caa a22 4500 445861916 CHVBK 20180317145446.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s00439-010-0911-7 doi (NATIONALLICENCE)springer-10.1007/s00439-010-0911-7 Uncovering hidden variance: pair-wise SNP analysis accounts for additional variance in nicotine dependence [Elektronische Daten] [Robert Culverhouse, Nancy Saccone, Jerry Stitzel, Jen Wang, Joseph Steinbach, Alison Goate, Tae-Hwi Schwantes-An, Richard Grucza, Victoria Stevens, Laura Bierut] Results from genome-wide association studies of complex traits account for only a modest proportion of the trait variance predicted to be due to genetics. We hypothesize that joint analysis of polymorphisms may account for more variance. We evaluated this hypothesis on a case-control smoking phenotype by examining pairs of nicotinic receptor single-nucleotide polymorphisms (SNPs) using the Restricted Partition Method (RPM) on data from the Collaborative Genetic Study of Nicotine Dependence (COGEND). We found evidence of joint effects that increase explained variance. Four signals identified in COGEND were testable in independent American Cancer Society (ACS) data, and three of the four signals replicated. Our results highlight two important lessons: joint effects that increase the explained variance are not limited to loci displaying substantial main effects, and joint effects need not display a significant interaction term in a logistic regression model. These results suggest that the joint analyses of variants may indeed account for part of the genetic variance left unexplained by single SNP analyses. Methodologies that limit analyses of joint effects to variants that demonstrate association in single SNP analyses, or require a significant interaction term, will likely miss important joint effects. Springer-Verlag, 2010 Culverhouse Robert Division of General Medical Sciences, Department of Medicine, Washington University, 63110, Saint Louis, MO, USA aut Saccone Nancy Department of Genetics, Washington University, 63110, Saint Louis, MO, USA aut Stitzel Jerry Department of Integrative Physiology, University of Colorado, 80309, Boulder, CO, USA aut Wang Jen Department of Psychiatry, Washington University, 63110, Saint Louis, MO, USA aut Steinbach Joseph Department of Anesthesiology Basic Science Research, Washington University, 63110, Saint Louis, MO, USA aut Goate Alison Department of Genetics, Washington University, 63110, Saint Louis, MO, USA aut Schwantes-An Tae-Hwi Department of Genetics, Washington University, 63110, Saint Louis, MO, USA aut Grucza Richard Department of Psychiatry, Washington University, 63110, Saint Louis, MO, USA aut Stevens Victoria Department of Epidemiology and Surveillance Research, American Cancer Society, 30329, Atlanta, GA, USA aut Bierut Laura Department of Psychiatry, Washington University, 63110, Saint Louis, MO, USA aut Human Genetics Springer-Verlag 129/2(2011-02-01), 177-188 0340-6717 129:2<177 2011 129 439 https://doi.org/10.1007/s00439-010-0911-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-010-0911-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Culverhouse Robert Division of General Medical Sciences, Department of Medicine, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 700 1- Saccone Nancy Department of Genetics, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 700 1- Stitzel Jerry Department of Integrative Physiology, University of Colorado, 80309, Boulder, CO, USA aut NATIONALLICENCE 700 1- Wang Jen Department of Psychiatry, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 700 1- Steinbach Joseph Department of Anesthesiology Basic Science Research, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 700 1- Goate Alison Department of Genetics, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 700 1- Schwantes-An Tae-Hwi Department of Genetics, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 700 1- Grucza Richard Department of Psychiatry, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 700 1- Stevens Victoria Department of Epidemiology and Surveillance Research, American Cancer Society, 30329, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Bierut Laura Department of Psychiatry, Washington University, 63110, Saint Louis, MO, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/2(2011-02-01), 177-188 0340-6717 129:2<177 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer