Distribution of the number of false discoveries in large-scale family-based association testing with application to the association between PTPN1 and hypertension and obesity
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We present a model-free approach to the study of the number of false discoveries for large-scale simultaneous family-based association tests (FBATs) in which the set of discoveries is decided by applying a threshold to the test statistics. When the association between a set of markers in a candidate gene and a group of phenotypes is studied by a class of FBATs, we indicate that a joint null hypothesis distribution for these statistics can be obtained by the fundamental statistical method of conditioning on sufficient statistics for the null hypothesis. Based on the joint null distribution of these statistics, we can obtain the distribution of the number of false discoveries for the set of discoveries defined by a threshold; the size of this set is referred to as its tail count. Simulation studies are presented to demonstrate that the conditional, not the unconditional, distribution of the tail count is appropriate for the study of false discoveries. The usefulness of this approach is illustrated by re-examining the association between PTPN1 and a group of blood-pressure-related phenotypes reported by Olivier et al. (Hum Mol Genet 13:1885–1892, 2004); our results refine and reinforce this association.
- Musunuru K, Lettre G, Young T, Farlow DN, Pirruccello JP, Ejebe KG, Keating BJ, Yang Q, Chen MH, Lapchyk N, Crenshaw A, Ziaugra L, Rachupka A, Benjamin EJ, Cupples LA, Fornage M, Fox ER, Heckbert SR, Hirschhorn JN, Newton-Cheh C, Nizzari MM, Paltoo DN, Papanicolaou GJ, Patel SR, Psaty BM, Rader DJ, Redline S, Rich SS, Rotter JI, Taylor HA Jr, Tracy RP, Vasan RS, Wilson JG, Kathiresan S, Fabsitz RR, Boerwinkle E, Gabriel SB (2010) Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet 3:267–275PubMedCrossRefGoogle Scholar
- Olivier M, Hsiung CA, Chuang LM, Ho LT, Ting CT, Bustos VI, Lee TM, De Witte A, Chen YD, Olshen R, Rodriguez B, Wen CC, Cox DR (2004) Single nucleotide polymorphisms in protein tyrosine phosphatase 1beta (PTPN1) are associated with essential hypertension and obesity. Hum Mol Genet 13:1885–1892PubMedCrossRefGoogle Scholar
- Tomaszewski M, Charchar FJ, Barnes T, Gawron-Kiszka M, Sedkowska A, Podolecka E, Kowalczyk J, Rathbone W, Kalarus Z, Grzeszczak W, Goodall AH, Samani NJ, Zukowska-Szczechowska E (2009) A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol. Arterioscler Thromb Vasc Biol 29:1316–1321PubMedCrossRefGoogle Scholar
- Van Steen K, McQueen MB, Herbert A, Raby B, Lyon H, Demeo DL, Murphy A, Su J, Datta S, Rosenow C, Christman M, Silverman EK, Laird NM, Weiss ST, Lange C (2005) Genomic screening and replication using the same data set in family-based association testing. Nat Genet 37:683–691PubMedCrossRefGoogle Scholar