Genome-wide association studies for complex traits: consensus, uncertainty and challenges

@article{McCarthy2008GenomewideAS,
  title={Genome-wide association studies for complex traits: consensus, uncertainty and challenges},
  author={Mark I. McCarthy and Gonçalo R. Abecasis and Lon R. Cardon and David B. Goldstein and Julian Little and John P. A. Ioannidis and Joel N. Hirschhorn},
  journal={Nature Reviews Genetics},
  year={2008},
  volume={9},
  pages={356-369}
}
The past year has witnessed substantial advances in understanding the genetic basis of many common phenotypes of biomedical importance. These advances have been the result of systematic, well-powered, genome-wide surveys exploring the relationships between common sequence variation and disease predisposition. This approach has revealed over 50 disease-susceptibility loci and has provided insights into the allelic architecture of multifactorial traits. At the same time, much has been learned… 
Lessons from the Genome-Wide Association Studies for Complex Multifactorial Disorders and Traits
TLDR
Genome-wide association studies between common sequence variation and phenotypic variation were recently performed and disclosed unexpected molecular pathways for different common, multifactorial disorders and traits, thereby providing new working hypotheses.
Planning a genome-wide association study: Points to consider
TLDR
Unlike previous approaches, these ‘genome-wide association studies’ (GWAS) have extensively delivered on the promise of uncovering genetic determinants of complex diseases, with hundreds of novel disease-associated variants being largely replicated by independent groups.
Genome-wide association studies and beyond.
  • J. Witte
  • Biology
    Annual review of public health
  • 2010
TLDR
Genome-wide association studies provide an important avenue for undertaking an agnostic evaluation of the association between common genetic variants and risk of disease, but the underlying mechanisms remain unclear and the findings explain only a limited amount of heritability.
From association to causality: the new frontier for complex traits
TLDR
How additional sequencing and genotyping of ever-increasing cohort sizes without functional interpretation is unlikely to improve the genetic basis of complex traits is highlighted and necessitate a paradigm shift in approach to complex traits.
Human genetic variation and its contribution to complex traits
TLDR
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.
Genome-Wide Association Studies: Contribution of Genomics to Understanding Blood Pressure and Essential Hypertension
  • G. Ehret
  • Medicine
    Current hypertension reports
  • 2010
TLDR
An introduction to genome-wide association studies (GWAS) is given and the current findings for blood pressure and hypertension are summarized.
Whole genome association studies in complex diseases: where do we stand?
TLDR
It is likely that the use of whole-genome sequencing to extend the study of rare variation in neuropsychiatry will greatly advance the understanding of neuropsychiatric genetics.
Benefits and limitations of genome-wide association studies
TLDR
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.
Genome‐wide association studies (GWAS): impact on elucidating the aetiology of diabetes
TLDR
This review provides an overview of recent breakthroughs in genome‐wide association studies in the context of type 1 and type 2 diabetes, and outlines strategies on how these findings will be applied to impact clinical care for these two highly prevalent disorders.
Epigenome-wide association studies for common human diseases
TLDR
This work discusses EWAS design, cohort and sample selections, statistical significance and power, confounding factors and follow-up studies, and how integration of EWASs with GWASs can help to dissect complex GWAS haplotypes for functional analysis.
...
...

References

SHOWING 1-10 OF 151 REFERENCES
Genome-wide association studies for common diseases and complex traits
TLDR
Genome-wide association studies will soon become possible, and could open new frontiers in the understanding and treatment of disease, however, the execution and analysis of such studies will require great care.
Genome-wide association studies: theoretical and practical concerns
TLDR
The main factors — including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases — that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci are outlined.
A comprehensive review of genetic association studies
TLDR
It is found that over 600 positive associations between common gene variants and disease have been reported; these associations, if correct, would have tremendous importance for the prevention, prediction, and treatment of most common diseases.
Replicating genotype – phenotype associations What constitutes replication of a genotype – phenotype association , and how best can it be achieved ?
TLDR
As the transition to genome-wide association studies occurs, the challenge will be to separate true associations from the blizzard of false positives attained through attempts to rep­ licate positive findings in subsequent studies, which is essential for establishing the credibility of a genotype–phenotype association.
Evaluating coverage of genome-wide association studies
TLDR
It is shown that although many of them provide substantial coverage of common variation in non-African populations, the precise extent is strongly dependent on the frequencies of alleles of interest and on specific considerations of study design.
The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports
TLDR
Using single nucleotide polymorphisms from a 100K genome-wide scan, this work examines the associations of common polymorphisms with phenotypic variation in this community-based cohort and provides a full-disclosure, web-based resource of results for future replication studies.
Copy-number variation and association studies of human disease
TLDR
Evidence that CNVs affect phenotypes is discussed, directions for basic knowledge to support clinical study of CNVs, the challenge of genotyping CNPs in clinical cohorts, the use of SNPs as markers for CNPs and statistical challenges in testing CNVs for association with disease are discussed.
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
TLDR
This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Evaluating and improving power in whole-genome association studies using fixed marker sets
TLDR
The extent to which the sets of SNPs contained on three whole-genome genotyping arrays capture common SNPs across the genome is evaluated, and it is found that the majority of commonSNPs are well captured by these products either directly or through linkage disequilibrium.
Genome-wide strategies for detecting multiple loci that influence complex diseases
TLDR
Analytical methods that explicitly look for statistical interactions between loci are shown to be computationally feasible, even for studies of hundreds of thousands of loci, and to be more powerful than traditional analyses under a range of models for interlocus interactions.
...
...