A Twin Study of Early-Childhood Asthma in Puerto Ricans

Background

The relative contributions of genetics and environment to asthma in Hispanics or to asthma in children younger than 3 years are not well understood.

Objective

To examine the relative contributions of genetics and environment to early-childhood asthma by performing a longitudinal twin study of asthma in Puerto Rican children ≤3 years old.

Methods

678 twin infants from the Puerto Rico Neo-Natal Twin Registry were assessed for asthma at age 1 year, with follow-up data obtained for 624 twins at age 3 years. Zygosity was determined by DNA microsatellite profiling. Structural equation modeling was performed for three phenotypes at ages 1 and 3 years: physician-diagnosed asthma, asthma medication use in the past year, and ≥1 hospitalization for asthma in the past year. Models were additionally adjusted for early-life environmental tobacco smoke exposure, sex, and age.

Results

The prevalences of physician-diagnosed asthma, asthma medication use, and hospitalization for asthma were 11.6%, 10.8%, 4.9% at age 1 year, and 34.1%, 40.1%, and 8.5% at 3 years, respectively. Shared environmental effects contributed to the majority of variance in susceptibility to physician-diagnosed asthma and asthma medication use in the first year of life (84%–86%), while genetic effects drove variance in all phenotypes (45%–65%) at age 3 years. Early-life environmental tobacco smoke, sex, and age contributed to variance in susceptibility.

Conclusion

Our longitudinal study in Puerto Rican twins demonstrates a changing contribution of shared environmental effects to liability for physician-diagnosed asthma and asthma medication use between ages 1 and 3 years. Early-life environmental tobacco smoke reduction could markedly reduce asthma morbidity in young Puerto Rican children.     

Epigenetics and twins: three variations on the theme

Twin studies have had a key role in the evaluation of heritability, a population-based estimate of the genetic contribution to phenotypic variation. These studies have led to the revelation that most normal and disease phenotypes are to some extent heritable. Recently, interest has shifted from phenomenological heritability to the identification of trait-specific genes. The era of twin studies, however, is not over: recent epigenetic and global gene expression studies suggest that the most interesting findings in twin-based research are still to come. The increasing realization of the influence of epigenetics in phenotypic outcomes means that the molecular mechanisms behind phenotypic differences in genetically identical organisms can be explored. Analyses of epigenetic twin differences and similarities might yet challenge the fundamental principles of complex biology, primarily the dogma that complex phenotypes result from DNA sequence variants interacting with the environment.     

Segregation analysis of phenotypic components of learning disabilities. I. Nonword memory and digit span

Dyslexia is a common and complex disorder with evidence for a genetic component. Multiple loci (i.e., quantitative-trait loci [QTLs]) are likely to be involved, but the number is unknown. Diagnosis is complicated by the lack of a standard protocol, and many diagnostic measures have been proposed as understanding of the component processes has evolved. One or more genes may, in turn, influence these measures. To date, little work has been done to evaluate the mode of inheritance of individual component-as opposed to composite-phenotypes, beyond family or twin correlation studies that initially demonstrate evidence for a genetic basis of such components. Here we use two approaches to segregation analysis in 102 nuclear families to estimate genetic models for component phenotypes associated with dyslexia: digit span and a nonword-repetition task. Both measures are related to phonological skills, one of the key component processes in dyslexia. We use oligogenic-trait segregation analysis to estimate the number of QTLs contributing to each phenotype, and we use complex segregation analysis to identify the most parsimonious inheritance models. We provide evidence in support of both a major-gene mode of inheritance for the nonword-repetition task, with approximately 2.4 contributing QTLs, and for a genetic basis of digit span, with approximately 1.9 contributing QTLs. Results obtained by reciprocal adjustment of measures suggest that genes contributing to digit span may contribute to the nonword-repetition score but that there are additional QTLs involved in nonword repetition. Our study adds to existing studies of the genetic basis of composite phenotypes related to dyslexia, by providing evidence for major-gene modes of inheritance of these single-measure component phenotypes.     

Contributions and promise of human behavioral genetics

Human behavioral genetics has contributed greatly to our understanding of human behavioral development. Twin, family, and adoption studies have shown that genetic effects are ubiquitous and that both genes and environments contribute to individual differences in behavior. The unique ability of behavioral genetic methods to separate genetic from environmental effects has also led to important discoveries about how the environment works in development and to the elucidation of the complex ways environments and genes interact across the life span. Although quantitative methods have been the mainstay of the field of human behavioral genetics since Galton's time, the Human Genome Project and advances in molecular genetics are providing new tools and promise as we enter the 21st century. Thus the future of human behavioral genetics lies in the cross-disciplinary exchanges and collaborations that will increasingly occur in the years to come among quantitative and molecular scientists who work with both animal and human systems. This research may someday culminate in an understanding of the biological basis of behavior that spans from how the brain develops and functions to a grasp of how genes influence thought at the molecular level.     

