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Journal ArticleDOI

Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.

TL;DR: Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association with glaucoma, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS).
Abstract: Glaucoma is a leading cause of irreversible blindness A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q241 region associated with glaucoma Further investigation revealed that the association is confined to exfoliation glaucoma (XFG) Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS) About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes The population-attributable risk is more than 99% The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG
Citations
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Journal ArticleDOI
07 Nov 2008-Science
TL;DR: The intellectual foundations of genetic mapping of Mendelian and complex traits in humans are discussed, lessons emerging from linkage analysis of MendELian diseases and genome-wide association studies of common diseases are examined, and questions and challenges that lie ahead are discussed.
Abstract: Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead

1,421 citations

Journal ArticleDOI
TL;DR: Most common SNPs have now been assessed in genome-wide studies for statistical associations with many complex traits, including many important common diseases, and only a limited amount of the heritable component of any complex trait has been identified.
Abstract: The last few years have seen extensive efforts to catalogue human genetic variation and correlate it with phenotypic differences. Most common SNPs have now been assessed in genome-wide studies for statistical associations with many complex traits, including many important common diseases. Although these studies have provided new biological insights, only a limited amount of the heritable component of any complex trait has been identified and it remains a challenge to elucidate the functional link between associated variants and phenotypic traits. Technological advances, such as the ability to detect rare and structural variants, and a clear understanding of the challenges in linking different types of variation with phenotype, will be essential for future progress.

1,060 citations

Journal ArticleDOI
TL;DR: This Review comprehensively assess the benefits and limitations of GWAS in human populations and discusses the relevance of performing more GWAS, with a focus on the cardiometabolic field.
Abstract: Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype–phenotype associations. GWAS have revolutionized the field of complex disease genetics over the past decade, providing numerous compelling associations for human complex traits and diseases. Despite clear successes in identifying novel disease susceptibility genes and biological pathways and in translating these findings into clinical care, GWAS have not been without controversy. Prominent criticisms include concerns that GWAS will eventually implicate the entire genome in disease predisposition and that most association signals reflect variants and genes with no direct biological relevance to disease. In this Review, we comprehensively assess the benefits and limitations of GWAS in human populations and discuss the relevance of performing more GWAS. Despite the success of human genome-wide association studies (GWAS) in associating genetic variants and complex diseases or traits, criticisms of the usefulness of this study design remain. This Review assesses the pros and cons of GWAS, with a focus on the cardiometabolic field.

1,002 citations

Journal ArticleDOI
19 Mar 2008-JAMA
TL;DR: The design, interpretation, application, and limitations of GWA studies for clinicians and scientists for whom this evolving science may have great relevance are described.
Abstract: Genome-wide association (GWA) studies use high-throughput genotyping technologies to assay hundreds of thousands of single-nucleotide polymorphisms (SNPs) and relate them to clinical conditions and measurable traits. Since 2005, nearly 100 loci for as many as 40 common diseases and traits have been identified and replicated in GWA studies, many in genes not previously suspected of having a role in the disease under study, and some in genomic regions containing no known genes. GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors. Although these studies are clearly many steps removed from actual clinical use, and specific applications of GWA findings in prevention and treatment are actively being pursued, at present these studies mainly represent a valuable discovery tool for examining genomic function and clarifying pathophysiologic mechanisms. This article describes the design, interpretation, application, and limitations of GWA studies for clinicians and scientists for whom this evolving science may have great relevance.

977 citations

Journal ArticleDOI
TL;DR: HapMap-based discoveries have shed new light on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments.
Abstract: The International HapMap Project was designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases. This expectation has been amply fulfilled with just the initial output of genome-wide association studies, identifying nearly 100 loci for nearly 40 common diseases and traits. These associations provided new insights into pathophysiology, suggesting previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. In addition, HapMap-based discoveries have shed new light on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments. In this review we examine the origin, development, and current status of the HapMap; its prospects for continued evolution; and its current and potential future impact on biomedical science.

