Current challenges and new opportunities for geneenvironment. The recent progress in sequencing technologies makes possible largescale medical sequencing efforts to assess the importance of rare variants in complex diseases. Gwas are particularly useful in finding genetic variations that contribute to common, complex diseases, such as asthma, cancer, diabetes, heart disease and mental illnesses. Optimized group sequential study designs for tests of genetic linkage and association in complex diseases article in the american journal of human genetics 693. Researchers have been motivated to discover and describe how the interplay of these factors influences disease risk and outcomes. Study designs for identification of rare disease variants. Given fixed genotyping resources, it is important to know which study designs are the most efficient. In this study, we applied gene set enrichment analysis gsea approach to detect the associations between elements and complex diseasestraits though integrating element. Observational studies are part of the toolbox of study designs. Association analysis of complex diseases using triads, parent. We have developed the power for genetic association analyses pga package which comprises algorithms and graphical user interfaces for sample size and minimum detectable risk.
Unless otherwise noted, the data are final totals for 2011 reported as of june 30, 2012. Descriptive studies include case reports, caseseries. They may be hypothesis generating or the only feasible or ethical design such as when studying the effects of obesity or smoking on health. For example, the heritability of amd was confirmed upon the release of the first genomewide association study gwas along with confirmatory reports that supported the findings of that stateofthe art method, thus setting the foundation. Findings from these studies have been extensively discussed 4,19, the key general conclusions being that tumour development is associated with gain of dnam at cgis, lossofimprinting, and epigenetic remodelling of repeat elements, particularly loss of dnam. This special issue is devoted to original research articles as well as overview papers that propose and discuss innovative study designs, novel probabilistic and statistical models, and analysis methods andor algorithms for genetic and genomic studies of complex diseases. We develop likelihoodbased statistical models and likelihood ratio tests to test for association between complex diseases and genetic markers by using combinations of full triads, parentchild dyads, and affected singleton monads for a unified analysis. There are many different technologies, study designs and analytical tools for identifying genetic risk factors. This article provides a broad outline of the design and analysis of such studies, focusing on casecontrol studies in candidate genes or regions. Through genomewide association studies gwas, thousands of common loci associated with complex diseases have been identified.
Analytic study designs the architecture of the various strategies for testing hypotheses through epidemiologic studies, a comparison of their relative strengths and weaknesses, and an indepth investigation of. The common errors encountered in association studies of complex diseases are summarized in box 1. Genomewide association studies gwas have evolved over the last ten years into a powerful tool for investigating the genetic architecture of human disease. Analytic study designs the architecture of the various strategies for testing hypotheses through epidemiologic studies, a comparison of their relative strengths and weaknesses, and an indepth investigation of major designs. The opportunities for genomewide scans to map complexdisease genes.
Observational study an overview sciencedirect topics. Linkage studies versus association studies introduction to. Genome association studies of complex diseases by casecontrol. Clinical trials of drugs and devices are experimental studies. Susceptibility to corticosteroidinduced adrenal suppression. In the study of complex diseases, as tb, because the effects of genes may be modified by environmental i. Traditionally, these effects have been thought of as independent. Several studies have used results from gwas to systematically identify genetic variants associated with multiple traits, both across the breadth of human biomedical traits and disorders 5, 8 and for groups of. The relative power of familybased and casecontrol designs for linkage disequilibrium studies of complex human diseases i. Epidemiological methods for studying genes and environmental. Jan 21, 2003 the potential of the genetic association approach for the identification of genetic variants that alter susceptibility to common complex disease is well recognised. The utilization of study designs and related analyses according to the aims. Anderson tw 1984 an introduction to multivariate statistical analysis, 2nd edition.
Study designs for rare diseases keith hull, md, phd fdacderdparp september 21, 2010 disclosures the views presented here do not necessarily reflect those of the food and drug administration 2 3. Summary of notifiable diseases united states, 2011. To address this problem, we extended the likelihoodbasedmethod. The potential of the genetic association approach for the identification of genetic variants that alter susceptibility to common complex disease is well recognised. Linkage mapping of complex diseases is often followed by association studies between phenotypes and marker genotypes through use of casecontrol or familybased designs. He cites as valuable facets of study design and causal inference the examination of speci. Genetic association an overview sciencedirect topics. Analysis of complex disease association studies sciencedirect. Genetic association studies are used to find candidate genes or genome regions that contribute to a specific disease by testing for a correlation between disease status and genetic variation.
