Molecular analysis of Candidate genes at the 22q region in Schizophrenia subjects

22q11.2 deletion syndrome (22q11.2DS), also known as Velo-Cardio-Facial Syndrome (VCFS) or DiGeorge Syndrome, is a genetic disorder due to a micro deletion on chromosome 22q11.2. VCFS is associated with abnormalities in brain structure and with an increased risk of psychiatric disorders, particularly schizophrenia (SCZ). DNA copy  number is a largely unexplored source of human genetic variation that may contribute risk for complex disease like SCZ. The aim of this study was to assess Copy number variations (CNV) at candidate genes located in 22q11 region in SCZ subjects. We report aberrations in copy number  at PRODH and COMT gene loci supporting the hypothesis that dosage effects of 22q genes could lead to disruptions in neurotransmitter signaling and related neurobehavioral symptoms observed in SCZ subjects. The results support the hypothesis that the complex phenotype of 22qDS results either from the overlapping regulation of several genes within this region or from its concerted participation in a highly regulated process

Ontogenetic De Novo Copy Number Variations (CNVs) as a Source of Genetic Individuality: Studies on Two Families with MZD Twins for Schizophrenia

Genetic individuality is the foundation of personalized medicine, yet its determinants are currently poorly understood. One issue is the difference between monozygotic twins that are assumed identical and have been extensively used in genetic studies for decades [1]. Here, we report genome-wide alterations in two nuclear families each with a pair of monozygotic twins discordant for schizophrenia evaluated by the Affymetrix 6.0 human SNP array. The data analysis includes characterization of copy number variations (CNVs) and single nucleotide polymorphism (SNPs). The results have identified genomic differences between twin pairs and a set of new provisional schizophrenia genes. Samples were found to have between 35 and 65 CNVs per individual. The majority of CNVs (∼80%) represented gains. In addition, ∼10% of the CNVs were de novo (not present in parents), of these, 30% arose during parental meiosis and 70% arose during developmental mitosis. We also observed SNPs in the twins that were absent from both parents. These constituted 0.12% of all SNPs seen in the twins. In 65% of cases these SNPs arose during meiosis compared to 35% during mitosis. The developmental mitotic origin of most CNVs that may lead to MZ twin discordance may also cause tissue differences within individuals during a single pregnancy and generate a high frequency of mosaics in the population. The results argue for enduring genome-wide changes during cellular transmission, often ignored in most genetic analyses

Distribution of repeat elements 1 kb upstream (5′) and 1 kb downstream (3′) of the <i>de novo</i> (2a) and <i>inherited</i> (2b) CNVs across eight individuals.

<p>These include LINE (blue), SINE (purple), LTR (yellow), Satellite (sky blue), simple repeats (black) and low complexity repeats (green) with numerical values on top of the bars representing percentage of that repeat.</p

Pedigree of two families with monozygotic twins discordant for schizophrenia.

<p>Members of the family one are indicated with (I-) and members of the family two are indicated with (II-). The designations included in this figure are followed in subsequent figures and tables.</p

Inherited CNVs in Family 2.

<p>Identity of inherited CNVs found in Family 1 (7), Family 2 (8) and the gene regions which they overlap. Inherited CNVs are those which are present in either or both parents and transmitted to either or both twins. All size is in kb. SD indicates the percentage of overlap between segmental duplications and CNVs. ‘0’ means there is no overlap between CNV and segmental duplication, ‘1’ means 90–100% and ‘2’ means 50–90% overlap. Parental CNVs not transmitted to offspring were not included in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t005" target="_blank">Table 5</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t006" target="_blank"></a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t007" target="_blank"></a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t008" target="_blank">8</a> so the total number of CNVs present in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t002" target="_blank">Table 2</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t003" target="_blank"></a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t004" target="_blank">4</a> was not same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t005" target="_blank">Table 5</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t006" target="_blank"></a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t007" target="_blank"></a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017125#pone-0017125-t008" target="_blank">8</a>. The table includes genomic locations as well as individual specific break points which allow for the assessment of regions of overlap with the Database of Genomic Variants (Toronto, Ontario). SI No. = Serial number. Novel indicates a CNV which is not present in The Database of Genomic Variants (DGV).</p

Distribution of CNV among family members according to size.

<p>Numerical values in each cell of the table indicate how many CNVs of that particular size range were observed in that particular individual.</p

Inherited CNVs in Family 1.

<p>Inherited CNVs in Family 1.</p

Demography and Clinical History.

<p>Demography and Clinical History of monozygotic (MZ) twins discordant for Schizophrenia (SCZ). Family one is indicated with (I), family two is indicated with (II). N/A = Not Applicable.</p

Chromosome wise distribution of CNV.

<p>Chromosome specific distribution of <i>de novo</i> (present in twin(s) and not in parents) and <i>inherited</i> (present in at least one parent) CNVs in family 1 and family 2.</p><p>Chr. No = Chromosome number.</p