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Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Li, Yun Rose and Glessner, Joseph T and Coe, Bradley P and Li, Jin and Mohebnasab, Maede and Chang, Xiao and Connolly, John and Kao, Charlly and Wei, Zhi and Bradfield, Jonathan and Kim, Cecilia and Hou, Cuiping and Khan, Munir and Mentch, Frank and Qiu, Haijun and Bakay, Marina and Cardinale, Christopher and Lemma, Maria and Abrams, Debra and Bridglall-Jhingoor, Andrew and Behr, Meckenzie and Harrison, Shanell and Otieno, George and Thomas, Alexandria and Wang, Fengxiang and Chiavacci, Rosetta and Wu, Lawrence and Hadley, Dexter and Goldmuntz, Elizabeth and Elia, Josephine and Maris, John and Grundmeier, Robert and Devoto, Marcella and Keating, Brendan and March, Michael and Pellagrino, Renata and Grant, Struan FA and Sleiman, Patrick MA and Li, Mingyao and Eichler, Evan E and Hakonarson, Hakon (2019) Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations. Nat Commun, 11 (1). 255 - ?.

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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 gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Li, Yun Rose
Glessner, Joseph T
Coe, Bradley P
Li, Jin
Mohebnasab, MaedeMAM1236@pitt.eduMAM12360000-0001-6623-9514
Chang, Xiao
Connolly, John
Kao, Charlly
Wei, Zhi
Bradfield, Jonathan
Kim, Cecilia
Hou, Cuiping
Khan, Munir
Mentch, Frank
Qiu, Haijun
Bakay, Marina
Cardinale, Christopher
Lemma, Maria
Abrams, Debra
Bridglall-Jhingoor, Andrew
Behr, Meckenzie
Harrison, Shanell
Otieno, George
Thomas, Alexandria
Wang, Fengxiang
Chiavacci, Rosetta
Wu, Lawrence
Hadley, Dexter
Goldmuntz, Elizabeth
Elia, Josephine
Maris, John
Grundmeier, Robert
Devoto, Marcella
Keating, Brendan
March, Michael
Pellagrino, Renata
Grant, Struan FA
Sleiman, Patrick MA
Li, Mingyao
Eichler, Evan E
Hakonarson, Hakon
Date: 14 November 2019
Date Type: Acceptance
Journal or Publication Title: Nat Commun
Volume: 11
Number: 1
Page Range: 255 - ?
DOI or Unique Handle: 10.1038/s41467-019-13624-1
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Uncontrolled Keywords: Comparative Genomic Hybridization, DNA Copy Number Variations, Databases, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, White People
Funders: NIEHS NIH HHS (P30 ES013508), NLM NIH HHS (U01 LM012675), NHGRI NIH HHS (U01 HG006830)
Date Deposited: 29 Aug 2022 17:19
Last Modified: 20 Dec 2022 15:55


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