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Ranking of genome-wide association scan signals by different measures.

Strömberg, Ulf LU ; Björk, Jonas LU ; Vineis, Paolo; Broberg Palmgren, Karin LU and Zeggini, Eleftheria (2009) In International Journal of Epidemiology 38. p.1364-1373
Abstract
BACKGROUND: The P-value approach has been employed to prioritizing genome-wide association (GWA) scan signals, with a genome-wide significance defined by a prior P-value threshold, although this is not ideal. A rationale put forward is that the association signals rather should be expected to give less support for single nucleotide polymorphisms (SNPs) that are rare (with associated low-power tests) than for common SNPs with equivalent P-values, unless investigators believe, a priori, that rare causative variants contribute to the disease and have more pronounced effects. METHODS: Using data from a GWA scan for type 2 diabetes (1924 cases, 2938 controls, 393 453 SNPs), we compared P-values with four alternative signal measures: likelihood... (More)
BACKGROUND: The P-value approach has been employed to prioritizing genome-wide association (GWA) scan signals, with a genome-wide significance defined by a prior P-value threshold, although this is not ideal. A rationale put forward is that the association signals rather should be expected to give less support for single nucleotide polymorphisms (SNPs) that are rare (with associated low-power tests) than for common SNPs with equivalent P-values, unless investigators believe, a priori, that rare causative variants contribute to the disease and have more pronounced effects. METHODS: Using data from a GWA scan for type 2 diabetes (1924 cases, 2938 controls, 393 453 SNPs), we compared P-values with four alternative signal measures: likelihood ratio (LR), Bayes factor (BF; with a specified prior distribution for true effects), 'frequentist factor' (FF; reflecting the ratio between estimated-post-data- 'power' and P-value) and probability of pronounced effect size (PrPES). RESULTS: The 19 common SNPs [minor allele frequency (MAF) among the controls >29%] yielding strong P-value signals (P < 5 x 10(-7)) were also top ranked by the other approaches. There was a strong similarity between the P-values, LR and BF signals, in terms of ranking SNPs. In contrast, FF and PrPES signals down-weighted rare SNPs (control MAF <10%) with low P-values. CONCLUSIONS: For prioritization of signals that do not achieve compelling levels of evidence for association, the main driving force behind observed differences between the various association signals appears to be SNP MAF. The statistical power afforded by follow-up samples for establishing replication should be taken into account when tailoring the signal selection strategy. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
International Journal of Epidemiology
volume
38
pages
1364 - 1373
publisher
Oxford University Press
external identifiers
  • wos:000271101800030
  • pmid:19734549
  • scopus:70349860293
ISSN
1464-3685
DOI
10.1093/ije/dyp285
language
English
LU publication?
yes
id
06c3bfff-4f2f-4d9b-9034-b658bb232129 (old id 1483688)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19734549?dopt=Abstract
date added to LUP
2009-10-07 09:07:23
date last changed
2017-01-01 07:35:16
@article{06c3bfff-4f2f-4d9b-9034-b658bb232129,
  abstract     = {BACKGROUND: The P-value approach has been employed to prioritizing genome-wide association (GWA) scan signals, with a genome-wide significance defined by a prior P-value threshold, although this is not ideal. A rationale put forward is that the association signals rather should be expected to give less support for single nucleotide polymorphisms (SNPs) that are rare (with associated low-power tests) than for common SNPs with equivalent P-values, unless investigators believe, a priori, that rare causative variants contribute to the disease and have more pronounced effects. METHODS: Using data from a GWA scan for type 2 diabetes (1924 cases, 2938 controls, 393 453 SNPs), we compared P-values with four alternative signal measures: likelihood ratio (LR), Bayes factor (BF; with a specified prior distribution for true effects), 'frequentist factor' (FF; reflecting the ratio between estimated-post-data- 'power' and P-value) and probability of pronounced effect size (PrPES). RESULTS: The 19 common SNPs [minor allele frequency (MAF) among the controls &gt;29%] yielding strong P-value signals (P &lt; 5 x 10(-7)) were also top ranked by the other approaches. There was a strong similarity between the P-values, LR and BF signals, in terms of ranking SNPs. In contrast, FF and PrPES signals down-weighted rare SNPs (control MAF &lt;10%) with low P-values. CONCLUSIONS: For prioritization of signals that do not achieve compelling levels of evidence for association, the main driving force behind observed differences between the various association signals appears to be SNP MAF. The statistical power afforded by follow-up samples for establishing replication should be taken into account when tailoring the signal selection strategy.},
  author       = {Strömberg, Ulf and Björk, Jonas and Vineis, Paolo and Broberg Palmgren, Karin and Zeggini, Eleftheria},
  issn         = {1464-3685},
  language     = {eng},
  pages        = {1364--1373},
  publisher    = {Oxford University Press},
  series       = {International Journal of Epidemiology},
  title        = {Ranking of genome-wide association scan signals by different measures.},
  url          = {http://dx.doi.org/10.1093/ije/dyp285},
  volume       = {38},
  year         = {2009},
}