Technical reproducibility of genotyping SNP arrays used in genome-wide association studies.

During the last several years, high-density genotyping SNP arrays have facilitated genome-wide association studies (GWAS) that successfully identified common genetic variants associated with a variety of phenotypes. However, each of the identified genetic variants only explains a very small fraction of the underlying genetic contribution to the studied phenotypic trait. Moreover, discordance observed in results between independent GWAS indicates the potential for Type I and II errors.

The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods.

Geographical genomics of human leukocyte gene expression variation in southern Morocco.

Studies of the genetics of gene expression can identify expression SNPs (eSNPs) that explain variation in transcript abundance. Here we address the robustness of eSNP associations to environmental geography and population structure in a comparison of 194 Arab and Amazigh individuals from a city and two villages in southern Morocco. Gene expression differed between pairs of locations for up to a third of all transcripts, with notable enrichment of transcripts involved in ribosomal biosynthesis and oxidative phosphorylation.

SNP selection and multidimensional scaling to quantify population structure.

In the new era of large-scale collaborative Genome Wide Association Studies (GWAS), population stratification has become a critical issue that must be addressed. In order to build upon the methods developed to control the confounding effect of a structured population, it is extremely important to visualize and quantify that effect. In this work, we develop methodology for single nucleotide polymorphism (SNP) selection and subsequent population stratification visualization based on deviation from Hardy-Weinberg equilibrium in conjunction with non-metric multidimensional scaling (MDS); a distance-based multivariate technique.

Genomic convergence analysis of schizophrenia: mRNA sequencing reveals altered synaptic vesicular transport in post-mortem cerebellum.

Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six, matched controls.

Combining p-values in large-scale genomics experiments.

In large-scale genomics experiments involving thousands of statistical tests, such as association scans and microarray expression experiments, a key question is: Which of the L tests represent true associations (TAs)? The traditional way to control false findings is via individual adjustments. In the presence of multiple TAs, p-value combination methods offer certain advantages. Both Fisher's and Lancaster's combination methods use an inverse gamma transformation.

Properties of the multiallelic trend test.

Disease genes can be mapped on the basis of associations between genetic markers and disease status, with the case-control design having the advantage of not requiring individuals from different generations. When the marker loci have multiple alleles, there has been debate on whether the power of tests for association increases or decreases. We show here that the multiple-allele version of Armitage's trend test has increased power over the two-allele version under the requirement of equifrequent alleles, but not in general.