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
N1 - Publisher Copyright:
© 2020, The Author(s).
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 - https://www.scopus.com/pages/publications/85077872254
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 -