Common Structural Genomic Variants in Linked with SCZ Regions

Abstract

After specific chromosomal regions were identified by linkage analyses and certain genes were identified as possible candidates, we used exploratory examination of copy number variants (CNVs) and runs of homozygosity (ROHs) based on microarray data to detect structural genomic variants within SCZ-linked regions. For mutation screening within SCZ-linked regions, the main priority in our study was loci with reliable signals in different isolates (with genomic homogeneity) and loci with LODs close to suggestive and significant levels as more robust in four ethnically and demographically subdivided isolates. Such structural genomic variants found in linked regions with candidate genes may have a higher likelihood of contributing to the expressed pathology. CNVs were identified using SVS (GoldenHelix) software if the size of deleted or duplicated region was 100 kb and contained at least 20 SNPs. Given the nonuniform patterns of ROHs across the genome, we were able to uncover regions with different lengths between groups. Differences in the average CN number of whole genomes autosomes varied from 1.3 to 3.1, with the average individual CN segment sizes ranging from 176 to 743.8 kb. Within certain chromosomes, the CN segmental lengths varied; the minimal length we obtained was 101 kb (one affected at 5q12) and a maximum of 4040 kb (at 8p23.2 of one affected). Other max sizes varied from 1015 to 1517 among a limited number of affected subjects’ regions we found in chromosomes 4, 14, 15, and 17. Among CN variants in SCZ cases, microduplications were more frequent than microdeletions by about 1.7 times: from total 205 CN we obtained in autosomes, 129 (63 %) are gains and 76 (37 %) are losses. Studying the isolate pedigrees enables the differentiation between CNV inheritance, as well as sporadic and de novo mutations, because all patients with clinically homogeneous phenotypes usually descended from a common ancestor. The most significant difference in ROH segment size is between SCZ and healthy groups, obtained for chromosomes 2, 6, 12, 17, 18, 19, and 22 where we found regions that were reliably linked with SCZ. Differences between the ROH length sizes for these groups were statistically significant with χ ² = 176.7, d = 21, p = 0.000: length sizes are two times greater among affected, compared to healthy pedigree members. In addition, affected SCZ cases demonstrated larger stretches of CN segments, in comparison with healthy subjects. We found the “hot spots” (a high frequency) in CNV in linked regions of chromosomes 2, 6, 10, 17, 8, 9, and 19 in the genomes of SCZ patients, suggesting that CNVs play an important role in SCZ pathogenesis. We analyzed the inbreeding effect on CNV polymorphisms. Results obtained show that patients with homozygous mutations and of lower inbreeding accumulation have statistically larger CNV segment sizes and fewer markers in the segments, in comparison to similar patients with homozygous mutations who have relatively high levels of inbreeding accumulation. The results obtained suggest that homozygous copy number variations, the origin of which is influenced by inbreeding, are significantly more likely to be intergenic, not affecting the function of protein-coding genes involved in the pathogenesis of SCZ. It is unclear whether this is typical for patients with schizophrenia or if characteristic of evolutionary formed genomic mechanisms of adaptive genetic structure related to the specific effects of inbreeding in the studied isolates. The finding requires further study.