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

Yun Rose Li; Joseph T. Glessner; Bradley P. Coe; Jin Li; Maede Mohebnasab; Xiao Chang; John Connolly; Charlly Kao; Zhi Wei; Jonathan Bradfield; Cecilia Kim; Cuiping Hou; Munir Khan; Frank Mentch; Haijun Qiu; Marina Bakay; Christopher Cardinale; Maria Lemma; Debra Abrams; Andrew Bridglall-Jhingoor; Meckenzie Behr; Shanell Harrison; George Otieno; Alexandria Thomas; Fengxiang Wang; Rosetta Chiavacci; Lawrence Wu; Dexter Hadley; Elizabeth Goldmuntz; Josephine Elia; John Maris; Robert Grundmeier; Marcella Devoto; Brendan Keating; Michael March; Renata Pellagrino; Struan F.A. Grant; Patrick M.A. Sleiman; Mingyao Li; Evan E. Eichler; Hakon Hakonarson

doi:10.1038/s41467-019-13624-1

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

Yun Rose Li, Joseph T. Glessner, Bradley P. Coe, Jin Li, Maede Mohebnasab, Xiao Chang, John Connolly, Charlly Kao, Zhi Wei, Jonathan Bradfield, Cecilia Kim, Cuiping Hou, Munir Khan, Frank Mentch, Haijun Qiu, Marina Bakay, Christopher Cardinale, Maria Lemma, Debra Abrams, Andrew Bridglall-JhingoorMeckenzie Behr, Shanell Harrison, George Otieno, Alexandria Thomas, Fengxiang Wang, Rosetta Chiavacci, Lawrence Wu, Dexter Hadley, Elizabeth Goldmuntz, Josephine Elia, John Maris, Robert Grundmeier, Marcella Devoto, Brendan Keating, Michael March, Renata Pellagrino, Struan F.A. Grant, Patrick M.A. Sleiman, Mingyao Li, Evan E. Eichler, Hakon Hakonarson

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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.

Original language	English (US)
Article number	255
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13624-1
State	Published - Dec 1 2020
Externally published	Yes

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-019-13624-1

Cite this

Li, Y. R., Glessner, J. T., Coe, B. P., Li, J., Mohebnasab, M., Chang, X., Connolly, J., Kao, C., Wei, Z., Bradfield, J., Kim, C., Hou, C., Khan, M., Mentch, F., Qiu, H., Bakay, M., Cardinale, C., Lemma, M., Abrams, D., ... Hakonarson, H. (2020). Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations. Nature communications, 11(1), Article 255. https://doi.org/10.1038/s41467-019-13624-1

@article{df3adefc1193405eb46028753dc9c85b,

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

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.",

author = "Li, {Yun Rose} and Glessner, {Joseph T.} and Coe, {Bradley P.} and Jin Li and Maede Mohebnasab and Xiao Chang and John Connolly and Charlly Kao and Zhi Wei and Jonathan Bradfield and Cecilia Kim and Cuiping Hou and Munir Khan and Frank Mentch and Haijun Qiu and Marina Bakay and Christopher Cardinale and Maria Lemma and Debra Abrams and Andrew Bridglall-Jhingoor and Meckenzie Behr and Shanell Harrison and George Otieno and Alexandria Thomas and Fengxiang Wang and Rosetta Chiavacci and Lawrence Wu and Dexter Hadley and Elizabeth Goldmuntz and Josephine Elia and John Maris and Robert Grundmeier and Marcella Devoto and Brendan Keating and Michael March and Renata Pellagrino and Grant, {Struan F.A.} and Sleiman, {Patrick M.A.} and Mingyao Li and Eichler, {Evan E.} and Hakon Hakonarson",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13624-1",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Li, YR, Glessner, JT, Coe, BP, Li, J, Mohebnasab, M, Chang, X, Connolly, J, Kao, C, Wei, Z, Bradfield, J, Kim, C, Hou, C, Khan, M, Mentch, F, Qiu, H, Bakay, M, Cardinale, C, Lemma, M, Abrams, D, Bridglall-Jhingoor, A, Behr, M, Harrison, S, Otieno, G, Thomas, A, Wang, F, Chiavacci, R, Wu, L, Hadley, D, Goldmuntz, E, Elia, J, Maris, J, Grundmeier, R, Devoto, M, Keating, B, March, M, Pellagrino, R, Grant, SFA, Sleiman, PMA, Li, M, Eichler, EE & Hakonarson, H 2020, 'Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations', Nature communications, vol. 11, no. 1, 255. https://doi.org/10.1038/s41467-019-13624-1

TY - JOUR

T1 - Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations

AU - Li, Yun Rose

AU - Glessner, Joseph T.

AU - Coe, Bradley P.

AU - Li, Jin

AU - Mohebnasab, Maede

AU - Chang, Xiao

AU - Connolly, John

AU - Kao, Charlly

AU - Wei, Zhi

AU - Bradfield, Jonathan

AU - Kim, Cecilia

AU - Hou, Cuiping

AU - Khan, Munir

AU - Mentch, Frank

AU - Qiu, Haijun

AU - Bakay, Marina

AU - Cardinale, Christopher

AU - Lemma, Maria

AU - Abrams, Debra

AU - Bridglall-Jhingoor, Andrew

AU - Behr, Meckenzie

AU - Harrison, Shanell

AU - Otieno, George

AU - Thomas, Alexandria

AU - Wang, Fengxiang

AU - Chiavacci, Rosetta

AU - Wu, Lawrence

AU - Hadley, Dexter

AU - Goldmuntz, Elizabeth

AU - Elia, Josephine

AU - Maris, John

AU - Grundmeier, Robert

AU - Devoto, Marcella

AU - Keating, Brendan

AU - March, Michael

AU - Pellagrino, Renata

AU - Grant, Struan F.A.

AU - Sleiman, Patrick M.A.

AU - Li, Mingyao

AU - Eichler, Evan E.

AU - Hakonarson, Hakon

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85077872254&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85077872254&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-13624-1

DO - 10.1038/s41467-019-13624-1

M3 - Article

C2 - 31937769

AN - SCOPUS:85077872254

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 255

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this