Benefits and limitations of genome-wide association studies

Tam, Vivian; Patel, Nikunj; Turcotte, Michelle; Bossé, Yohan; Paré, Guillaume; Meyre, David

doi:10.1038/s41576-019-0127-1

Cited by 1,553 publications

(1,227 citation statements)

References 348 publications

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“…b-Thalassemia A group of autosomal recessive hereditary anemias characterized by reduced or absent beta-globin chain synthesis, leading to alpha-and beta-chain imbalances that cause clinical manifestations of hemolytic anemia and impaired iron handling. its high multiple testing burden from evaluating millions of variants, its inability to capture a substantial portion of heritability, and the difficulty of functionally characterizing association signals (Tam et al, 2019).…”

Section: Sickle Cell Disease (Scd)mentioning

confidence: 99%

“…CVAS focus on traits with polygenic architectures comprised of many variants with small individual effects and usually include a large proportion of healthy individuals in the study population. Notable current limitations of CVAS include its high multiple testing burden from evaluating millions of variants, its inability to capture a substantial portion of heritability, and the difficulty of functionally characterizing association signals (Tam et al , ).…”

Section: Introductionmentioning

confidence: 99%

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The genetics of human hematopoiesis and its disruption in disease

2019

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Hematopoiesis, or the process of blood cell production, is a paradigm of multi‐lineage cellular differentiation that has been extensively studied, yet in many aspects remains incompletely understood. Nearly all clinically measured hematopoietic traits exhibit extensive variation and are highly heritable, underscoring the importance of genetic variation in these processes. This review explores how human genetics have illuminated our understanding of hematopoiesis in health and disease. The study of rare mutations in blood and immune disorders has elucidated novel roles for regulators of hematopoiesis and uncovered numerous important molecular pathways, as seen through examples such as Diamond‐Blackfan anemia and the GATA2 deficiency syndromes. Additionally, population studies of common genetic variation have revealed mechanisms by which human hematopoiesis can be modulated. We discuss advances in functionally characterizing common variants associated with blood cell traits and discuss therapeutic insights, such as the discovery of BCL11A as a modulator of fetal hemoglobin expression. Finally, as genetic techniques continue to evolve, we discuss the prospects, challenges, and unanswered questions that lie ahead in this burgeoning field.

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Section: Sickle Cell Disease (Scd)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The genetics of human hematopoiesis and its disruption in disease

2019

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“…First, we classified strains as resistant if they carried SNPs or genes with significant, positive associations with resistance. This approach predicted all isolates in our study to be pan-resistant, reflecting the high burden of false positive associations identified by GWAS (Tam et al 2019). We also tested stricter Pvalue (P=10 -5 and 10 -10 ) and beta cutoffs (0.1 and 0.2), however these did not result in high accuracy (median accuracy: 12%, IQR: 1-55%).…”

Section: Accuracy Of Resistance Prediction Using Gwas Hitsmentioning

confidence: 99%

Contrasting approaches to genome-wide association studies impact the detection of resistance mechanisms in Staphylococcus aureus

Wheeler

Reuter

Chewapreecha

et al. 2019

Preprint

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Rapid detection of antibiotic resistance using whole-genome sequencing (WGS) could improve clinical outcomes and limit the spread of resistance. For this to succeed, we need an accurate way of linking genotype to phenotype, that identifies new resistance mechanisms as they appear. To assess how close we are to this goal, we characterized antimicrobial resistance determinants in >4,000 Staphylococcus aureus genomes of isolates associated with bloodstream infection in the United Kingdom and Ireland. We sought to answer three questions: 1) how well did known resistance mechanisms explain phenotypic resistance in our collection, 2) how many previously identified resistance mechanisms appeared in our collection, and 3) how many of these were detectable using four contrasting genome-wide association study (GWAS) methods. Resistance prediction based on the detection of known resistance determinants was 98.8% accurate. We identified challenges in correcting for population structure, clustering orthologous genes, and identifying causal mechanisms in rare or common phenotypes, which reduced the recovery of known mechanisms. Limited sensitivity and specificity of these methods made prediction using GWAS-discovered hits alone less accurate than using literature-derived genetic determinants. However, GWAS methods identified novel mutations associated with resistance, including five mutations in rpsJ, which improved tetracycline resistance prediction for 28 isolates, and a T118I substitution in fusA which resulted in better fusidic acid resistance prediction for 5 isolates. Thus, GWAS approaches in conjunction with phenotypic testing data can support the development of comprehensive databases to enable real-time use of WGS for patient management.

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“…Nonetheless, epigenome‐wide studies may increase the risk of accidental findings, as in many cases the experimental hypothesis is tested by replicating statistical comparisons and/or associations on a high number of sites, thus requiring adequately large sample sizes. In other words, despite genome‐wide association studies may be beneficial to support novel mechanisms and unforeseen associations, these links may not necessarily be interpreted as causative mechanisms and will require more in‐depth investigation with target‐gene approaches . As such, robust epigenome‐wide studies should be considered the gold‐standard approach when the objective is not testing a specific mechanism of action that may shed light on previously documented associations between environmental exposures and outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…In other words, despite genome-wide association studies may be beneficial to support novel mechanisms and unforeseen associations, these links may not necessarily be interpreted as causative mechanisms and will require more in-depth investigation with target-gene approaches. 66 As such, robust epigenomewide studies should be considered the gold-standard approach when the objective is not testing a specific mechanism of action that may shed light on previously documented associations between environmental exposures and outcomes.…”

Section: State Of the Artmentioning

confidence: 99%

Maternal caregiving and DNA methylation in human infants and children: Systematic review

Provenzi

Brambilla

Minico

et al. 2019

Genes Brain and Behavior

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The integration of behavioral epigenetics' principles (eg, DNA methylation) into the study of human infants' development has mainly focused on the effects of early adverse exposures, paying less attention to protective caregiving experiences. The present review focused on DNA methylation linked to variations in maternal behavior in human infants and children. Literature search occurred on three databases (PubMed, Scopus and Web of Science) and 11 records were selected. Key variables were abstracted from each article including: sample size and characteristics, time and type of maternal caregiving behavior exposure, time and locus of methylation biomarker, presence/absence, time and type of adverse exposure. Six out of eleven records documented the predictive effect of maternal caregiving on DNA methylation, whereas the remaining five reported on the role of maternal behavior as an influencing factor of the adversity‐to‐methylation link. Consistent with evidence from the animal model, the quality of maternal caregiving in humans (a) might be associated with variations in DNA methylation status of specific genes involved in socio‐emotional development and (b) might partially buffer the association between early adversities and epigenetic variations in infants and children. Current evidence suggests that the quality of maternal caregiving can contribute to behavioral development trajectories of human infants and children at least partially through epigenetic regulation. Open questions and methodological aspects are discussed to guide future human developmental research in behavioral epigenetics.

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Benefits and limitations of genome-wide association studies

Cited by 1,553 publications

References 348 publications

The genetics of human hematopoiesis and its disruption in disease

The genetics of human hematopoiesis and its disruption in disease

Contrasting approaches to genome-wide association studies impact the detection of resistance mechanisms in Staphylococcus aureus

Maternal caregiving and DNA methylation in human infants and children: Systematic review

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