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278
Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans
- HUMAN MOLECULAR GENETICS
, 2002
"... Epistasis, the interaction between genes, is a topic of current interest in molecular and quantitative genetics. A large amount of research has been devoted to the detection and investigation of epistatic interactions. However, there has been much confusion in the literature over definitions and int ..."
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Epistasis, the interaction between genes, is a topic of current interest in molecular and quantitative genetics. A large amount of research has been devoted to the detection and investigation of epistatic interactions. However, there has been much confusion in the literature over definitions and interpretations of epistasis. In this review, we provide a historical background to the study of epistatic interaction effects and point out the differences between a number of commonly used definitions of epistasis. A brief survey of some methods for detecting epistasis in humans is given. We note that the degree to which statistical tests of epistasis can elucidate underlying biological interactions may be more limited than previously assumed.
A complete enumeration and classification of two-locus disease models. Hum Hered 50
, 2000
"... www.karger.com ..."
The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes
, 1996
"... Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot ..."
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Cited by 34 (3 self)
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Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell-mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative
CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-relatedmacular degeneration,”Nature
- Genetics,
, 2006
"... In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and arou ..."
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Cited by 26 (2 self)
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In developed countries, age-related macular degeneration is a common cause of blindness in the elderly. A common polymorphism, encoding the sequence variation Y402H in complement factor H (CFH), has been strongly associated with disease susceptibility. Here, we examined 84 polymorphisms in and around CFH in 726 affected individuals (including 544 unrelated individuals) and 268 unrelated controls. In this sample, 20 of these polymorphisms showed stronger association with disease susceptibility than the Y402H variant. Further, no single polymorphism could account for the contribution of the CFH locus to disease susceptibility. Instead, multiple polymorphisms defined a set of four common haplotypes (of which two were associated with disease susceptibility and two seemed to be protective) and multiple rare haplotypes (associated with increased susceptibility in aggregate). Our results suggest that there are multiple disease susceptibility alleles in the region and that noncoding CFH variants play a role in disease susceptibility. Age-related macular degeneration (AMD; OMIM 603075) is a complex degenerative disorder that primarily affects the elderly. Disease susceptibility is influenced by multiple genetic 1-5 and environmental factors After quality assessment of genotype data (see Methods), we tested each SNP for association in 544 unrelated affected individuals and 268 unrelated controls
Kimmel M: Forward-Time Simulations of Human Populations with Complex Diseases
- PLoS Genet
"... Due to the increasing power of personal computers, as well as the availability of flexible forward-time simulation programs like simuPOP, it is now possible to simulate the evolution of complex human diseases using a forward-time approach. This approach is potentially more powerful than the coalesce ..."
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Cited by 23 (1 self)
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Due to the increasing power of personal computers, as well as the availability of flexible forward-time simulation programs like simuPOP, it is now possible to simulate the evolution of complex human diseases using a forward-time approach. This approach is potentially more powerful than the coalescent approach since it allows simulations of more than one disease susceptibility locus using almost arbitrary genetic and demographic models. However, the application of such simulations has been deterred by the lack of a suitable simulation framework. For example, it is not clear when and how to introduce disease mutants—especially those under purifying selection—to an evolving population, and how to control the disease allele frequencies at the last generation. In this paper, we introduce a forward-time simulation framework that allows us to generate large multi-generation populations with complex diseases caused by unlinked disease susceptibility loci, according to specified demographic and evolutionary properties. Unrelated individuals, small or large pedigrees can be drawn from the resulting population and provide samples for a wide range of study designs and ascertainment methods. We demonstrate our simulation framework using three examples that map genes associated with affection status, a quantitative trait, and the age of onset of a hypothetical cancer, respectively. Nonadditive fitness models, population structure, and gene–gene interactions are simulated. Case-control, sibpair, and large pedigree samples are drawn from the simulated populations and are examined by a variety of gene-mapping methods. Citation: Peng B, Amos CI, Kimmel M (2007) Forward-time simulations of human populations with complex diseases. PLoS Genet 3(3): e47. doi:10.1371/journal.pgen.0030047
Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping
- Alcohol. Clin. Exp. Res
, 2000
"... Background There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: AdditionaLgenotyping in the 1 ..."
