their siblings. Probandwise concordance rates of 25.3% (SE +/- 4.4) for monozygotic (MZ), 5.4% (+/-2.8) for dizygotic (DZ), and 2.9% (+/-0.6) for their nontwin siblings were found. MZ twin concordance was in excess of DZ twin concordance. The excess concordance in MZ was derived primarily from like-sexed female pairs with a probandwise concordance rate of 34 of 100 (34 +/- 5.7%) compared with 3 of 79 (3.8 +/- 2.8%) for female DZ pairs. We did not demonstrate an MZ/DZ difference in males, although the sample size was small. We observed a 2-fold increase in risk to DZ twins over nontwin siblings of twins, but the difference was not significant.

The genetic determination of left ventricular mass in healthy adults.

The extent to which left ventricular (LV) mass, an independent cardiovascular risk factor, is determined by genetic factors is unclear. The aim of this study was to assess the heritability of LV mass and its association with three potential candidate genes. A population-based adult twin study model was utilized. Echocardiographic assessment of LV mass was performed in 110 twin pairs (mean age 55.9+/-10.9 years). An estimate of genetic determination, heritability, was calculated for the main echocardiographic parameters. The cohort were genotyped for the G-protein beta-3, aldosterone synthase, and beta-1 adrenoceptor genes. The intra-class correlation coefficients for LV mass were 0.69 for monozygotic (r-MZ) twins and 0.32 for dizygotic (r-DZ) twins, P=0.008 (heritability estimate of 0.69). This pattern persisted following correction for known confounding factors. Within-pair differences in the monozygotic, discordant and concordant dizygotic twins showed no differences for the three genes with respect to left ventricular wall thickness or mass. There was a non-significant trend towards a relationship between LV mass and the beta-1 adrenoceptor genotype. Within a normal population left ventricular mass has a significant genetic determination. Further investigation of potential candidate genes is required.

A Major Susceptibility Locus for Specific Language Impairment Is Located on 13q21

Children who fail to develop language normally-in the absence of explanatory factors such as neurological disorders, hearing impairment, or lack of adequate opportunity-are clinically described as having specific language impairment (SLI). SLI has a prevalence of approximately 7% in children entering school and is associated with later difficulties in learning to read. Research indicates that genetic factors are important in the etiology of SLI. Studies have consistently demonstrated that SLI aggregates in families. Increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of the familial clustering. We have collected five pedigrees of Celtic ancestry that segregate SLI, and we have conducted genomewide categorical linkage analysis, using model-based LOD score techniques. Analysis was conducted under both dominant and recessive models by use of three phenotypic classifications: clinical diagnosis, language impairment (spoken language quotient <85) and reading discrepancy (nonverbal IQ minus non-word reading >15). Chromosome 13 yielded a maximum multipoint LOD score of 3.92 under the recessive reading discrepancy model. Simulation to correct for multiple models and multiple phenotypes indicated that the genomewide empirical P value is <.01. As an alternative measure, we also computed the posterior probability of linkage (PPL), obtaining a PPL of 53% in the same region. One other genomic region yielded suggestive results on chromosome 2 (multipoint LOD score 2.86, genomic P value <.06 under the recessive language impairment model). Our findings underscore the utility of traditional LOD-score-based methods in finding genes for complex diseases, specifically, SLI.

Genetics of autism

Autism is influenced by complex, yet strong genetic factors. The strongest evidence for genetic factors comes from twin studies that show a high concordance for autism in monozygotic twins and relatively small concordance in dizygotic twins. The strong decrease in risk from monozygotic twins to dizygotic twins and siblings suggests that two or more genes interact to contribute to autism susceptibility. Statistical modeling of the genetics of autism suggests that two to five susceptibility genes are acting in concert. The recurrence risk for siblings (4.5%) is 45–90 times greater than the population risk (0.05–0.1%), providing further evidence for a complex and strong genetic contribution. In addition to an increased risk of autism for relatives, relatives have been found to have an increased frequency of lesser variants of autism including social, language, and cognitive difficulties. Autism has been associated with several single gene disorders, particularly tuberous sclerosis. Several chromosomal abnormalities have been identified in autism, including the fragile X syndrome, Down's syndrome, and Turner's syndrome. More recently, duplications of the Prader-Willi/Angelman syndrome region of proximal 15q have been reported in patients with autism. The parent of origin of such proximal 15q duplications may influence the risk for autism. Because of the similarity of the phenotype of 15q11–13 duplications in typical autism, linkage analysis has been conducted in autism, and linkage and linkage disequilibrium have been reported for markers on 15q11–13. Several genome-wide screens are under way, with the first full report suggesting a potential susceptibility locus on 7q. Heterogeneity and the multiplicative nature of autism susceptibility genes increase the number of families needed to demonstrate and replicate linkage. Conversely, when susceptibility genes are identified, there will be several potential targets for conventional pharmacotherapy, which often modifies gene expression, as well as direct gene therapy. MRDD Research Reviews 1998;4:113–120. © 1998 Wiley-Liss, Inc.

