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

作者：Yun Rose Li, Joseph Glessner, Bradley P. Coe, Jin Li, Maedeh Mohebnasab, Xiao Chang, John J. Connolly, Charlly Kao, Zhi Wei, Jonathan P. Bradfield, Cecilia Kim, Cuiping Hou, Munir Khan, Frank Mentch, Haijun Qiu, Marina Bakay, Christopher J. Cardinale, Maria Lemma, Debra Abrams, Andrew Bridglall-Jhingoor, Meckenzie Behr, Shanell Harrison, George Otieno, Alexandria Thomas, Fengxiang Wang, Rosetta Chiavacci, Lawrence Shih-Hsin Wu, Dexter Hadley, Elizabeth Goldmuntz, Josephine Elia, John M. Maris, Robert W. Grundmeier, Marcella Devoto, Brendan J. Keating, Michael March, Renata Pellagrino, Struan F.A. Grant, Patrick Sleiman, Mingyao Li, Evan E. Eichler, Håkon Håkonarson · 发表于：Nature Communications · 年份：2020 · DOI：10.1038/s41467-019-13624-1 · 被引用次数：87 · 研究领域：Genomic variations and chromosomal abnormalities、Genomics and Rare Diseases、Chromosomal and Genetic Variations

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.