The continuing value of twin studies in the omics era

The classical twin study has been a powerful heuristic in biomedical, psychiatric and behavioural research for decades. Twin registries worldwide have collected biological material and longitudinal phenotypic data on tens of thousands of twins, providing a valuable resource for studying complex phenotypes and their underlying biology. In this Review, we consider the continuing value of twin studies in the current era of molecular genetic studies. We conclude that classical twin methods combined with novel technologies represent a powerful approach towards identifying and understanding the molecular pathways that underlie complex traits.     

Analysis of twin data using SAS

Summary .  Twin studies are essential for assessing disease inheritance. Data generated from twin studies are traditionally analyzed using specialized computational programs. For many researchers, especially those who are new to twin studies, understanding and using those specialized computational programs can be a daunting task. Given that SAS (Statistical Analysis Software) is the most popular software for statistical analysis, we suggest that the use of SAS procedures for twin data may be a helpful alternative and demonstrate that we can obtain similar results from SAS to those produced by specialized computational programs. This numerical validation is practically useful, because a natural concern with general statistical software is whether it can deal with data that are generated from special study designs such as twin studies and if it can test a particular hypothesis. We concluded through our extensive simulation that SAS procedures can be used easily as a very convenient alternative to specialized programs for twin data analysis.     

The concentration of glutathione in human erythrocytes is a heritable trait

Glutathione (GSH) is a ubiquitous, redox-active, small molecule that is critical to cellular and organism health. In red blood cells (RBCs), the influence of the environment (e.g., diet and lifestyle) on GSH levels has been demonstrated in numerous studies. However, it remains unknown if levels of GSH are determined principally by environmental factors or if there is a genetic component, i.e., heritability. To investigate this we conducted a twin study. Twin studies are performed by comparing the similarity in phenotypes between mono- and dizygotic twin pairs. We determined the heritability of GSH, as well as its oxidation product glutathione disulfide (GSSG), the sum of GSH equivalents (tGSH), and the status of the GSSG/2GSH couple (marker of oxidation status, E_hc) in RBCs. In our study population we found that the estimated heritability for the intracellular concentration of GSH in RBCs was 57 %; for GSSG it was 51 %, tGSH 63 %, and E_hc 70 %. We conclude that a major portion of the phenotype of these traits is controlled genetically. We anticipate that these heritabilities will also be reflected in other cell types. The discovery that genetics plays a major role in the innate levels of redox-active species in RBCs is paradigm shifting and opens new avenues of research in the field of redox biology. Inherited RBC antioxidant levels may be important disease modifiers. By identifying the relative contributions of genes and the environment to antioxidant variation between individuals, new therapeutic strategies can be developed. Understanding the genetic determinants of these inherited traits may allow personalized approaches to relevant therapies.     

A twin approach to unraveling epigenetics

The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits.     

A differential viability model for twin-pair blood group data.

Much interest in human genetics studies of blood systems is focussed on the possible incompatibility of discordant twin pairs. Here we discuss a differential viability model which accounts for deviations from the standard multinomial model for twin pair data based on the Hardy-Weinberg frequencies. We discuss related estimation and testing problems, illustrating the techniques with data from the Louisville Twin Study.     

Twin registers across the globe: what's out there in 2002?

Twin research offers the greatest power for the genetic analysis of complex multifactorial traits and diseases in humans. Modern twin analyses extend beyond the classical twin study for estimating the heritability of a trait. The human genome project can fulfil its promises only after functional characterisation of single genes in the context of genetic background and environment. Twin research can make a major contribution in that regard. Twin research is greatly facilitated by the willingness, motivation, cooperation, and generosity of the participants and their families. A second important aspect is the availability of twin registries that serve as a resource for genetic epidemiology. Currently, there is no systematic overview of the twin collections worldwide. This special issue will help to overcome the limited accessibility of this resource by providing basic information on most of the existing twin registers. Furthermore, an additional goal is to facilitate collaboration between registers. Some basic principles, potentials, and problems will be exemplified by my personal experience in the Berlin Twin Study.     

