Power Calculation of Multi-step Combined Principal Components with Applications to Genetic Association Studies.
Ontology highlight
ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC4870571 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:MotivationIn large-scale genetic association studies with tens of hundreds of single nucleotide polymorphisms (SNPs) genotyped, the traditional statistical framework of logistic regression using maximum likelihood estimator (MLE) to infer the odds ratios of SNPs may not work appropriately. This is because a large number of odds ratios need to be estimated, and the MLEs may be not stable when some of the SNPs are in high linkage disequilibrium. Under this situation, the P-value combination procedures seem to provide good alternatives as they are constructed on the basis of single-marker analysis.ResultsThe commonly used P-value combination methods (such as the Fisher's combined test, the truncated product method, the truncated tail strength and the adaptive rank truncated product) may lose power when the significance level varies across SNPs. To tackle this problem, a group combined P-value method (GCP) is proposed, where the P-values are divided into multiple groups and then are combined at the group level. With this strategy, the significance values are integrated at different levels, and the power is improved. Simulation shows that the GCP can effectively control the type I error rates and have additional power over the existing methods-the power increase can be as high as over 50% under some situations. The proposed GCP method is applied to data from the Genetic Analysis Workshop 16. Among all the methods, only the GCP and ARTP can give the significance to identify a genomic region covering gene DSC3 being associated with rheumatoid arthritis, but the GCP provides smaller P-value.Availability and implementationhttp://www.statsci.amss.ac.cn/yjscy/yjy/lqz/201510/t20151027_313273.htmlContactliqz@amss.ac.cnSupplementary informationSupplementary data are available at Bioinformatics online.
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Project description:BackgroundConcentrated breeding effort to produce various body structures and behaviors of dogs to suit human demand has inadvertently produced unwanted traits and diseases that accompany the morphological and behavioral phenotypes. We explored the relationship between pelvic conformation and canine hip dysplasia (HD) because purebred dogs which are predisposed, or not, to HD share common morphologic features, respectively. Thirteen unique bilateral anatomical features of the pelvis were measured on 392 dogs of 51 breeds and 95 mixed breed dogs. Principal components (PCs) were derived to describe pelvic morphology. Dogs were genotyped at ~183,000 single nucleotide polymorphisms and their hip conformation was measured by the Norberg angle and angle of inclination between the femoral neck and diaphysis.ResultsNo associations reached genome wide significance for the Norberg angle when averaged over both hips. PC1 was negatively correlated with the Norberg angle (r = -0.31; P < 0.05) but not the angle of inclination (r = -0.08; P > 0.05). PC1, 2, 4, and 5 differed significantly between male and female dogs confirming pelvic sexual dimorphism. With sex as a covariate, the eigenvector contribution to PC1 reflected the overall size of the pelvis and was significantly associated with the IGF-1 locus, a known contributor to canine body size. PC3, which represented a tradeoff between ilial length and ischial length in which a longer ischium is associated with a shorter ilium, was significantly associated with a marker on canine chromosome 16:5181388 bp. The closest candidate gene is TPK1, a thiamine-dependent enzyme and part of the PKA complex. Associations with the remaining PCs did not reach genome wide significance.ConclusionIGF-1 was associated with the overall size of the pelvis and sex is related to pelvic size. Ilial/ischial proportion is genetically controlled and the closest candidate gene is thiamine-dependent and affects birth weight and development of the nervous system. Dogs with larger pelves tend to have smaller NAs consistent with increased tendency toward HD in large breed dogs. Based on the current study, pelvic shape alone was not strongly associated with canine hip dysplasia.
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