An examination of single nucleotide polymorphism selection prioritization strategies for tests of gene-gene interaction.
An examination of single nucleotide polymorphism selection prioritization strategies for tests of gene-gene interaction.
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DOI：
10.1016/j.biopsych.2011.01.034
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发表时间：
2011-07-15
影响因子：
10.6
通讯作者：
O'Donovan, Michael C.
中科院分区：
文献类型：
--
作者：
Moskvina, Valentina;Craddock, Nick;Mueller-Myhsok, Bertram;Kam-Thong, Tony;Green, Elaine;Holmans, Peter;Owen, Michael J.;O'Donovan, Michael C.
鉴于精神疾病的全基因组关联研究（GWAS）仅确定了少量令人信服的相关变异，因此有兴趣使用基因-基因相互作用的测试来寻求相关变异的额外证据。全面的成对SNP-SNP相互作用分析是计算密集型的，并且考虑到可能的相互作用的数量，多次测试的惩罚是严重的。为了最大限度地减少这些统计和计算负担，我们探索了优先考虑SNP进行相互作用分析的方法。使用Wellcome Trust Case Control Consortium双相情感障碍GWAS（1868例，2938例对照）进行主要相互作用分析。使用遗传关联信息网络BD数据集（1001例病例，1033例对照）进行复制分析。优先考虑SNP进行相互作用分析，其显示超过许多名义上显著阈值的关联证据，在全基因组显著基因内，或在功能相关的基因内。对于没有一组优先的SNP，我们获得了支持以下假设的证据，即选择策略识别出了富集真实（统计学）相互作用的变体对。根据许多标准优先化的SNP不具有在该大小的样品中可检测到的显著相互作用的提高的先验概率。正如现在被广泛接受的单SNP分析，我们认为，使用的显着性水平只反映了测试的数量进行不提供适当程度的保护，对潜在的GWAS研究产生大量的假阳性相互作用。
Given that genome wide association studies (GWAS) of psychiatric disorders have identified only a small number of convincingly associated variants, there is interest in seeking additional evidence for associated variants using tests of gene-gene interaction. Comprehensive pair-wise SNP-SNP interaction analysis is computationally intensive and the penalty for multiple testing is severe given the number of interactions possible. Aiming to minimize these statistical and computational burdens, we have explored approaches to prioritise SNPs for interaction analyses. Primary interaction analyses were performed using the Wellcome Trust Case Control Consortium Bipolar Disorder GWAS (1868 cases, 2938 controls). Replication analyses were performed using the Genetic Association Information Network BD dataset (1001 cases, 1033 controls). SNPs were prioritized for interaction analysis that showed evidence for association that surpassed a number of nominally significant thresholds, are within genome-wide significant genes, or are within genes that are functionally related. For no set of prioritized SNPs did we obtain evidence to support the hypothesis that the selection strategy identified pairs of variants that were enriched for true (statistical) interactions. SNPs prioritized according to a number of criteria do not have a raised prior probability for significant interaction that is detectable in samples of this size. As is now widely accepted for single SNP analysis, we argue the use of significance levels reflecting only the number of tests performed does not offer an appropriate degree of protection against the potential for GWAS studies to generate an enormous number of false positive interactions.
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DOI：
10.1038/nrg2579
发表时间：
2009-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Cordell HJ
通讯作者：
Cordell HJ
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Stone, Jennifer L.;O'Donovan, Michael C.;Gurling, Hugh;Kirov, George K.;Blackwood, Douglas H. R.;Corvin, Aiden;Craddock, Nick J.;Gill, Michael;Hultman, Christina M.;Lichtenstein, Paul;McQuillin, Andrew;Pato, Carlos N.;Ruderfer, Douglas M.;Owen, Michael J.;St Clair, David;Sullivan, Patrick F.;Sklar, Pamela;Purcell, Shaun M.;Scolnick, E. M.;Holmans, P. A.;Georgieva, L.;Nikolov, I.;Norton, N.;Williams, H.;Williams, N. M.;Toncheva, D.;Milanova, V.;Thelander, E. F.;Morris, D. W.;O'Dushlaine, C. T.;Kenny, E.;Waddington, J. L.;Choudhury, K.;Datta, S.;Pimm, J.;Thirumalai, S.;Puri, V.;Krasucki, R.;Lawrence, J.;Quested, D.;Bass, N.;Curtis, D.;Crombie, C.;Fraser, G.;Kwan, S. L.;Muir, W. J.;McGhee, K. A.;Pickard, B.;Malloy, P.;Maclean, A. W.;Van Beck, M.;Visscher, P. M.;Macgregor, S.;Pato, M. T.;Medeiros, H.;Middleton, F.;Carvalho, C.;Morley, C.;Fanous, A.;Conti, D.;Knowles, J. A.;Ferreira, C. P.;Azevedo, M. H.;McCarroll, S. A.;Gates, C.;Daly, M. J.;Sklar, P.
通讯作者：
Sklar, P.
影响因子：
30.8
作者：
Ferreira, Manuel A. R.;O'Donovan, Michael C.;Meng, Yan A.;Jones, Ian R.;Ruderfer, Douglas M.;Jones, Lisa;Fan, Jinbo;Kirov, George;Perlis, Roy H.;Green, Elaine K.;Smoller, Jordan W.;Grozeva, Detelina;Stone, Jennifer;Nikolov, Ivan;Chambert, Kimberly;Hamshere, Marian L.;Nimgaonkar, Vishwajit L.;Moskvina, Valentina;Thase, Michael E.;Caesar, Sian;Sachs, Gary S.;Franklin, Jennifer;Gordon-Smith, Katherine;Ardlie, Kristin G.;Gabriel, Stacey B.;Fraser, Christine;Blumenstiel, Brendan;Defelice, Matthew;Breen, Gerome;Gill, Michael;Morris, Derek W.;Elkin, Amanda;Muir, Walter J.;McGhee, Kevin A.;Williamson, Richard;MacIntyre, Donald J.;MacLean, Alan W.;Clair, David St;Robinson, Michelle;Van Beck, Margaret;Pereira, Ana C. P.;Kandaswamy, Radhika;McQuillin, Andrew;Collier, David A.;Bass, Nicholas J.;Young, Allan H.;Lawrence, Jacob;Ferrier, I. Nicol;Anjorin, Adebayo;Farmer, Anne;Curtis, David;Scolnick, Edward M.;McGuffin, Peter;Daly, Mark J.;Corvin, Aiden P.;Holmans, Peter A.;Blackwood, Douglas H.;Gurling, Hugh M.;Owen, Michael J.;Purcell, Shaun M.;Sklar, Pamela;Craddock, Nick
通讯作者：
Craddock, Nick
影响因子：
1.9
作者：
Moskvina, V;Holmans, P;Craddock, N
通讯作者：
Craddock, N