Y chromosome CNV discovery in a Norwegian population.

<p>A. Signal intensity plot (Log 2 ratio) for a control male without CNV variants. Signals from each of the 8179 probes are represented by one dot. B. Regions of the Y chromosome containing ampliconic and palindromic sequences are represented by colored arrows using the same nomenclature as in Repping et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137223#pone.0137223.ref041" target="_blank">41</a>]. The same colors were used to represent the signal intensity of the corresponding regions in the rest of the figure. Not all ampliconic sequences are covered by SNP/CN probes in the array. The lower part of Fig 2B includes only detectable regions. C to I. Signal intensity plots (Log 2 ratio) for different type of CNVs discovered in a Norwegian population. The lower part of each subfigure shows the name of each CNV following the nomenclature used in Repping et al. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137223#pone.0137223.ref041" target="_blank">41</a>]. Staples delineate the positions of duplications (on the top of the figure) or deletions (on the bottom). J. Signal intensity plot for a previously undescribed duplication hereby named P6 dupl.</p

Principal component analysis of Y chromosome specific SNP variation between haplogroups.

<p>A. The figure shows the graphical representation of the first two eigenvectors after PCA analysis. Y-axis corresponds to the first vector explaining 24.1% of the variation and X-axis explains 13.4% of the remaining variation. Each dot represents the results from one individual and the colour represent each HG as denoted by letters in the figure. The plus symbols in black denote individuals for which HG determination was ambiguous. The black triangles denote individuals for which no HG could be assigned. B. The results from the individuals carrying the blue-grey dupl are represented in blue, while the results from individuals carrying “blue-grey like dupl.” are in red. All cases are included within the NO-M214(xM175) haplogroup. In total 11 individuals carry these variants (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137223#pone.0137223.t001" target="_blank">Table 1</a>) but they are superimposed in the figure, due to high similarity between their HG.</p

Distribution and frequency of CNV patterns significantly overrepresented within haplogroups.

<p>The table shows the distribution of CNV patterns among haplogroups for ten variants that showed overrepresentation in one or more haplogroups. Ambiguous individuals, for which haplotype determination was not possible, are shown in the table for completeness, but they were not included in the statistical analysis. The p-values after Pearson Chi-Square analysis, likelihood ratio and Fisher’s exact test are shown at the bottom of the table, together with the total amount of each CNV type. The % frequency is derived from CNV type observations divided by 1506 individuals for which haplogroup could be determined. The stars mark values that are significant with the standard residual indicated in parenthesis. (Ind.) individuals, (dupl) duplication, (del) deletion and (nd) not done.</p><p>Distribution and frequency of CNV patterns significantly overrepresented within haplogroups.</p

qPCR validation of the newly discovered P6 duplication.

<p>Amplification plots for a female (green), a control male (purple) and a male with P6 dupl. (blue) are shown for markers RH38681 (A), sY1081 (B) and sY933 (C). D. Intensity signal plot (Log 2 ratio) for an individual with P6 dupl. showing that markers sY1081 and sY933 are positioned within the duplicated region, while RH38681 is located outside.</p

Sample distribution and frequency of any CNV in each haplogroup.

<p>From a total of 1718 individuals, 1506 could be assigned to specific haplogroups based on a limited set of phylogenetically informative Y-SNPs within the Affymetrix 6.0 arrays. The table shows the distribution among haplogroups for these individuals, as well as the frequency of CNVs within each haplogroup. The highest frequency (95%) of CNVs was found among individuals of NO-M214(xM175) haplogroup.</p><p>Sample distribution and frequency of any CNV in each haplogroup.</p

Distribution of CNV patterns that were significantly overrepresented in one haplogroup only.

<p>Each part of the figure shows the graphical representation of the first two eigenvectors after PCA analysis A. The figure shows PCA values for individuals with P3 dupl. significantly overrepresented in haplogroup E-M96. B. Individuals with b2/b3 del. significantly overrepresented in haplogroup NO-M214(xM175). C. Individuals with gr/gr del. (c8) significantly overrepresented in haplogroup D-M174. This CNV is also present in other haplogroups. D. Individuals with gr/gr dupl. (c9) + distal dupl. significantly overrepresented in haplogroup J-P256.</p

Increased amygdala activity in <i>CACNA1C</i> SNP rs1006737 risk allele carriers.

<p>Carriers of the <i>CACNA1C</i> SNP rs1006737 risk allele A have significantly increased activity in the left amygdala in the total sample (x = −24, y = −2, z = −14; FWE P = 0.026) and BD subgroup (x = −24, y = 0, z = −14; FWE P = 0.041), and non-significantly increased activity in the right amygdala in the total sample (x = 26, y = 0, z = −16) and BD subgroup (x = 22, y = 0, z = −20) compared with GG homozygotes during a negative faces paradigm. Abbreviations: BD, bipolar disorder; FWE, family-wise error. Threshold for significance in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056970#pone-0056970-g001" target="_blank">Figure 1</a> is set to Nominal P<0.05 within the ROI.</p

Results for <i>CACNA1C</i> SNP rs1006737 (AA+AG>GG) effect on amygdala activation in a sample of bipolar disorder and schizophrenia cases and healthy controls.

<p>Abbreviations: BD, bipolar disorder; SZ, schizophrenia; CTR, healthy controls; FWE, Family-wise error rate; n.s., non-significant.</p><p>Only nominally significant results (Nominal P = <0.05) are shown.</p

Combinations of genetic variants associated with bipolar disorder

<div><p>The main objective of the study was to find genetic variants that in combination are significantly associated with bipolar disorder. In previous studies of bipolar disorder, combinations of three and four single nucleotide polymorphisms (SNP) genotypes taken from 803 SNPs were analyzed, and five clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of ten SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from the new cluster and from the five previous clusters were identified in the genomes of 266 or 44% of the 607 patients in the study whereas none of the 1355 control participants had any of these combinations in their genome.The SNP genotypes in the smaller combinations were the normal homozygote, heterozygote or variant homozygote. In the combinations containing 10 SNP genotypes almost all the genotypes were the normal homozygote. Such a finding may indicate that accumulation in the genome of combinations containing few SNP genotypes may be a risk factor for bipolar disorder when those combinations contain relatively many rare SNP genotypes, whereas combinations need to contain many SNP genotypes to be a risk factor when most of the SNP genotypes are the normal homozygote.</p></div

Part of the cluster with combinations of 10 SNP genotypes.

<p>Part of the cluster with combinations of 10 SNP genotypes.</p