Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.
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ABSTRACT:
SUBMITTER: Li YR
PROVIDER: S-EPMC6959272 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.
Li Yun Rose YR Glessner Joseph T JT Coe Bradley P BP Li Jin J Mohebnasab Maede M Chang Xiao X Connolly John J Kao Charlly C Wei Zhi Z Bradfield Jonathan J Kim Cecilia C Hou Cuiping C Khan Munir M Mentch Frank F Qiu Haijun H Bakay Marina M Cardinale Christopher C Lemma Maria M Abrams Debra D Bridglall-Jhingoor Andrew A Behr Meckenzie M Harrison Shanell S Otieno George G Thomas Alexandria A Wang Fengxiang F Chiavacci Rosetta R Wu Lawrence L Hadley Dexter D Goldmuntz Elizabeth E Elia Josephine J Maris John J Grundmeier Robert R Devoto Marcella M Keating Brendan B March Michael M Pellagrino Renata R Grant Struan F A SFA Sleiman Patrick M A PMA Li Mingyao M Eichler Evan E EE Hakonarson Hakon H
Nature communications 20200114 1
Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one ...[more]
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Project description:BackgroundProctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity.MethodsWe investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369).ResultsIn prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.ConclusionsWe report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual's susceptibility to developing radiotoxicity.
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