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. Robust associations were observed in the leukocyte samples: cis eSNPs (P < 10(-08)) were identified for 346 genes, and trans eSNPs (P < 10(-11)) for 10 genes. All of these associations were consistent both across the three sample locations and after controlling for ancestry and relatedness. No evidence of large-effect trans-acting mediators of the pervasive environmental influence was found; instead, genetic and environmental factors acted in a largely additive manner.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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. High reliability of genotyping technology is needed to have confidence in using SNP data and interpreting GWAS results. Therefore, reproducibility of two widely genotyping technology platforms from Affymetrix and Illumina was assessed by analyzing four technical replicates from each of the six individuals in five laboratories. Genotype concordance of 99.40% to 99.87% within a laboratory for the sample platform, 98.59% to 99.86% across laboratories for the same platform, and 98.80% across genotyping platforms was observed. Moreover, arrays with low quality data were detected when comparing genotyping data from technical replicates, but they could not be detected according to venders' quality control (QC) suggestions. Our results demonstrated the technical reliability of currently available genotyping platforms but also indicated the importance of incorporating some technical replicates for genotyping QC in order to improve the reliability of GWAS results. The impact of discordant genotypes on association analysis results was simulated and could explain, at least in part, the irreproducibility of some GWAS findings when the effect size (i.e. the odds ratio) and the minor allele frequencies are low.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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. The trend test has the advantage of remaining valid even when the sampled population is not in Hardy-Weinberg equilibrium. A departure from Hardy-Weinberg means that association tests depend on gametic and nongametic linkage disequilibrium between marker and disease loci, and we illustrate the magnitude of these effects with simulated data.
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BFBNIB, DOBA, FSPLJ, FZAB, GIS, IJS, INZLJ, IZUM, KILJ, NLZOH, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK, ZRSKP
In this article, Śidák values in Table 1 and Figure 2 were reported incorrectly. In Table 1, the first column of the results (Śidák) should read as 0.738, 0.335, 0.529, 0.178, 0.327, 0.138, 0.203, ...0.290. Consequently, the value in bold should be 0.879, under ‘RTP (10)’. In Figure 2, the first point (at K=1, which corresponds to Śidák) in both graphs is incorrect: power at K=1 in graph (a) should be at 0.199; expected–log(p‐value) at K=1 in graph (b) should be at 1.949.
The only affected sentence in the manuscript text is in Appendix 2: ‘Interestingly, there is no monotonicity in going from K=1 (Śidák correction) to K=2,3, etc.’ (there is in fact monotonicity).
Incorrect values do not affect any other discussion or conclusions of the paper.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The importance of marker association tests has recently been established for locating disease susceptibility genes in the human genome, attaining finer-scaled maps than the linkage variety of tests ...through the detection of linkage disequilibrium (LD). Many of these association tests were originally defined for biallelic markers under ideal assumptions, with multiallelic extensions often complicated by the covariance among genotype or allele proportions. The well-established allele and genotype case-control tests based on Pearson chi-square test statistics are exceptions since they adapt easily to multiallelic versions, however each of these has its shortcomings. We demonstrate that the multiallelic trend test is an attractive alternative that lacks these limitations. A formula for marker genotype frequencies that incorporates the coefficients quantifying various disequilibria is presented, accommodating any type of disease model. This enables the simulation of samples for estimating the significance level and calculating sample sizes necessary for achieving a certain level of power. There is a similar complexity in extending the family-based tests of association to markers with more than two alleles. Fortunately, the nonparametric sibling disequilibrium test (SDT) statistic has a natural extension to a quadratic form for multiallelic markers. In the original presentation of the statistic however, information from one of the marker alleles is needlessly discarded. This is necessary for the parametric form of the statistic due to a linear dependency among the statistics for the alleles, but the non-parametric representation eliminates this dependency. We show how a statistic making use of all the allelic information can be formed. Obstacles also arise when multiple loci affect disease susceptibility. In the presence of gene-gene interaction, single-marker tests may be unable to detect an association between individual markers and disease status. We implement and evaluate tree-based methods for the mapping of multiple susceptibility genes. Adjustments to correlated p-values from markers in LD with each other are also examined. This study of epistatic gene models reveals the importance of three-locus disequilibria of which we discuss various statistical tests.
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