Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (affect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed. (+info)
The role of genetic factors in autoimmune disease: implications for environmental research.
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Studies in both humans and in animal models of specific disorders suggest that polymorphisms of multiple genes are involved in conferring either a predisposition to or protection from autoimmune diseases. Genes encoding polymorphic proteins that regulate immune responses or the rates and extent of metabolism of certain chemical structures have been the focus of much of the research regarding genetic susceptibility. We examine the type and strength of evidence concerning genetic factors and disease etiology, drawing examples from a number of autoimmune diseases. Twin studies of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type I diabetes, and multiple sclerosis (MS) indicate that disease concordance in monozygotic twins is 4 or more times higher than in dizygotic twins. Strong familial associations (odds ratio ranging from 5-10) are seen in studies of MS, type I diabetes, Graves disease, discoid lupus, and SLE. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Recent genomewide searches in RA, SLE, and MS provide evidence for multiple susceptibility genes involving major histocompatibility complex (MHC) and non-MHC loci; there is also evidence that many autoimmune diseases share a common set of susceptibility genes. The multifactorial nature of the genetic risk factors and the low penetrance of disease underscore the potential influence of environmental factors and gene-environment interactions on the etiology of autoimmune diseases. (+info)
The genetics of age-related macular degeneration.
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Age-related macular degeneration (AMD) is increasingly recognized as a complex genetic disorder in which one or more genes contribute to an individual's susceptibility for developing the condition. Twin and family studies as well as population-based genetic epidemiologic methods have convincingly demonstrated the importance of genetics in AMD, though the extent of heritability, the number of genes involved, and the phenotypic and genetic heterogeneity of the condition remain unresolved. The extent to which other hereditary macular dystrophies such as Stargardts disease, familial radial drusen (malattia leventinese), Best's disease, and peripherin/RDS-related dystrophy are related to AMD remains unclear. Alzheimer's disease, another late onset, heterogeneous degenerative disorder of the central nervous system, offers a valuable model for identifying the issues that confront AMD genetics. (+info)
Dissecting the genetic architecture of lipids, lipoproteins, and apolipoproteins: lessons from twin studies.
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We review the ways in which twin studies have been used to investigate the genetic architecture of lipids, lipoproteins, and apolipoproteins. We focus on the age dependency of genetic effects and the importance of pleiotropy for the lipid system. Finally, consequences are discussed of age dependency and pleiotropy for the design and power of twin studies aimed at detecting the actual quantitative trait loci (QTLs) involved. It is concluded that twin studies have played an important role and will remain highly valuable for the elucidation of the genetic architecture of lipids, lipoproteins, and apolipoproteins. Twins can efficiently be used to identify the location and function of QTLs. Taking account of pleiotropy and age-dependent gene expression in study design and data analysis will improve the power and efficiency to find these QTLs for components of the lipid system. (+info)
Recent advances in the genetics of severe childhood obesity.
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Childhood obesity is becoming a global epidemic. Twin studies suggest a heritability of fat mass, and disorders of energy balance that arise from genetic defects have been identified. In the past three years, five single gene disorders resulting in early onset obesity have been characterised. The discovery of these genetic defects has biological and clinical implications which are greater than the rarity of the individual diseases might suggest. (+info)
Gene-environment interaction and the mapping of complex traits: some statistical models and their implications.
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The manifestation of many complex diseases or traits is very likely the result of an inextricable interplay of the biological and the environmental. Yet the role of environmental effect has traditionally been played down, for various reasons. In this paper, some simple statistical models that incorporate gene-environment interaction (GEI) have been proposed and their behavior and implications investigated. These implications concern the conditional independence assumption in likelihood calculation of pedigree data, the fine-tuning of the sib pair method for mapping quantitative traits, apportioning of disease or trait variation due to specific causes. In addition, they concern properties of gene mapping methods that do not take GEI into account, and they bring into question the utility of commonly used measures of genetic effects such as recurrence risk ratio for relative pairs, twin concordance rates, and heritability coefficients. In the presence of GEI, all these measures are functions not only of genetic effects and gene frequency, but also of environmental effects, the distribution of environmental factors in the population, and of GEI. Above all, these measures are all measures of familial aggregation, since they can be significant even in the absence of any genetic component of the disease. Thus their use as indicators of the genetic basis of complex diseases is cast into doubt. (+info)
Role of genetic factors in the pathogenesis of osteoporosis.
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Osteoporosis is a common disease with a strong genetic component characterised by low bone mass, microarchitectural deterioration of bone tissue and an increased risk of fracture. Twin and family studies have shown that genetic factors play an important role in regulating bone mineral density and other determinants of osteoporotic fracture risk, such as ultrasound properties of bone, skeletal geometry and bone turnover. Osteoporosis is a polygenic disorder, determined by the effects of several genes, each with relatively modest effects on bone mass and other determinants of fracture risk. It is only on rare occasions that osteoporosis occurs as the result of mutations in a single gene. Linkage studies in man and experimental animals have defined multiple loci which regulate bone mass but the genes responsible for these effects remain to be defined. Population-based studies and case-control studies have similarly identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, including the vitamin D receptor, oestrogen receptor and collagen type IalphaI gene. The individual contribution of these genes to the pathogenesis of osteoporosis is small however, reflected by the fact that the relationship between individual candidate genes and osteoporosis has been inconsistent in different studies. An important aim of future work will be to define how the genes which regulate bone mass, bone turnover and other aspects of bone metabolism interact with each other and with environmental variables to cause osteoporosis in individual patients. If that aim can be achieved then there is every prospect that preventative therapy could be targeted to those at greatest risk of the osteoporosis, before fractures have occurred. (+info)
Both the environment and genes are important for concentrations of cadmium and lead in blood.
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Concentrations of cadmium and lead in blood (BCd and BPb, respectively) are traditionally used as biomarkers of environmental exposure. We estimated the influence of genetic factors on these markers in a cohort of 61 monozygotic and 103 dizygotic twin pairs (mean age = 68 years, range = 49-86). BCd and BPb were determined by graphite furnace atomic absorption spectrophotometry. Variations in both BCd and BPb were influenced by not only environmental but also genetic factors. Interestingly, the genetic influence was considerably greater for nonsmoking women (h(2) = 65% for BCd and 58% for BPb) than for nonsmoking men (13 and 0%, respectively). The shared familial environmental (c(2)) influence for BPb was 37% for men but only 3% for women. The association between BCd and BPb could be attributed entirely to environmental factors of mutual importance for levels of the two metals. Thus, blood metal concentrations in women reflect not only exposure, as previously believed, but to a considerable extent hereditary factors possibly related to uptake and storage. Further steps should focus on identification of these genetic factors and evaluation of whether women are more susceptible to exposure to toxic metals than men. (+info)