Haines is director of the program in human genetics, department of molecular physiology and biophysics, vanderbilt university school of medicine. Epidemiology is concerned with the study of the distribution. Most association studies have a casecontrol study design, in which. Casecontrol studies have numerous advantages for the ge. Environmental epidemiology is a complex field that in some cases provides keen insights into environmentally caused diseases and in others provides unclear results that must be followed up by other types of studies. Ioannidis, department of hygiene and epidemiology, university of ioannina school of medicine, ioannina 45110, greece email.
Both nurture environmental and nature genetic factors play an important role in human disease etiology. Furthermore, more complex familybased designs are possible 119 that might allow combined association and linkage analysis 120, and familybased association tests have also been developed for. Highthroughput single nucleotide polymorphism snp genotyping technologies make massive genotype data, with a large number of individuals, publicly available. We will begin with study designs that provide the weakest arguments for such an association and end with those that have the strongest evidence. The journal of dental hygiene is the refereed, scientific publication of the. A limitation of our study is the small sample size used for the genomewide association study when compared with studies using genomewide association to investigate individual susceptibility to developing a complex disease. Identifying strains that contribute to complex diseases.
We have developed the power for genetic association analyses pga package which comprises algorithms and graphical user interfaces for sample size and minimum detectable. Triad families are routinely used to test association between genetic variants and complex diseases. To understand health and disease we must study how nature and nurture interact. Study designs for identification of rare disease variants in. Objective two functional single nucleotide polymorphisms snp in the ptpn22 gene rs24746601 and rs33996649 have been associated with autoimmunity. Journal of dental hygiene supplement to adha access periodontal diseases and adverse pregnancy. Journal of dental hygiene supplement of dental hygiene. Gwas are particularly useful in finding genetic variations that contribute to common, complex. We introduce here a unified framework for association testing of rare variants in familybased designs or designs based on.
Pdf association study designs for complex diseases. Efficient study designs for test of genetic association using sibship data and unrelated cases and controls. Study designs for rare disease keith hull, md, phd ccrrd september 21, 2010 1192011 12 summary mechanisms is place to help develop drugs for rare diseases rare diseases present challenges regarding optimal study design 34 variety of alternative study designs available that can. The impact of the human genome project on complex disease. Consider a casecontrol design with n cases from an affected. The role of dnam variation in complex disease has mainly been explored in the context of cancer, in what may be considered as early ewas.
Nov 01, 2011 the recent progress in sequencing technologies makes possible largescale medical sequencing efforts to assess the importance of rare variants in complex diseases. Li m, boehnke m and abecasis gr am j hum genet 2006 78. Gwass typically focus on associations between singlenucleotide polymorphisms snps and traits like major human. Help develop better strategies to detect, treat and prevent the disease. Advanced designs and statistical methods for genetic and. This perspective is ill informed for nonmendelian complex disorders which result as an interaction between genetics and environment. Download a pdf by jeremy howick about study designs. Genetic association studies of complex neurological diseases. Explanations for this lack of reproducibility are wellrehearsed, and typically include poor study design, incorrect assumptions about the underlying genetic architecture and simple overinterpretation of data.
Advances in spatial epidemiology plus geographical information systems and global positioning systems are already being applied to the study of infectious diseases, and their forthcoming application to chronic diseases should enable more rigorous and sensitive identification of spatial variation in complex diseases 62, 69. Kochs postulates mandated one organism for a disease and sir austin bradford hills 1965 causal criteria suggested one cause for a disease. Interpretation of genetic association studies in complex. One possibility is to apply it to casecontrol samples. Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases john p. The results of such efforts depend heavily on the use of efficient study designs and analytical methods. This may lead to loss of power and insufficient utilization of genetic information in a study. Genome wide association studies a genomewide association study. Genomewide association studies for common diseases and. Efficient study designs for test of genetic association using. Optimized group sequential study designs for tests of.