Septo-optic dysplasia - novel insights into the aetiology

Septo-optic dysplasia (SOD) is a highly heterogeneous condition comprising a variable phenotype of optic nerve hypoplasia, midline brain abnormalities and pituitary hypoplasia with consequent endocrine deficits. The majority of cases are sporadic and several aetiologies have been suggested to account for the pathogenesis of the condition. However, a number of familial cases have been described and the identification of mutations in key developmental genes including HESX1, SOX2 and SOX3 in patients with SOD and associated phenotypes suggests that a genetic causation is likely in the more common sporadic cases of the condition. The precise aetiology of SOD is most likely multifactorial involving contributions from environmental factors in addition to an important role for crucial developmental genes. The variability of the penetrance and phenotypes within a single SOD pedigree may also suggest a complex interaction between genetics and the environment, and at present, the understanding of these interactions is rudimentary. Further study of these critical factors may shed light on the aetiology of this complex disorder. We have reviewed recent literature selecting relevant references based on the keywords HESX1, SOX2, SOX3, Septo-optic dysplasia, genetics and pituitary development.     

Primary osteoarthritis of the hip in monozygotic and dizygotic male twins.

Population and total hip replacement surveys show that primary osteoarthritis of the hip is uncommon in African Americans and rare in Asians, suggesting a genetic basis for this disease. We studied genetic influences on primary osteoarthritis of the hip by estimating monozygotic (MZ) and dizygotic (DZ) twin correlations using a two-stage data collection. A total of 6419 male veteran twins of the NAS-NRC Twin Registry, born between 1917 and 1927, were contacted by telephone (first stage). Telephone interview determined that 2% reported a total hip replacement for arthritis rather than fracture. X-rays of twin pairs in which one twin had undergone total hip replacement were sought and reviewed (second stage), and concordance for primary arthritis was determined based on x-ray diagnosis. Heritability of primary osteoarthritis, Kellgren & Lawrence Grade II and higher, was estimated using a covariance structure analysis for 2-stage data. The best-fitting model included only components for additive genetics and for unique environment. Additive genetics accounted for 53% (95% confidence interval 30-72%) in the liability for self reported hip replacement surgery and unique environment for the remaining 47% (95% confidence interval 28-70%). Additive genetics accounted for 61% (95% confidence interval 18-86%) of the variance in liability for x-ray determined primary osteoarthritis with unique environment accounting for the remaining 39%. These data establish a genetic influence on primary osteoarthritis of the hip in male twins and suggest that further work is indicated to isolate the genes responsible for this disease.     

Focus: Rare Disease: The Embryological Landscape of Mayer-Rokitansky-Kuster-Hauser Syndrome: Genetics and Environmental Factors

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder caused by Müllerian ducts dysgenesis affecting 1 in 5000 women with a typical 46,XX karyotype. The etiology of MRKH syndrome is complex and largely unexplained. Familial clustering suggests a genetic component and the spectrum of clinical presentations seems consistent with an inheritance pattern characterized by incomplete penetrance and variable expressivity. Mutations of several candidate genes have been proposed as possible causes based on genetic analyses of human patients and animal models. In addition, studies of monozygotic twins with discordant phenotypes suggest a role for epigenetic changes following potential exposure to environmental compounds. The spectrum of clinical presentations is consistent with intricate disruptions of shared developmental pathways or signals during early organogenesis. However, the lack of functional validation and translational studies have limited our understanding of the molecular mechanisms involved in this condition. The clinical management of affected women, including early diagnosis, genetic testing of MRKH syndrome, and the implementation of counseling strategies, is significantly impeded by these knowledge gaps. Here, we illustrate the embryonic development of tissues and organs affected by MRKH syndrome, highlighting key pathways that could be involved in its pathogenesis. In addition, we will explore the genetics of this condition, as well as the potential role of environmental factors, and discuss their implications to clinical practice.     

哮喘的分子遗传学研究进展

哮喘病和易感症的遣传学病因是复杂的,现可通过候选基因和易感位点筛选技术来进行研究。本文综述了哮喘易感基因的研究进展,同时讨论了哮喘遗传学研究对哮喘临床的应用前景。 Abstract:The genetics of asthma and atopy is complex,but can be approached by studies of both candidate genes and mapping of susceptibility loci.The progress in susceptibility genes for asthma and atopy is reviewed.New therapeutic approaches to asthma which are based on the study on asthma genetics for future are summarized.     

Recent advances in asthma genetics

There are over 100 genes that have been reported to be associated with asthma or related phenotypes. In 2006–2007 alone there were 53 novel candidate gene associations reported in the literature. Replication of genetic associations and demonstration of a functional mechanism for the associated variants are needed to confirm an asthma susceptibility gene. For most of the candidate genes there is little functional information. In a previous review by Hoffjan et al. published in 2003, functional information was reported for 40 polymorphisms and here we list another 22 genes which have such data. Some important genes such as filaggrin, interleukin-13, interleukin-17 and the cysteinyl leukotriene receptor-1 which not only were replicated by independent association studies but also have functional data are reviewed in this article.     