902 citations

References
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Journal ArticleDOI
TL;DR: In this paper, the role and limitations of retrospective investigations of factors possibly associated with the occurrence of a disease are discussed and their relationship to forward-type studies emphasized, and examples of situations in which misleading associations could arise through the use of inappropriate control groups are presented.
Abstract: The role and limitations of retrospective investigations of factors possibly associated with the occurrence of a disease are discussed and their relationship to forward-type studies emphasized. Examples of situations in which misleading associations could arise through the use of inappropriate control groups are presented. The possibility of misleading associations may be minimized by controlling or matching on factors which could produce such associations; the statistical analysis will then be modified. Statistical methodology is presented for analyzing retrospective study data, including chi-square measures of statistical significance of the observed association between the disease and the factor under study, and measures for interpreting the association in terms of an increased relative risk of disease. An extension of the chi-square test to the situation where data are subclassified by factors controlled in the analysis is given. A summary relative risk formula, R, is presented and discussed in connection with the problem of weighting the individual subcategory relative risks according to their importance or their precision. Alternative relative-risk formulas, R I , R2, Ra, and R4/ which require the calculation of subcategory-adjusted proportions ot the study factor among diseased persons and controls for the computation of relative risks, are discussed. While these latter formulas may be useful in many instances, they may be biased or inconsistent and are not, in fact, overages of the relative risks observed in the separate subcategories. Only the relative-risk formula, R, of those presented, can be viewed as such an average. The relationship of the matched-sample method to the subclassification approach is indicated. The statistical methodolo~y presented is illustrated with examples from a study of women with epidermoid and undifferentiated pulmonary ccrclnomc.e-J. Nat. Cancer Inst, 22: 719748, 1959.

14,433 citations

Journal ArticleDOI
TL;DR: Estimates from data on low vision and blindness as defined in the International statistical classification of diseases, injuries and causes of death, 10th revision show cataract remains the leading cause of visual impairment in all regions of the world, except in the most developed countries.
Abstract: This paper presents estimates of the prevalence of visual impairment and its causes in 2002, based on the best available evidence derived from recent studies. Estimates were determined from data on low vision and blindness as defined in the International statistical classification of diseases, injuries and causes of death, 10th revision. The number of people with visual impairment worldwide in 2002 was in excess of 161 million, of whom about 37 million were blind. The burden of visual impairment is not distributed uniformly throughout the world: the least developed regions carry the largest share. Visual impairment is also unequally distributed across age groups, being largely confined to adults 50 years of age and older. A distribution imbalance is also found with regard to gender throughout the world: females have a significantly higher risk of having visual impairment than males. Notwithstanding the progress in surgical intervention that has been made in many countries over the last few decades, cataract remains the leading cause of visual impairment in all regions of the world, except in the most developed countries. Other major causes of visual impairment are, in order of importance, glaucoma, age-related macular degeneration, diabetic retinopathy and trachoma.

4,163 citations

Journal ArticleDOI
TL;DR: The performance of the genomic control method is quite good for plausible effects of liability genes, which bodes well for future genetic analyses of complex disorders.
Abstract: A dense set of single nucleotide polymorphisms (SNP) covering the genome and an efficient method to assess SNP genotypes are expected to be available in the near future. An outstanding question is how to use these technologies efficiently to identify genes affecting liability to complex disorders. To achieve this goal, we propose a statistical method that has several optimal properties: It can be used with case control data and yet, like family-based designs, controls for population heterogeneity; it is insensitive to the usual violations of model assumptions, such as cases failing to be strictly independent; and, by using Bayesian outlier methods, it circumvents the need for Bonferroni correction for multiple tests, leading to better performance in many settings while still constraining risk for false positives. The performance of our genomic control method is quite good for plausible effects of liability genes, which bodes well for future genetic analyses of complex disorders.

3,130 citations

Journal ArticleDOI
TL;DR: This review describes a scheme for diagnosis of glaucoma in population based prevalence surveys that makes provision for diagnosing glauca in eyes with severe visual loss where formal field testing is impractical, and for blind eyes in which the optic disc cannot be seen because of media opacities.
Abstract: This review describes a scheme for diagnosis of glaucoma in population based prevalence surveys. Cases are diagnosed on the grounds of both structural and functional evidence of glaucomatous optic neuropathy. The scheme also makes provision for diagnosing glaucoma in eyes with severe visual loss where formal field testing is impractical, and for blind eyes in which the optic disc cannot be seen because of media opacities.

2,004 citations

Journal ArticleDOI
31 Jan 1997-Science
TL;DR: A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping and will aid in early diagnosis of glaucoma.
Abstract: Glaucoma is a major cause of blindness and is characterized by progressive degeneration of the optic nerve and is usually associated with elevated intraocular pressure. Analyses of sequence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping. Thirteen glaucoma patients were found to have one of three mutations in this gene (3.9 percent of the population studied). One of these mutations was also found in a control individual (0.2 percent). Identification of these mutations will aid in early diagnosis, which is essential for optimal application of existing therapies.

1,401 citations