Viechtbauer, W. | Search bioRxiv

bioRxiv2020

Meta-analysis of epigenome-wide association studies in Alzheime's disease highlights 220 differentially methylated loci across cortex

Epigenome-wide association studies of Alzheimers disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimers disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further > 600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).

genomics↗

bioRxiv2020

Revisiting and expanding the meta-analysis of variation: The log coefficient of variation ratio, lnCVR

Meta-analyses are frequently used to quantify the difference in the average values of two groups (e.g., control and experimental treatment groups), but examine the difference in the variability (variance) of two groups. For such comparisons, the two relatively new effect size statistics, namely the log-transformed variability ratio (the ratio of two standard deviations; lnVR) and the log-transformed CV ratio (the ratio of two coefficients of variation; lnCVR) are useful. In practice, lnCVR may be of most use because a treatment may affect the mean and the variance simultaneously. We review current, and propose new, estimators for lnCVR and lnVR. We also present methods for use when the two groups are dependent (e.g., for cross-over and pre-test-post-test designs). A simulation study evaluated the performance of these estimators and we make recommendations about which estimators one should use to minimise bias. We also present two worked examples that illustrate the importance of accounting for the dependence of the two groups. We found that the degree to which dependence is accounted for in the sampling variance estimates can impact heterogeneity parameters such as{tau} 2 (i.e., the between-study variance) and I2 (i.e., the proportion of the total variability due to between-study variance), and even the overall effect, and in turn qualitative interpretations. Meta-analytic comparison of the variability between two groups enables us to ask completely new questions and to gain fresh insights from existing datasets. We encourage researchers to take advantage of these convenient new effect size measures for the meta-analysis of variation.

bioinformatics↗