Genome-wide association study
In genetic epidemiology, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait. GWAS typically focus on associations between single-nucleotide polymorphisms (SNPs) and traits like major diseases. Genome-wide data sets are increasingly being used to identify biological pathways and networks underlying complex diseases, and in drug development process.
These studies normally compare the DNA of two groups of participants: people with the disease (cases) and similar people without (controls). Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays. If one type of the variant (one allele) is more frequent in people with the disease, the SNP is said to be "associated" with the disease. The associated SNPs are then considered to mark a region of the human genome which influences the risk of disease. In contrast to methods which specifically test one or a few genetic regions, the GWA studies investigate the entire genome. The approach is therefore said to be non-candidate-driven in contrast to gene-specific candidate-driven studies. GWA studies identify SNPs and other variants in DNA which are associated with a disease, but cannot on their own specify which genes are causal.
The first successful GWA study was published in 2005 and investigated patients with age-related macular degeneration. It found two SNPs which had significantly altered allele frequency when comparing with healthy controls. As of 2011[update], hundreds or thousands of individuals are tested, over 1,200 human GWA studies have examined over 200 diseases and traits, and almost 4,000 SNP associations have been found. Several GWA studies have received criticism for omitting important quality control steps, rendering the findings invalid, but modern publications address these issues. However, the methodology itself still has opponents.
Any two human genomes differ in millions of different ways. There are small variations in the individual nucleotides of the genomes (SNPs) as well as many larger variations, such as deletions, insertions and copy number variations. Any of these may cause alterations in an individual's traits, or phenotype, which can be anything from disease risk to physical properties such as height. Around the year 2000, prior to the introduction of GWA studies, the primary method of investigation was through inheritance studies of genetic linkage in families. This approach had proven highly useful towards single gene disorders. However, for common and complex diseases the results of genetic linkage studies proved hard to reproduce. A suggested alternative to linkage studies was the genetic association study. This study type asks if the allele of a genetic variant is found more often than expected in individuals with the phenotype of interest (e.g. with the disease being studied). Early calculations on statistical power indicated that this approach could be better than linkage studies at detecting weak genetic effects.
In addition to the conceptual framework several additional factors enabled the GWA studies. One was the advent of biobanks, which are repositories of human genetic material which greatly reduced the cost and difficulty of collecting sufficient numbers of biological specimens for study. Another was the International HapMap Project which from 2003 had identified a majority of the common SNPs which are interrogated in a GWA study. The haploblock structure identified by HapMap project also allowed the focus on the subset of SNPs that would describe most of the variation. Also the development of the methods to genotype all these SNPs using genotyping arrays was an important prerequisite.
The most common approach of GWA studies is the case-control setup which compares two large groups of individuals, one healthy control group and one case group affected by a disease. All individuals in each group are genotyped for the majority of common known SNPs. The exact number of SNPs depends on the genotyping technology, but are typically one million or more. For each of these SNPs it is then investigated if the allele frequency is significantly altered between the case and the control group. In such setups, the fundamental unit for reporting effect sizes is the odds ratio. The odds ratio reports the ratio between two proportions, which in the context of GWA studies are the proportion of individuals in the case group having a specific allele, and the proportions of individuals in the control group having the same allele. When the allele frequency in the case group is much higher than in the control group, the odds ratio will be higher than 1, and vice versa for lower allele frequency. Additionally, a P-value for the significance of the odds ratio is typically calculated using a simple chi-squared test. Finding odds ratios that are significantly different from 1 is the objective of the GWA study because this shows that a SNP is associated with disease.
There are several variations to this case-control approach. A common alternative to case-control GWA studies is the analysis of quantitative phenotypic data, e.g. height or biomarker concentrations or even gene expression. Likewise, alternative statistics designed for dominance or recessive penetrance patterns can be used. Calculations are typically done using bioinformatics software such as PLINK, which also includes support for many of these alternative statistics.
In addition to the calculation of association, it is common to take several variables into account that could potentially confound the results. Sex and age are common examples of this. Moreover, it is also known that many genetic variations are associated with the geographical and historical populations in which the mutations first arose. Because of this association, studies must take account of the geographical and ethnical background of participants by controlling for what is called population stratification.
After odds ratios and P-values have been calculated for all SNPs, a common approach is to create a Manhattan plot. In the context of GWA studies, this plot shows the negative logarithm of the P-value as a function of genomic location. Thus the SNPs with the most significant association will stand out on the plot, usually as stacks of points because of haploblock structure. Importantly, the P-value threshold for significance is corrected for multiple testing issues. The exact threshold varies by study, but typically P-values must be very low (10 to the power of -7 or -8) to be considered significant in the face of the millions of tested SNPs. GWA studies typically perform the first analysis in a discovery cohort, followed by validation of the most significant SNPs in an independent validation cohort.
The first GWA study, conducted in 2005, compared 96 patients with age-related macular degeneration (ARMD) with 50 healthy controls. It identified two SNPs with significantly altered allele frequency between the two groups. These SNPs were located in the gene encoding complement factor H, which was an unexpected finding in the research of ARMD. The findings from these first GWA studies have subsequently prompted further functional research towards therapeutical manipulation of the complement system in ARMD. Another landmark publication in the history of GWA studies was the Wellcome Trust Case Control Consortium (WTCCC) study, the largest GWA study ever conducted at the time of its publication in 2007. The WTCCC included 14,000 cases of seven common diseases (~2,000 individuals for each of coronary heart disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, Crohn's disease, bipolar disorder, and hypertension) and 3,000 shared controls. This study was successful in uncovering many new disease genes underlying these diseases.