Genetics of autism

Autism is influenced by complex, yet strong genetic factors. The strongest evidence for genetic factors comes from twin studies that show a high concordance for autism in monozygotic twins and relatively small concordance in dizygotic twins. The strong decrease in risk from monozygotic twins to dizygotic twins and siblings suggests that two or more genes interact to contribute to autism susceptibility. Statistical modeling of the genetics of autism suggests that two to five susceptibility genes are acting in concert. The recurrence risk for siblings (4.5%) is 45–90 times greater than the population risk (0.05–0.1%), providing further evidence for a complex and strong genetic contribution. In addition to an increased risk of autism for relatives, relatives have been found to have an increased frequency of lesser variants of autism including social, language, and cognitive difficulties. Autism has been associated with several single gene disorders, particularly tuberous sclerosis. Several chromosomal abnormalities have been identified in autism, including the fragile X syndrome, Down's syndrome, and Turner's syndrome. More recently, duplications of the Prader-Willi/Angelman syndrome region of proximal 15q have been reported in patients with autism. The parent of origin of such proximal 15q duplications may influence the risk for autism. Because of the similarity of the phenotype of 15q11–13 duplications in typical autism, linkage analysis has been conducted in autism, and linkage and linkage disequilibrium have been reported for markers on 15q11–13. Several genome-wide screens are under way, with the first full report suggesting a potential susceptibility locus on 7q. Heterogeneity and the multiplicative nature of autism susceptibility genes increase the number of families needed to demonstrate and replicate linkage. Conversely, when susceptibility genes are identified, there will be several potential targets for conventional pharmacotherapy, which often modifies gene expression, as well as direct gene therapy. MRDD Research Reviews 1998;4:113–120. © 1998 Wiley-Liss, Inc.

Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment.

To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis (AS). Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database. Clinical and radiographic examinations were performed to establish diagnoses, and disease severity was assessed using a combination of validated scoring systems. HLA typing for HLA-B27, HLA-B60, and HLA-DR1 was performed by polymerase chain reaction with sequence-specific primers, and zygosity was assessed using microsatellite markers. Genetic and environmental variance components were assessed with the program Mx, using data from this and previous studies of twins with AS. Six of 8 monozygotic (MZ) twin pairs were disease concordant, compared with 4 of 15 B27-positive dizygotic (DZ) twin pairs (27%) and 4 of 32 DZ twin pairs overall (12.5%). Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease-concordant MZ twins compared with concordant DZ twins. HLA-B27 and B60 were associated with the disease in probands, and the rate of disease concordance was significantly increased among DZ twin pairs in which the co-twin was positive for both B27 and DR1. Additive genetic effects were estimated to contribute 97% of the population variance. Susceptibility to AS is largely genetically determined, and the environmental trigger for the disease is probably ubiquitous. HLA-B27 accounts for a minority of the overall genetic susceptibility to AS.

Psoriasis in Australian twins

Occurrence of psoriasis has been found to be strongly genetically controlled in Northern European and U.S. twin and family studies. Our purpose was to assess cumulative incidence and heritability of psoriasis in the Australian population. Australian twins reporting psoriasis on a screening questionnaire received from 3808 pairs were mailed a detailed instrument designed to validate the diagnosis, supplemented by telephone interview and examination of medical records. Only 94 of 160 subjects who screened positive were confirmed to have psoriasis. The cumulative incidence of confirmed psoriasis was 2% in 30- to 60-year-old subjects. The monozygotic twin casewise concordance for confirmed psoriasis was 35% (12 of 34 pairs), and the dizygotic twin concordance 12% (5 of 43 pairs), giving an estimated heritability of 80%, was similar to that found in a genetic reanalysis of three previous twin studies. A case-control analysis of psoriasis-discordant twin pairs found no evidence for influences of alcohol or coffee intake, overweight, birth weight, or personality in the origin of psoriasis. Occurrence of psoriasis in the Australian population is highly heritable, but identical twins are often discordant; the factor responsible for the onset of disease in one twin and not the other is unclear.