Assessment of de novo copy-number variations in Italian patients with schizophrenia: Detection of putative mutations involving regulatory enhancer elements

<p><b>Objectives:</b> Variants appearing de novo in genes regulating key neurodevelopmental processes and/or in non-coding <i>cis</i>-regulatory elements (CREs), as enhancers, may increase the risk for schizophrenia. However, CREs involvement in schizophrenia needs to be explored more deeply.</p> <p><b>Methods:</b> We investigated de novo copy-number variations (CNVs) in the whole-genomic DNA obtained from 46 family trios of schizophrenia probands by using the Enhancer Chip, a customised array CGH able to investigate the whole genome with a 300-kb resolution, specific disease loci at a ten-fold higher resolution, and which was highly enriched in probes in more than 1,250 enhancer elements selected from Vista Enhancer Browser.</p> <p><b>Results:</b> In seven patients, we found de novo CNVs, two of which overlapped VISTA enhancer elements. De novo CNVs encompass genes (<i>CNTNAP2</i>, <i>MAGI1</i>, <i>TSPAN7</i> and <i>MET</i>) involved in brain development, while that involving the enhancer element hs1043, also includes <i>ZIC1</i>, which plays a role in neural development and is responsible of behavioural abnormalities in <i>Zic</i> mutant mice.</p> <p><b>Conclusions:</b> These findings provide further evidence for the involvement of de novo CNVs in the pathogenesis of schizophrenia and suggest that CNVs affecting regulatory enhancer elements could contribute to the genetic vulnerability to the disorder.</p

Inter-rater agreement and reliability of the assessment of lithium response in the two-stage case-vignette rating procedure: kappa and intra-class correlation analysis.

<p>TS: total score.</p><p>ICC: intra-class correlation.</p><p>CI: confidence interval.</p>*<p>Mixed and random effects models.</p>§<p>70 raters.</p>¶<p>48 raters.</p

Empirical and theoretical distributions of the total score in the Consortium on Lithium Genetics sample.

<p>Frequentist, <b>A</b>, and Bayesian minimum message length, <b>B</b>, mixture modeling identify three subpopulations of non responders (grey), partial responders (red), and full responders (blue) in total scores of 1,308 bipolar disorder patients characterized for response to lithium maintenance treatment.</p

Distribution of total and A scores in the Consortium on Lithium Genetics sample.

<p>Histogram plot of the scale scores in 1,308 bipolar disorder patients characterized for response to lithium maintenance treatment.</p

Number of raters from the Consortium on Lithium Genetics (ConLiGen) centres participating in the two-stage case-vignette rating procedure for inter-rater reliability and agreement.

<p>ConLiGen: Consortium on Lithium Genetics.</p>*<p>Hokkaido, Osaka, Tokio, Riken Brain Science Institute.</p