An integrated phenomic approach to multivariate allelic association.
The increased feasibility of genome-wide association has resulted in association becoming the primary method used to localize genetic variants that cause phenotypic variation. Much attention has been focused on the vast multiple testing problems arising from analyzing large numbers of single nucleotide polymorphisms. However, the inflation of experiment-wise type I error rates through testing numerous phenotypes has received less attention. Multivariate analyses can be used to detect both pleiotropic effects that influence a latent common factor, and monotropic effects that operate at a variable-specific levels, whilst controlling for non-independence between phenotypes. In this study, we present a maximum likelihood approach, which combines both latent and variable-specific tests and which may be used with either individual or family data. Simulation results indicate that in the presence of factor-level association, the combined multivariate (CMV) analysis approach performs well with a minimal loss of power as compared with a univariate analysis of a factor or sum score (SS). As the deviation between the pattern of allelic effects and the factor loadings increases, the power of univariate analyses of both factor and SSs decreases dramatically, whereas the power of the CMV approach is maintained. We show the utility of the approach by examining the association between dopamine receptor D2 TaqIA and the initiation of marijuana, tranquilizers and stimulants in data from the Add Health Study. Perl scripts that takes ped and dat files as input and produces Mx scripts and data for running the CMV approach can be downloaded from www.vipbg.vcu.edu/~sarahme/WriteMx.
Medland
Sarah Elizabeth
SE
Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia. sarahMe@qimr.edu.au
Neale
Michael Churton
MC
D000483:Alleles; D005190:Family; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D002189:Marijuana Abuse / Q000235:genetics; D015999:Multivariate Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017448:Receptors, Dopamine D2 / Q000235:genetics; D015203:Reproducibility of Results; D035781:Siblings
D017448:Receptors, Dopamine D2
Mol Psychiatry. 1999 May;4(3):290-6
10395223
Nicotine Tob Res. 2004 Aug;6(4):583-97
15370155
Am J Psychiatry. 1999 Sep;156(9):1440-3
10484959
Am J Hum Genet. 2007 Dec;81(6):1278-83
17966091
Alcohol Clin Exp Res. 2007 Oct;31(10):1645-53
17850642
Behav Genet. 1998 Sep;28(5):329-40
9926615
Twin Res. 2004 Jun;7(3):292-8
15193174
Biostatistics. 2003 Apr;4(2):195-206
12925516
Am J Epidemiol. 2008 Jan 15;167(2):125-38
17989061
Behav Genet. 2004 Sep;34(5):541-7
15319577
Drug Alcohol Depend. 1993 Oct;33(3):271-85
8261891
Nicotine Tob Res. 2007 Dec;9(12):1251-7
18058343
Am J Hum Genet. 2002 Jun;70(6):1599-602
11992269
Behav Brain Funct. 2007 Apr 28;3:22
17466074
Am J Hum Genet. 1999 Jan;64(1):259-67
9915965
Stat Appl Genet Mol Biol. 2004;3:Article17
16646795