Study designs for rare disease keith hull, md, phd ccrrd september 21, 2010 1192011 2. There are two basic types of study designs used for genetic association. Summary of notifiable diseases united states, 2011 please. Uds is an interactive diagnostic study of the lower urinary tract composed of a number of tests that can be used to obtain functional information about urine storage and emptying. Designs for linkage analysis and association studies of. Genetic association studies are the most commonly used study designs to find disease genes in complex traits. To scan several thousand snps on many individuals to find genetic variations associated with a particular disease. Genomewide association studies are becoming an increasingly effective tool for identifying genetic factors contributing to complex diseases. We compared trio based and casecontrol study designs in different disease models, and partitioned the performance differences into separate. His research into the localization and identification of genes involved in human disease includes studying alzheimers disease, multiple sclerosis, parkinsons disease, autism, macular degeneration, and other complex diseases. Genetic and environmental factors are thought to contribute to the etiology of most complex diseases. Introduction families have dominated genetic studies, dating back to mendels.
University of oxford, nuffield department of clinical medicine, headington, oxford ox3 9du, uk. Most common diseases are complex genetic traits, with multiple genetic. However, it is generally seen that although certain diseases may have a single cause, most diseases are outcomes of a complex interplay of. Urodynamics uds is the dynamic study of the transport, storage and evacuation of urine. When patterns change such as dna methylation at specific loci, discriminating the phenotypically affected cases from control. In practice, one may collect not only complete triads, but also incomplete families such as dyads affected child with one parent and singleton monads. Our first distinction is whether the study is analytic or nonanalytic. For complex diseases which often involve function of multigenetic variants each with small or moderate effect, linkage analysis has little power compared to association studies. Oral health, atherosclerosis, and cardiovascular disease. A nonanalytic or descriptive study does not try to quantify the relationship but tries to give us a picture of what is happening in a population, e. Efficient study designs for test of genetic association. The aim of this study was to investigate the role of the r263q snp for the first time and to reevaluate the role of the r620w snp in the genetic predisposition to systemic sclerosis ssc susceptibility and clinical phenotypes.
Some study designs are better suited for the establishment of causal inferences between dental infections and chd. The criteria needed to establish a causal association are presented in table 1. Successful design and conduct of genomewide association studies. The approaches used in these diseases have been successfully applied to numerous other complex diseases.
Design considerations for genomic association studies. Motivated by high throughput genotyping technology, our aim in this study was to experimentally compare the power and accuracy of casecontrol and family trio based approaches for haplotype based, large scale, association gene mapping. Statistical power calculations inform the design and interpretation of genetic association studies, but few programs are tailored to casecontrol studies of single nucleotide polymorphisms snps in unrelated subjects. Gwas have been applied to hundreds of complex traits and common diseases, yielding thousands of genetic associations that surpass accepted standards for statistical significance. Pdf association study designs for complex diseases ashok. We will focus here on the genomewide association study or gwas that measures and analyzes.
Observational studies are a fundamental part of epidemiology and account for many of the research papers published in specialty research journals. Researchers have been motivated to discover and describe how the interplay of these factors influences. Genetic analysis of complex diseases wiley online books. The study of linkage disequilibrium ld is not only important in the design of efficient, powerful association studies, but also yields new insights into the history of. An outstanding question is how to use snp technology effi ciently. Strategies for genetic studies of complex diseases. Triad studies are important and popular since they are robust in terms of being less prone to false positives due to population structure. We describe some basic study designs as well as general approaches to analysis for qualitative, quantitative, and complex traits. Analysis of the influence of ptpn22 gene polymorphisms in. An epigenomewide association study ewas is an examination of a genomewide set of quantifiable epigenetic marks, such as dna methylation, in different individuals to derive associations between epigenetic variation and a particular identifiable phenotypetrait. Association study designs for complex diseases nature. An empirical comparison of casecontrol and trio based.
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