Importantly, detecting phenotype association with a genetic marker does not indicate that the genetic marker is causally related to the phenotype, but may only reflect linkage disequilibrium with the causal variant. Case-control studies are the most frequently performed type of genetic association studies because they are simpler to implement than family-based designs. In their simplest form, population-based genetic association studies are similar to epidemiologic case-control studies and involve identifying genetic markers with significant allele, genotype, or haplotype frequency differences between individuals with the phenotype of interest cases and a set of unrelated control individuals.
Indeed, case-control genetic association studies have already contributed to identifying genes associated with complex disorders, as in the cases of apolipoprotein E-4 with late-onset Alzheimer disease 31 and factor V gene with venous thrombosis. Silverman and Palmer 33 have reviewed these factors that may adversely affect the results of any association study in complex diseases.
They have recommended five key elements in the performance of valid case-control genetic association studies for complex diseases: 1 proper selection of gene polymorphisms, 2 accounting for population stratification, 3 assessment of Hardy-Weinberg equilibrium, 4 replication, and 5 adjustment for multiple comparisons.
Ideally, cases and control study subjects should be drawn from the same base population. Failure to do so will often result in biased selection that can adversely influence the results, often resulting in a spurious association.
Because of the small genetic effect sizes seen and expected for complex traits, sample sizes in the thousands are generally required in addition to replication to generate rigorously validated association results. Family-based genetic association tests are based on the transmission disequilibrium test, which provides a test of linkage and association without bias from population stratification or admixture. Only trios with at least one heterozygous parent at the genetic marker of interest are used for testing.
The test is predicated on the assumption that if a genetic locus is uninvolved neither linked nor associated in the phenotype of interest, one would expect the two parental alleles at that locus to be transmitted equally to an affected child i. Family-based association studies cost more than case-control studies because one has to recruit and genotype three people instead of two.
In addition, not all diseases can use the family-based design because often parents have died and hence are not available for study. Despite these disadvantages, there are also powerful reasons to use trios if possible. First, unlike the case-control study, the family-based association study is immune to population stratification because the parental genotype is used as the control. Second, within each trio, only one person the subject must be phenotyped. This is particularly useful when phenotyping is very expensive or invasive. Family-based testing also offers an important method of assessing genotyping quality, because data can be analyzed for mendelian errors.
The transmission disequilibrium test has been extended in many ways, for instance, to allow family-based tests of association for extended pedigrees. Genetic association studies using candidate gene approaches and, more recently, genome-wide association GWA studies have been performed in large multinational patient cohorts. The major histocompatibility complex is the dominant genetic region implicated in autoimmune disease, including SSc.
The interpretation of human leukocyte antigen HLA associations is complicated by the extensive linkage disequilibrium of risk haplotypes. It has long been known that specific HLA alleles are associated with SSc and specific autoantibodies. Table summarizes SSc susceptibility genes identified to date, although there will undoubtedly be many more discovered. In addition to classic SNPs, informative genetic polymorphisms in SSc also include copy number variations, rare allelic variants, and epigenetic changes.
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TABLE Selected Systemic Sclerosis Susceptibility Genes. Based on published candidate gene studies and genome-wide association studies as of Remarkably, all three genes are closely linked to the type I IFN system. In contrast, the majority of genetic associations are common genetic variations SNPs with a low effect size.
Such SNPs are most often found in the noncoding region of the genome and their functional consequences have not been established yet. Some of these variations have been associated with phenotypical alterations in the IFN system. Several of the genetic associations linked to the IFN system are also associated with other autoimmune diseases, thus highlighting type I IFN as a central player in breaking the immune tolerance.
Robert A. Genetic association studies test if alleles at a single nucleotide polymorphism SNP are found more often in cases than in controls, or in individuals with elevated levels of a quantitative trait.
Progress and promise in understanding the genetic basis of common diseases
Genes that have been replicated in multiple studies include those in: lipid metabolism pathways, such as apolipoprotein A5 APOA5 Grallert et al. Since the publication of the reference human genome sequence, advancements in high-throughput genotyping technologies and databases of common genetic variation have enabled genome-wide association studies GWAS to test over a million SNPs in a single experiment.
Genome-wide investigations into the individual components of MetS using GWAS, however, have been enormously successful.
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Many of the identified genes have previously known functional roles or are mutated in monogenic disease and represent positive controls for the GWAS approach. Additionally, many novel genes with no previously known roles in metabolic pathways have been robustly associated and their biological functions are under study. Genes associated with components of metabolic syndrome in genome-wide association studies. Genes in bold type are associated with multiple components of metabolic syndrome. Data from Dupuis et al. Pleiotropy describes the situation where a gene impacts multiple phenotypic traits.
In the interacting metabolic pathways involved in MetS pathophysiology, pleiotropy is to be expected. The genetic overlap between insomnia and mood disorders may point toward why cognitive behavioral therapy may be effective for both sleep and anxiety. Current drugs, for their part, have limited efficacy, can be addictive and have side effects.
Simon Makin is a freelance science writer based in London.
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