Rare coding variants in 35 genes associate with circulating lipid levels—A multi-ancestry analysis of 170,000 exomes
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Date
2022-01-06Author
George, HindyDornbos, 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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Show full item recordAbstract
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 < 1%) predicted damaging coding variation by using sequence data from >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.
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