Since these first landmark GWA studies, there have been two general trends. One has been towards larger and larger sample sizes. At the end of 2011, the largest sample sizes were in the range of 200,000 individuals. The reason is the drive towards reliably detecting risk-SNPs that have smaller odds ratios and lower allele frequency. Another trend has been towards the use of more narrowly defined phenotypes, such as blood lipids, proinsulin or similar biomarkers. These are termed intermediate phenotypes and their analyses are suggested to be of value to functional research into biomarkers. Beyond intermidiary phenotyping, GWAS can be combined with molecular pathological epidemiology (MPE, ref.). Detailed disease endpoint phenotyping can be conducted by means of molecular pathology or surrogate histopathology or immunohistochemistry analysis of diseased tissues and cells within GWAS, although there are currently financial and logistic challenges in conducting molecular pathologic analysis on 1000s of disease tissue specimens. As an alternative approach, potential risk variants identified by GWAS can be examined in combination with molecular pathology analysis on diseased tissues. This GWAS-MPE approach can give not only more precise effect estimates, even larger effects, for specific molecular subtypes of the disease, but also insights into disease etiology and pathogenesis by linking genetic variants to molecular pathologic signatures of the disease.
A central point of debate on GWA studies has been that most of the SNP variations found by GWA studies are associated with only a small increased risk of the disease, and have only a small predictive value. The median odds ratio is 1.33 per risk-SNP, with only a few showing odds ratios above 3.0. These magnitudes are considered small because they do not explain much of the heritable variation. This heritable variation is known from heritability studies based on monozygotic twins. For example it is known that 80–90% of height is heritable. This means that if 29 cm separates the tallest 5% from the shortest 5% of the population, then genetics account for 27 cm. Of these 27 cm, however, the GWA studies only account for a minority. In the height example it is 6 cm, and for most other major complex phenotypes it is a similar small fraction.
One of the challenges for a successful GWA study in the future will be to apply the findings in a way that accelerates drug and diagnostics development, including better integration of genetic studies into the drug-development process and a focus on the role of genetic variation in maintaining health as a blueprint for designing new drugs and diagnostics. Several studies have looked into the use of risk-SNP markers as a means of directly improving the accuracy of prognosis. Some have found that the accuracy of prognosis improves, while others report only minor benefits from this use. Generally, a problem with this direct approach is the small magnitudes of the effects observed. A small effect ultimately translates into a poor separation of cases and controls and thus only a small improvement of prognosis accuracy. An alternative application is therefore the potential for GWA studies to elucidate pathophysiology.
One such success is related to identifying the genetic variant associated with response to anti-hepatitis C virus treatment. For genotype 1 hepatitis C treated with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b combined with ribavirin, a GWA study has shown that SNPs near the human IL28B gene, encoding interferon lambda 3, are associated with significant differences in response to the treatment. A later report demonstrated that the same genetic variants are also associated with the natural clearance of the genotype 1 hepatitis C virus.
The goal of elucidating pathophysiology has also led to increased interest in the association between risk-SNPs and the gene expression of nearby genes, the so-called expression quantitative trait loci (eQTL) studies. The reason is that GWAS studies identify risk-SNPs, but not risk-genes, and specification of genes is one step closer towards actionable drug targets. As a result, major GWA studies of 2011 typically included extensive eQTL analysis. One of the strongest eQTL effects observed for a GWA-identified risk SNP is the SORT1 locus. Functional follow up studies of this locus using small interfering RNA and gene knock-out mice have shed light on the metabolism of low-density lipoproteins, which have important clinical implications for cardiovascular disease.
GWA studies have several issues and limitations that can be taken care of through proper quality control and study setup. Lack of well defined case and control groups, insufficient sample size, control for multiple testing and control for population stratification are common problems. To this end it has been noted "the GWA approach can be problematic because the massive number of statistical tests performed presents an unprecedented potential for false-positive results". Ignoring these correctible issues has been cited as contributing to a general sense of problems with the GWA methodology. In addition to easily correctible problems such as these, some more subtle but important issues have surfaced. A high profile GWA study investigating individuals with very long life spans in order to identify SNPs associated with longevity has been mentioned as an example of this. The publication came under scrutiny because of a discrepancy between the type of genotyping array in the case and control group, which caused several SNPs to be falsely highlighted as associated with longevity. The study was subsequently retracted.
In addition to these preventable issues, GWA studies have attracted more fundamental criticism, mainly because of their assumption that common genetic variation plays a large role in explaining the heritable variation of common disease. This aspect of GWA studies has attracted the criticism that, although it could not have been known prospectively, GWA studies were ultimately not worth the expenditure. Alternative strategies suggested involve linkage analysis. More recently, the rapidly decreasing price of complete genome sequencing have also provided a realistic alternative to genotyping array-based GWA studies. It can be discussed if the use of this new technique will still be referred to as a GWA study, but high-throughput sequencing does have potential to side-step some of the shortcomings of non-sequencing GWA.
GWAS and eQTLs
There are millions of genetic variants in human genome and the interpretation of their functional effects is one of the biggest challenges in genomics, nowadays.
eQTLs are genomics loci which act as regulatory elements of the genetic expression. The polymorphism or variants of these regions can be related to expression levels and in some cases could add knowledge to the functional dimension.
Some of the variants identified in GWAS studies are eQTLs and trQTLs, therefore the integration of genome sequencing, eQTLs, and cell phenotypes, helps to understand: causal disease genes, causal genetic variants underlying GWAS and the biological processes of those.
- Association mapping
- Gene-environment interaction
- Genetic association
- Genetic epidemiology
- Genetic linkage
- Linkage disequilibrium
- Molecular epidemiology
- Molecular pathological epidemiology
- Molecular pathology
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