Additional file 2: of Divisive hierarchical maximum likelihood clustering

Computational consideration of DRAGON search. In this file derivation of computational complexity of DRAGON search is given. (PDF 84 kb

Additional file 1: Figure S1. of Arete – candidate gene prioritization using biological network topology with additional evidence types

Evaluation of performance for multi-disease and single-disease gene subsets. (PDF 183 kb

Additional file 3: of Divisive hierarchical maximum likelihood clustering

Clustering accuracy using InfoGain feature selection method. In this file, InfoGain filtering method was used to perform feature selection. Thereafter, various clustering methods were used to evaluate the performance of DRAGON method. (PDF 68 kb

Additional file 1: of Divisive hierarchical maximum likelihood clustering

Divisive hierarchical maximum likelihood clustering. In this file an illustration of DRAGON method is given. Additionally, performance (in terms of Rand index) is given for synthetic data (Flame, Pathbased and Aggregation). (PDF 963 kb

Presentation_1_Sample Size for Successful Genome-Wide Association Study of Major Depressive Disorder.pdf

<p>Major depressive disorder (MDD) is a complex, heritable psychiatric disorder. Advanced statistical genetics for genome-wide association studies (GWASs) have suggested that the heritability of MDD is largely explained by common single nucleotide polymorphisms (SNPs). However, until recently, there has been little success in identifying MDD-associated SNPs. Here, based on an empirical Bayes estimation of a semi-parametric hierarchical mixture model using summary statistics from GWASs, we show that MDD has a distinctive polygenic architecture consisting of a relatively small number of risk variants (~17%), e.g., compared to schizophrenia (~42%). In addition, these risk variants were estimated to have very small effects (genotypic odds ratio ≤ 1.04 under the additive model). Based on the estimated architecture, the required sample size for detecting significant SNPs in a future GWAS was predicted to be exceptionally large. It is noteworthy that the number of genome-wide significant MDD-associated SNPs would rapidly increase when collecting 50,000 or more MDD-cases (and the same number of controls); it can reach as much as 100 SNPs out of nearly independent (linkage disequilibrium pruned) 100,000 SNPs for ~120,000 MDD-cases.</p

The top 20 significantly up- or down-regulated genes in the M+V-treated cochleae relative to control vehicle-treated cochleae.

<p>*M+V, l-methionine and valproic acid; ctrl, vehicle control.</p><p>**Genes in bold were validated by qRT-PCR.</p><p>The top 20 significantly up- or down-regulated genes in the M+V-treated cochleae relative to control vehicle-treated cochleae.</p

Attenuation of Progressive Hearing Loss in DBA/2J Mice by Reagents that Affect Epigenetic Modifications Is Associated with Up-Regulation of the Zinc Importer Zip4

<div><p>Various factors that are important for proper hearing have been identified, including serum levels of zinc. Here we investigated whether epigenetic regulatory pathways, which can be modified by environmental factors, could modulate hearing. RT-PCR detected expression of genes encoding DNA methyltransferase and histone deacetylase (Hdac) in the postnatal as well as adult mouse auditory epithelium. DBA/2J mice, which are a model for progressive hearing loss, were injected subcutaneously with one or a combination of the following reagents: L-methionine as a methyl donor, valproic acid as a pan-Hdac inhibitor, and folic acid and vitamin B12 as putative factors involved in age-related hearing loss. The mice were treated from ages 4 to 12 weeks (N ≥ 5), and auditory brainstem response (ABR) thresholds were measured at 8, 16, and 32 kHz. Treatment of the mice with a combination of L-methionine and valproic acid (M+V) significantly reduced the increase in the ABR threshold at 32 kHz. Treatment with any of these reagents individually produced no such effect. Microarray analyses detected 299 gene probes that were significantly up- or down-regulated in the cochleae of mice treated with M+V compared with the control vehicle-treated mice. Quantitative RT-PCR confirmed significant up-regulation of a zinc importer gene, <i>Zip4</i>, in the cochleae of mice treated with M+V. Immunohistochemistry demonstrated an intense Zip4 signal in cochlear tissues such as the lateral wall, organ of Corti, and spiral ganglion. Finally, mice treated with the <i>Zip4</i> inducer (–)-epigallocatechin-3-<i>O</i>-gallate showed a significant reduction in the increase of the ABR threshold at 32 kHz and up-regulation of <i>Zip4</i> expression in the cochlea. This study suggests that epigenetic regulatory pathways can modify auditory function and that zinc intake in the cochlea via Zip4 mediates maintenance of mammalian hearing.</p></div

<i>Dnmt</i>s and <i>Hdac</i>s in the developing mouse auditory epithelium.

<p>(A) Expression levels of <i>Dnmt</i>s in the auditory epithelia of FVB mice at P1, P14, and 12 weeks (12w). Values shown are the mean ± s.d.; *<i>p</i> < 0.05, **<i>p</i> < 0.01 (N = 3 mice, one-way ANOVA and Scheffe’s test). (B) Expression of <i>Hdac</i>s in the developing auditory epithelia of FVB mice as assessed with RT-PCR.</p

The top 20 significantly up- or down-regulated genes in the M+V-treated cochleae relative to control vehicle-treated cochleae.

<p>*M+V, l-methionine and valproic acid; ctrl, vehicle control.</p><p>**Genes in bold were validated by qRT-PCR.</p><p>The top 20 significantly up- or down-regulated genes in the M+V-treated cochleae relative to control vehicle-treated cochleae.</p

Effects of reagents that affect epigenetic modification on progressive hearing loss in DBA mice.

<p>ABR threshold increases at 8, 16, and 32 kHz in DBA mice from 4 to 12 weeks of age that were treated with different reagents. Values shown are the mean ± s.d.; *<i>p</i> < 0.05, **<i>p</i> <0.01 (one-way ANOVA and Scheffe’s test). The numbers of animals in each group were as follows: 5 for untreated (unt), 19 for control (ctrl), 21 for M+V, 10 each for MET and VPA, and 11 each for FA and VB12. SPL, sound pressure level.</p