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    Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.

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    Author
    Hindy, George
    Dornbos, Peter
    Chaffin, Mark D
    Liu, Dajiang J
    Wang, Minxian
    Selvaraj, Margaret Sunitha
    Zhang, David
    Park, Joseph
    Aguilar-Salinas, Carlos A
    Antonacci-Fulton, Lucinda
    Ardissino, Diego
    Arnett, Donna K
    Aslibekyan, Stella
    Atzmon, Gil
    Ballantyne, Christie M
    Barajas-Olmos, Francisco
    Barzilai, Nir
    Becker, Lewis C
    Bielak, Lawrence F
    Bis, Joshua C
    Blangero, John
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Bottinger, Erwin
    Bowden, Donald W
    Bown, Matthew J
    Brody, Jennifer A
    Broome, Jai G
    Burtt, Noël P
    Cade, Brian E
    Centeno-Cruz, Federico
    Chan, Edmund
    Chang, Yi-Cheng
    Chen, Yii-Der I
    Cheng, Ching-Yu
    Choi, Won Jung
    Chowdhury, Rajiv
    Contreras-Cubas, Cecilia
    Córdova, Emilio J
    Correa, Adolfo
    Cupples, L Adrienne
    Curran, Joanne E
    Danesh, John
    de Vries, Paul S
    DeFronzo, Ralph A
    Doddapaneni, Harsha
    Duggirala, Ravindranath
    Dutcher, Susan K
    Ellinor, Patrick T
    Emery, Leslie S
    Florez, Jose C
    Fornage, Myriam
    Freedman, Barry I
    Fuster, Valentin
    Garay-Sevilla, Ma Eugenia
    García-Ortiz, Humberto
    Germer, Soren
    Gibbs, Richard A
    Gieger, Christian
    Glaser, Benjamin
    Gonzalez, Clicerio
    Gonzalez-Villalpando, Maria Elena
    Graff, Mariaelisa
    Graham, Sarah E
    Grarup, Niels
    Groop, Leif C
    Guo, Xiuqing
    Gupta, Namrata
    Han, Sohee
    Hanis, Craig L
    Hansen, Torben
    He, Jiang
    Heard-Costa, Nancy L
    Hung, Yi-Jen
    Hwang, Mi Yeong
    Irvin, Marguerite R
    Islas-Andrade, Sergio
    Jarvik, Gail P
    Kang, Hyun Min
    Kardia, Sharon L R
    Kelly, Tanika
    Kenny, Eimear E
    Khan, Alyna T
    Kim, Bong-Jo
    Kim, Ryan W
    Kim, Young Jin
    Koistinen, Heikki A
    Kooperberg, Charles
    Kuusisto, Johanna
    Kwak, Soo Heon
    Laakso, Markku
    Lange, Leslie A
    Lee, Jiwon
    Lee, Juyoung
    Lee, Seonwook
    Lehman, Donna M
    Lemaitre, Rozenn N
    Linneberg, Allan
    Liu, Jianjun
    Loos, Ruth J F
    Lubitz, Steven A
    Lyssenko, Valeriya
    Ma, Ronald C W
    Martin, Lisa Warsinger
    Martínez-Hernández, Angélica
    Mathias, Rasika A
    McGarvey, Stephen T
    McPherson, Ruth
    Meigs, James B
    Meitinger, Thomas
    Melander, Olle
    Mendoza-Caamal, Elvia
    Metcalf, Ginger A
    Mi, Xuenan
    Mohlke, Karen L
    Montasser, May E
    Moon, Jee-Young
    Moreno-Macías, Hortensia
    Morrison, Alanna C
    Muzny, Donna M
    Nelson, Sarah C
    Nilsson, Peter M
    O'Connell, Jeffrey R
    Orho-Melander, Marju
    Orozco, Lorena
    Palmer, Colin N A
    Palmer, Nicholette D
    Park, Cheol Joo
    Park, Kyong Soo
    Pedersen, Oluf
    Peralta, Juan M
    Peyser, Patricia A
    Post, Wendy S
    Preuss, Michael
    Psaty, Bruce M
    Qi, Qibin
    Rao, D C
    Redline, Susan
    Reiner, Alexander P
    Revilla-Monsalve, Cristina
    Rich, Stephen S
    Samani, Nilesh
    Schunkert, Heribert
    Schurmann, Claudia
    Seo, Daekwan
    Seo, Jeong-Sun
    Sim, Xueling
    Sladek, Rob
    Small, Kerrin S
    So, Wing Yee
    Stilp, Adrienne M
    Tai, E Shyong
    Tam, Claudia H T
    Taylor, Kent D
    Teo, Yik Ying
    Thameem, Farook
    Tomlinson, Brian
    Tsai, Michael Y
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Tusié-Luna, Teresa
    Udler, Miriam S
    van Dam, Rob M
    Vasan, Ramachandran S
    Viaud Martinez, Karine A
    Wang, Fei Fei
    Wang, Xuzhi
    Watkins, Hugh
    Weeks, Daniel E
    Wilson, James G
    Witte, Daniel R
    Wong, Tien-Yin
    Yanek, Lisa R
    Kathiresan, Sekar
    Rader, Daniel J
    Rotter, Jerome I
    Boehnke, Michael
    McCarthy, Mark I
    Willer, Cristen J
    Natarajan, Pradeep
    Flannick, Jason A
    Khera, Amit V
    Peloso, Gina M
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    Date
    2021-12-16
    Journal
    American Journal of Human Genetics
    Publisher
    Cell Press
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1016/j.ajhg.2021.11.021
    Abstract
    Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency [removed]170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.
    Rights/Terms
    Copyright © 2021 American Society of Human Genetics. All rights reserved.
    Keyword
    association
    cholesterol
    exome sequencing
    gene-based association
    lipid
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17626
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ajhg.2021.11.021
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