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• W1983264513 abstract "In their polemic critique of genetic association studies, Giovanni Gambaro and colleagues (Jan 22, p 308),1Gambaro G Anglani F D'Angelo A Association studies of genetic polymorphisms and complex disease.Lancet. 2000; 355: 308-311Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar argue that such studies have become too profligate, without sufficient regard to plausible a priori scientific hypotheses or to methodological limitations. We suggest that if association studies are done carefully, and certain methodological issues (such as the choice of genetic markers and the careful definition of clinical phenotypes and control populations) are adequately addressed, then these studies can yield useful information both about disease processes and gene function. In association studies, genetic variation in candidate genes is used to explore interindividual differences in disease susceptibility.2Lander ES Schork NJ Genetic dissection of complex traits.Science. 1994; 265: 2037-2048Crossref PubMed Scopus (2753) Google Scholar They are more sensitive than linkage studies in identifying the relatively small genetic effects that underlie many complex diseases. The choice of candidate genes arises either from their positional identification by linkage analysis, or more frequently because the gene product can be plausibly argued to contribute to the disease process. Candidate genes should be identified using all available data, but, in the absence of linkage studies, the choice of candidate genes is necessarily hypothesis-driven and some biologically lateral thinking is usually necessary. For example, many diseases result in a complex cascade of inflammatory mediators. Measurement of these mediators will confirm the presence of host inflammation, but may not distinguish crucial pathways involved in susceptibility and outcome. An association between functional variants of a mediator gene and clinical phenotype may identify central pathophysiological processes in disease. Examples of this approach in infectious diseases alone include an understanding of the role of natural resistance-associated macrophage in mycobacterial susceptibility, the role of tumour necrosis factor in malaria, and the role of plasminogen-activating-factor inhibitor in meningococcal disease.3Hill AV Genetics and genomics of infectious disease susceptibility.Br Med Bull. 1999; 55: 401-413Crossref PubMed Scopus (68) Google Scholar The choice of genetic markers is also important. Single nucleotide polymorphisms (SNPs) are the markers of choice as they are stable, frequent, and amenable to automated genotyping. SNPs do not occur in isolation; rather they arise on the haplotypic background of other variant alleles, so that SNPs are in linkage disequilibrium (LD) with neighbouring polymorphisms. LD depends not only on genetic distance but also on local recombination rates, so that LD varies both between and within genes. Although association studies ultimately seek to identify functional SNPs, these are rarely known, and studies usually rely on markers assumed to be close enough to true functional variant or variants to be in strong LD. In many genes, the extent of sequence variation and the distribution of LD are unknown. Detailed examination of polymorphism and LD across human genes suggest that the use of one or two SNPs is insufficient to detect most associations, even if the SNPs themselves fall on associated haplotypes.4Clark AG Weiss KM Nickerson DA et al.Haplotype structure and population genetic inferences from nucleotide‐sequence variation in human lipoprotein lipase.Am J Hum Genet. 1998; 63: 595-612Summary Full Text Full Text PDF PubMed Scopus (392) Google Scholar Dipping into candidate genes, using one or two SNPs of unknown function, is therefore unlikely to yield useful information. The absence of an association between an SNP and a disease may not imply that the candidate locus is not important, rather that the genetic markers used were inadequate to address the original hypothesis. Another important issue is unrecognised population stratification that may result in a spurious association. Family-based studies, where parents act as biological controls for their affected offspring, have been used to circumvent this issue5Rieder MJ Taylor SL Clark AG Nickerson DA Sequence variation in the human angiotensin converting enzyme.Nat Genet. 1999; 22: 59-62Crossref PubMed Scopus (402) Google Scholar and are increasingly used. Although methodological issues continue to be debated, an outright rejection of genetic association studies is unfounded and ignores the considerable contribution of this approach to the understanding of human disease." @default.
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• W1983264513 title "In defence of genetic association studies" @default.
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• W1983264513 doi "https://doi.org/10.1016/s0140-6736(05)73985-4" @default.
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