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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Abstract

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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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Li, Yun Rose Glessner, Joseph T Coe, Bradley P Li, Jin Mohebnasab, Maede MAM1236@pitt.edu MAM1236 0000-0001-6623-9514 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
URI:	http://d-scholarship.pitt.edu/id/eprint/43667

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