DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1,048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.</p

Additional file 2: of Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

PRISMA CHECKLIST This additional file includes the PRISMA checklist for reporting systematic reviews; this has been completed for the current review, highlighting where in the review each item on the checklist is addressed. (DOCX 28 kb

Additional file 1: of Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? a systematic review

Appendix I: Search Strategies [Search terms used for databases]. Appendix II: Data Extraction Form [Form used to extract data from included studies]. Appendix III: Quality Assessment Tool [Adapted Newcastle-Ottawa Scale used for quality assessment of studies]. Appendix IV: Excluded Studies [Table listing all studies which underwent full-text screening and were subsequently excluded, with reasons for exclusion]. Appendix V: Included Studies [Table of all included studies with key details – study design, sample size, country, definitions of treatment-resistance and response, variables measured, full results, and overall quality assessment score]. Appendix VI: Quality Assessment for Included Studies [Tables outlining full quality assessment scoring for each included study]. (DOCX 180 kb

Additional file 2: of 5-hydroxymethylcytosine is highly dynamic across human fetal brain development

Supplementary Figures. (DOC 3539 kb

Additional file 1: of 5-hydroxymethylcytosine is highly dynamic across human fetal brain development

Supplementary Tables. (ZIP 82808 kb

Study on transepithelial movement of 3H-androgen in the rat seminiferous and epididymal tubules

微小穿刺法と微小灌流法を用いた。精細管の管内アンドロゲン濃度は間質液中のその濃度が10-2, 000nMに増大するに従い直線的に増大したが, 精巣上体頭部における管内アンドロゲン濃度は間質液中の濃度が増大するに従い双曲線的に増大し, 精細管におけるそれよりもはるかに高い値を示した。灌流液中に0.1nMのジニトロフェノール, 0.1mMのKCN, 100μg/mlのサイクロヘキサミドを加えたとき, 管内アンドロゲンの移行は組織ATP濃度とともに有意に減少した。アンドロゲン結合蛋白を含まない人工的精上体頭部の管内液で管内を灌流したとき濃度勾配に抗したアンドロゲン移行は完全に抑制されたThe mechanisms involved in the maintenance of the endocrinological microenvironment of the seminiferous and epididymal tubules were examined in a series of experiments utilizing in vivo microperifusion, microperfusion, and micropuncture technique. The intraluminal 3H-androgen concentration in the seminiferous tubules increased linearly as the interstitial 3H-androgen concentrations increased from 10 nM to 2, 000 nM, but in the caput epididymidal tubules, the intraluminal 3H-androgen concentration increased hyperbolically across the same range of peritubular 3H-androgen concentration. Intraluminal 3H-androgen concentrations in the caput epididymidis did not rise above approximately 340 nM even when the peritubular 3H-androgen concentration exceeded 2, 000 nM. Perifusion of caput tubules with 0.1 mM dinitrophenol or potassium cyanide or 100 micrograms/ml cyclohexamide significantly reduced the proluminal 3H-androgen movement, but tubules perifused with control medium did not support antigrade 3H-androgen movement in the absence of native lumen fluids which contain androgen-binding protein. Energy-requiring protein synthesis is necessary for antigrade 3H-androgen movement in the caput epididymidis, but the mechanism for the interaction of intracellular protein(s) and 3H-androgen movement remains undetermined

Skewed X-inactivation ratios (deviation from 50∶50) in females at ages 5 and 10 years (The percentage reported is cumulative for each group).

<p>Skewed X-inactivation ratios (deviation from 50∶50) in females at ages 5 and 10 years (The percentage reported is cumulative for each group).</p

Longitudinal analysis of allelic XCI ratios in female children over early childhood development.

<p>(<b><i>A</i></b>) Individual changes in absolute XCI ratio between ages 5 and 10 years. (<b><i>B</i></b>) Inter-individual stability correlation for XCI ratio, between ages 5 and 10 years. <i>XCI = X-Chromosome Inactivation</i>.</p

Allelic skewing of female children at ages 5 and 10 years as ascertained by the HUMARA assay performed in triplicate.

<p>Allelic skewing of female children at (<b><i>A</i></b>) age 5 and (<b><i>B</i></b>) age 10. Allelic skewing is defined as the percentage deviation from the presumed ‘normal’ 50∶50 XCI patterns and is assigned to 5 “bins” representing increments of 10%. More instances of extreme allelic XCI skewing are observed at age 10 than age 5. <i>XCI = X-Chromosome Inactivation</i>.</p

Additional file 5: of Genome-wide methylomic analysis in individuals with HNF1B intragenic mutation and 17q12 microdeletion

Figure S2. This Figure shows four significant differentially methylated regions (DMRs) identified between controls and 17q12 deletion carriers. A) SYNRG (corrected P = 1.32E-17), B) AATF (corrected P = 1.64E-11). C) LHX1 (corrected P = 3.37E-18), D) SMIM24 (corrected P = 1.01E-07). (PDF 223 kb