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Cited by 23 (12 self)
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Background There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: AdditionaLgenotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-111-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets.
Asthma And Allergic Diseases In Australian Twins And Their Families
, 1997
"... The occurrence of asthma or wheezing, and other allergic diseases, in 3808 pairs of twins aged 18 to 88 years was recorded by mailed questionnaire in 1980 (a pairwise response rate of 64%; individual, 69%). This sample (Cohort 1) was resurveyed in 1988 (78% pairwise followup), and a further 2159 pai ..."
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Cited by 20 (2 self)
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The occurrence of asthma or wheezing, and other allergic diseases, in 3808 pairs of twins aged 18 to 88 years was recorded by mailed questionnaire in 1980 (a pairwise response rate of 64%; individual, 69%). This sample (Cohort 1) was resurveyed in 1988 (78% pairwise followup), and a further 2159 pairs aged 18 to 25 years (Cohort 2) responded usefully to a similar item on asthma on another instrument in 1989 sent to 4078 pairs (pairwise 53%). The crude cumulative incidence of wheezing was 13.2% in 1980, 18.9% in 1988, and 21.8% in 1989. Genetic analyses performed using this screening data suggested a strong genetic component to wheezing, hayfever and allergy, and sizeable genetic correlations between different atopic conditions. Genetic influences specific to particular traits such as wheezing were also detectable. A secular increase in incidence of wheeze experienced by consecutive birth cohorts seemed to be due to nonfamilial environmental factors. A more detailed respiratory symptoms...
Human neural tube defects: developmental biology, epidemiology, and genetics
- Neurotoxicol. Teratol
, 2005
"... Abstract Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth defect after congenital heart defects. The most comm ..."
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Cited by 18 (0 self)
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Abstract Birth defects (congenital anomalies) are the leading cause of death in babies under 1 year of age. Neural tube defects (NTD), with a birth incidence of approximately 1/1000 in American Caucasians, are the second most common type of birth defect after congenital heart defects. The most common presentations of NTD are spina bifida and anencephaly. The etiologies of NTDs are complex, with both genetic and environmental factors implicated. In this manuscript, we review the evidence for genetic etiology and for environmental influences, and we present current views on the developmental processes involved in human neural tube closure.
Appendectomy in Australian twins
- American Journal of Human Genetics
, 1990
"... nINTRODUCTION Smoking has been variously associated with diseases of the gastrointestinal tract: increased risk of Crohn’s disease (1) and peptic ulcer disease (2), as well as a decreased risk of ul-cerative colitis (UC) (3). However, it has also been reported that appendectomy is protective against ..."
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Cited by 18 (0 self)
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nINTRODUCTION Smoking has been variously associated with diseases of the gastrointestinal tract: increased risk of Crohn’s disease (1) and peptic ulcer disease (2), as well as a decreased risk of ul-cerative colitis (UC) (3). However, it has also been reported that appendectomy is protective against UC (4) and that this reduced risk is specific to appendectomies in persons younger than 20 years of age (5, 6), in particular when these are due to appendicitis (6). Since both smoking and appen-dectomy appear to be protective against UC, dependencies between the two factors might indicate that this protective effect is partly due to confounding. An increased risk of appendectomy among active smokers and children of parents who smoke was reported by Montgomery, Pounder, and Wakefield (7). Although no claims of causation were made, it was suggested that smoking might disable an immune response associated with UC and leave the appendix vulnerable to inflamma-tion. The study has been criticized for failing to account for the timing of exposure to smoking relative to appendec-tomy (8). Butland and Strachan (9) found further evidence for the association between passive smoking and appendec-tomy in children younger than 16 years of age. The aim of this paper is to investigate the association be-tween reported personal tobacco smoking and appendec-tomy in a large Australian twin cohort. Two statistical approaches were employed. The first was a cohort analysis using a time-dependent smoking status variable. The second was a co-twin case-control analysis in which the twin struc-ture of the data afforded an assessment of whether depen-dencies between smoking and appendectomy are due to unique environment or common genetic influences.