Glutathione S-transferase polymorphisms, asthma susceptibility and confounding variables: a meta-analysis

Oxidative stress is one of the main risk factors for asthma development. Glutathione S-transferases play an important role in antioxidant defences and may influence asthma susceptibility. In particular, GSTM1 and GSTT1 positive/null genotypes and the GSTP1*Ile105 Val polymorphism have been analyzed in a number of genetic association studies, with conflicting outcomes. Two previous meta-analyses have attempted to clarify the associations between GST genes and asthma, but these studies have also showed contrasting results. Our aim was to perform a meta-analysis that included independent genetic association studies on GSTM1, GSTP1, and GSTT1, evaluating also the effect of potential confounding variables (i.e. ethnicity, population age, and urbanization). Systematic review and meta-analysis of the effects of GST genes on asthma were conducted. The meta-analyses were performed using a fixed or, where appropriate, random effects model. The meta-analysis of the GSTM1 (n = 35), GSTT1 (n = 31) and GSTP1 (n = 28) studies suggests that no significant associations with asthma susceptibility were observed for GSTM1 and GSTP1 gene polymorphisms, whereas a significant outcome was detected for the GSTT1 positive/null genotype (pooled OR = 1.33, 95 %CI = 1.10–1.60). However, high between-study heterogeneity was identified in all the general analyses (p _{heterogenetity} < 0.05). The stratification analysis seems to explain the heterogeneity only in few cases. This picture is probably due to the interactive process of genetics and environment that characterizes disease pathogenesis. Further studies on interactions of GST genes with the potential oxidative stress sources and with other antioxidant genes are needed to explain the role of GST enzymes in asthma.     

Linkage analysis of Schizophrenia: Challenges and promise

Abstract

Schizophrenia is a serious mental illness affecting nearly 1 per cent of the general population. Family, twin, and adoption studies suggest that genetics plays a major role in the etiology of schizophrenia. The inheritance pattern appears complex, similar to that of other common conditions like heart disease. To uncover a causal genetic factor, researchers have recently begun to apply a linkage analysis strategy to schizophrenia. Early results suggest that there are many challenges facing scientists who undertake schizophrenia genetics research. While one study has shown significant linkage of schizophrenia to a region on chromosome 5, several other studies have not found linkage to this area. The likelihood that there are several major genes predisposing to the illness and uncertainties about inheritance patterns and diagnostic boundaries are potential difficulties to overcome. Many more families need to be studied, and creative complementary research strategies pursued, to achieve the potential success offered by a genetic linkage approach.     

Down syndrome: searching for the genetic culprits

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and results in a large number of phenotypes, including learning difficulties, cardiac defects, distinguishing facial features and leukaemia. These are likely to result from an increased dosage of one or more of the ∼310 genes present on Hsa21. The identification of these dosage-sensitive genes has become a major focus in DS research because it is essential for a full understanding of the molecular mechanisms underlying pathology, and might eventually lead to more effective therapy. The search for these dosage-sensitive genes is being carried out using both human and mouse genetics. Studies of humans with partial trisomy of Hsa21 have identified regions of this chromosome that contribute to different phenotypes. In addition, novel engineered mouse models are being used to map the location of dosage-sensitive genes, which, in a few cases, has led to the identification of individual genes that are causative for certain phenotypes. These studies have revealed a complex genetic interplay, showing that the diverse DS phenotypes are likely to be caused by increased copies of many genes, with individual genes contributing in different proportions to the variance in different aspects of the pathology.     

Linkage analysis of schizophrenia: challenges and promise.

Schizophrenia is a serious mental illness affecting nearly 1 per cent of the general population. Family, twin, and adoption studies suggest that genetics plays a major role in the etiology of schizophrenia. The inheritance pattern appears complex, similar to that of other common conditions like heart disease. To uncover a causal genetic factor, researchers have recently begun to apply a linkage analysis strategy to schizophrenia. Early results suggest that there are many challenges facing scientists who undertake schizophrenia genetics research. While one study has shown significant linkage of schizophrenia to a region on chromosome 5, several other studies have not found linkage to this area. The likelihood that there are several major genes predisposing to the illness and uncertainties about inheritance patterns and diagnostic boundaries are potential difficulties to overcome. Many more families need to be studied, and creative complementary research strategies pursued, to achieve the potential success offered by a genetic linkage approach.