Replicating genotype–phenotype associations

Chanock, Stephen J.; Manolio, Teri A.; Boehnke, Michael; Boerwinkle, Eric; Hunter, David J.; Thomas, Gilles; Hirschhorn, Joel N.; Abecasis, Gonçalo R.; Altshuler, David; Bailey-Wilson, Joan E.; Brooks, Lisa; Cardon, Lon R.; Daly, Mark J.; Donnelly, Peter; Fraumeni, Joseph F.; Freimer, Nelson B.; Gerhard, Daniela S.; Gunter, Chris; Guttmacher, Alan E.; Guyer, Mark S.; Harris, Emily; Hoh, Josephine; Hoover, Robert N.; Kong, Augustine; Merikangas, Kathleen R.; Morton, Cynthia C.; Palmer, Lyle J.; Phimister, Elizabeth G.; Rice, John P.; Roberts, Jerry; Rotimi, Charles N.; Tucker, Margaret A.; Vogan, Kyle; Wacholder, Sholom; Wijsman, Ellen M.; Winn, Deborah M.; Collins, Francis S.

doi:10.1038/447655a

Cited by 1,220 publications

(490 citation statements)

References 78 publications

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“…Such a replication in an independent dataset would greatly strengthen the credibility of the variant we propose (Chanock et al, 2007). While all science progresses by the independent validation of experimental results, with GWA studies replication reduces the probability that the result is related to subtle population stratification (though our study is conducted in a homogeneous population, well suited for GWA studies) or to the issue of multiple comparisons (which we control for using the gold standard and, many argue, overly conservative Bonferroni correction).…”

Section: Discussionmentioning

confidence: 72%

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Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

et al. 2012

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* These authors contributed equally.As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.

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Section: Discussionmentioning

confidence: 72%

“…For instance, winner's curse would be exacerbated by the smaller size of the replication sample. Chanock et al (2007) suggest, as far as possible, study design and phenotype should match to maximize the chance of replication.…”

Section: Discussionmentioning

confidence: 99%

Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

et al. 2012

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“…There are likely many contributing risk alleles for all complex traits and complex diseases such that no single allele can explain all of the phenotypic variation 50. This becomes problematic during replication using different breeds and populations because the markers identified might merely reflect breed differences, or the markers might represent different alleles conferring different levels of risk across breeds or populations.…”

Section: Genome‐wide Association Studiesmentioning

confidence: 99%

Genetic Susceptibility to Rhodococcus equi

McQueen

Dindot

2015

Veterinary Internal Medicne

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Rhodococcus equi pneumonia is a major cause of morbidity and mortality in neonatal foals. Much effort has been made to identify preventative measures and new treatments for R. equi with limited success. With a growing focus in the medical community on understanding the genetic basis of disease susceptibility, investigators have begun to evaluate the interaction of the genetics of the foal with R. equi. This review describes past efforts to understand the genetic basis underlying R. equi susceptibility and tolerance. It also highlights the genetic technology available to study horses and describes the use of this technology in investigating R. equi. This review provides readers with a foundational understanding of candidate gene approaches, single nucleotide polymorphism‐based, and copy number variant‐based genome‐wide association studies, and next generation sequencing (both DNA and RNA).

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“…FcgRIIa-131H/R; FcgRIIIa-158 V/F NO 1) Some conflicting data; positive data mostly from small studies Bibeau et al, 2009;Musolino et al, 2008;Kim et al, 2006;Weng and Levy, 2003;Carlotti et al, 2007 false discovery is minimized either (optimally) by inclusion of a replication set, or by conservative adjustment for multiple comparisons (Chanock et al, 2007;van den Oord, 2008). Studies which are underpowered to adequately test less common variantsdvariants which in reality may be potentially important pharmacogenomic markersdcan have (falsely) negative results and can confuse the ability to understand conflicting data from several studies on a given drugegene pair.…”

Section: Fcgriia Fcgriiiamentioning

confidence: 99%

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

O’Donnell

Ratain

2012

Molecular Oncology

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A B S T R A C TPharmacogenomics is the study of genetic factors determining drug response or toxicity.The use of pharmacogenomics is especially desirable in oncology because the therapeutic index of oncology drugs is often narrow, the need for favorable drug response is often acute, and the consequences of drug toxicity can be life-threatening. In this review, we examine the state of pharmacogenomics in oncology, focusing only on germline pharmacogenomic variants. We consider several critical points when assessing the quality of pharmacogenomic findings and their relevance to clinical use, and discuss potential confounding factors limiting interpretation and implementation. Several of the most extensively studied drugegene pairs (irinotecan and UGT1A1; tamoxifen and CYP2D6; 5-fluorouracil and DPYD) are inspected in depth as illustrations of both the state of advancementdand the current limitations ofdpresent knowledge. We argue that there will likely soon be a critical mass of important germline pharmacogenomic biomarkers in oncology which deserve clinical implementation to provide optimal, personalized oncologic care.We conclude with a vision of how routine clinical testing of such germline markers could one day change the paradigm for cancer care.

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Replicating genotype–phenotype associations

Cited by 1,220 publications

References 78 publications

Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

Associations Between Variants Near a Monoaminergic Pathways Gene (PHOX2B) and Amygdala Reactivity: A Genome-Wide Functional Imaging Study

Genetic Susceptibility to Rhodococcus equi

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

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