Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes
| العنوان: | Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes |
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| المؤلفون: | George Hindy, Peter Dornbos, Mark D. Chaffin, Dajiang J. Liu, Minxian Wang, Margaret Sunitha Selvaraj, David Zhang, Joseph Park, Carlos A. Aguilar-Salinas, Lucinda Antonacci-Fulton, Diego Ardissino, Donna K. Arnett, Stella Aslibekyan, Gil Atzmon, Christie M. Ballantyne, Francisco Barajas-Olmos, Nir Barzilai, Lewis C. Becker, Lawrence F. Bielak, Joshua C. Bis, John Blangero, Eric Boerwinkle, Lori L. Bonnycastle, Erwin Bottinger, Donald W. Bowden, Matthew J. Bown, Jennifer A. Brody, Jai G. Broome, Noël P. Burtt, Brian E. Cade, Federico Centeno-Cruz, Edmund Chan, Yi-Cheng Chang, Yii-Der I. Chen, Ching-Yu Cheng, Won Jung Choi, Rajiv Chowdhury, Cecilia Contreras-Cubas, Emilio J. Córdova, Adolfo Correa, L. Adrienne Cupples, Joanne E. Curran, John Danesh, Paul S. de Vries, Ralph A. DeFronzo, Harsha Doddapaneni, Ravindranath Duggirala, Susan K. Dutcher, Patrick T. Ellinor, Leslie S. Emery, Jose C. Florez, Myriam Fornage, Barry I. Freedman, Valentin Fuster, Ma. Eugenia Garay-Sevilla, Humberto García-Ortiz, Soren Germer, Richard A. Gibbs, Christian Gieger, Benjamin Glaser, Clicerio Gonzalez, Maria Elena Gonzalez-Villalpando, Mariaelisa Graff, Sarah E. Graham, Niels Grarup, Leif C. Groop, Xiuqing Guo, Namrata Gupta, Sohee Han, Craig L. Hanis, Torben Hansen, Jiang He, Nancy L. Heard-Costa, Yi-Jen Hung, Mi Yeong Hwang, Marguerite R. Irvin, Sergio Islas-Andrade, Gail P. Jarvik, Hyun Min Kang, Sharon L.R. Kardia, Tanika Kelly, Eimear E. Kenny, Alyna T. Khan, Bong-Jo Kim, Ryan W. Kim, Young Jin Kim, Heikki A. Koistinen, Charles Kooperberg, Johanna Kuusisto, Soo Heon Kwak, Markku Laakso, Leslie A. Lange, Jiwon Lee, Juyoung Lee, Seonwook Lee, Donna M. Lehman, Rozenn N. Lemaitre, Allan Linneberg, Jianjun Liu, Ruth J.F. Loos, Steven A. Lubitz, Valeriya Lyssenko, Ronald C.W. Ma, Lisa Warsinger Martin, Angélica Martínez-Hernández, Rasika A. Mathias, Stephen T. McGarvey, Ruth McPherson, James B. Meigs, Thomas Meitinger, Olle Melander, Elvia Mendoza-Caamal, Ginger A. Metcalf, Xuenan Mi, Karen L. Mohlke, May E. Montasser, Jee-Young Moon, Hortensia Moreno-Macías, Alanna C. Morrison, Donna M. Muzny, Sarah C. Nelson, Peter M. Nilsson, Jeffrey R. O’Connell, Marju Orho-Melander, Lorena Orozco, Colin N.A. Palmer, Nicholette D. Palmer, Cheol Joo Park, Kyong Soo Park, Oluf Pedersen, Juan M. Peralta, Patricia A. Peyser, Wendy S. Post, Michael Preuss, Bruce M. Psaty, Qibin Qi, D.C. Rao, Susan Redline, Alexander P. Reiner, Cristina Revilla-Monsalve, Stephen S. Rich, Nilesh Samani, Heribert Schunkert, Claudia Schurmann, Daekwan Seo, Jeong-Sun Seo, Xueling Sim, Rob Sladek, Kerrin S. Small, Wing Yee So, Adrienne M. Stilp, E. Shyong Tai, Claudia H.T. Tam, Kent D. Taylor, Yik Ying Teo, Farook Thameem, Brian Tomlinson, Michael Y. Tsai, Tiinamaija Tuomi, Jaakko Tuomilehto, Teresa Tusié-Luna, Miriam S. Udler, Rob M. van Dam, Ramachandran S. Vasan, Karine A. Viaud Martinez, Fei Fei Wang, Xuzhi Wang, Hugh Watkins, Daniel E. Weeks, James G. Wilson, Daniel R. Witte, Tien-Yin Wong, Lisa R. Yanek, Sekar Kathiresan, Daniel J. Rader, Jerome I. Rotter, Michael Boehnke, Mark I. McCarthy, Cristen J. Willer, Pradeep Natarajan, Jason A. Flannick, Amit V. Khera, Gina M. Peloso |
| المساهمون: | NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos), Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, Clinicum, Department of Medicine, HUS Internal Medicine and Rehabilitation, University of Helsinki, Department of Public Health |
| المصدر: | Hindy, G, Dornbos, P, Chaffin, M D, Liu, D J, Wang, M, Selvaraj, M S, Zhang, D, Park, J, Aguilar-Salinas, C A, Antonacci-Fulton, L, Ardissino, D, Arnett, D K, Aslibekyan, S, Atzmon, G, Ballantyne, C M, Barajas-Olmos, F, Barzilai, N, Becker, L C, Bielak, L F, Bis, J C, Blangero, J, Boerwinkle, E, Bonnycastle, L L, Bottinger, E, Bowden, D W, Bown, M J, Brody, J A, Broome, J G, Burtt, N P, Cade, B E, Centeno-Cruz, F, Chan, E, Chang, Y C, Chen, Y D I, Cheng, C Y, Choi, W J, Chowdhury, R, Contreras-Cubas, C, Córdova, E J, Correa, A, Cupples, L A, Curran, J E, Danesh, J, de Vries, P S, Grarup, N, Hansen, T, Linneberg, A, Loos, R J F, Pedersen, O, Witte, D R, AMP-T2D-GENES, Myocardial Infarction Genetics Consortium, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium & NHLBI TOPMed Lipids Working Group 2022, ' Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes ', American Journal of Human Genetics, vol. 109, no. 1, pp. 81-96 . https://doi.org/10.1016/j.ajhg.2021.11.021 Am J Hum Genet Hindy, G, Dornbos, P, Chaffin, M D, Liu, D J, Wang, M, Selvaraj, M S, Zhang, D, Park, J, Aguilar-Salinas, C A, Antonacci-Fulton, L, Ardissino, D, Arnett, D K, Aslibekyan, S, Atzmon, G, Ballantyne, C M, Barajas-Olmos, F, Barzilai, N, Becker, L C, Bielak, L F, Bis, J C, Blangero, J, Boerwinkle, E, Bonnycastle, L L, Bottinger, E, Bowden, D W, Bown, M J, Brody, J A, Broome, J G, Burtt, N P, Cade, B E, Centeno-Cruz, F, Chan, E, Chang, Y C, Chen, Y D I, Cheng, C Y, Choi, W J, Chowdhury, R, Contreras-Cubas, C, Córdova, E J, Correa, A, Cupples, L A, Curran, J E, Danesh, J, de Vries, P S, DeFronzo, R A, Grarup, N, Hansen, T, Pedersen, O, Wang, F F, Witte, D R, AMP-T2D-GENES, Myocardial Infarction Genetics Consortium, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium & NHLBI TOPMed Lipids Working Group 2022, ' Rare coding variants in 35 genes associate with circulating lipid levels—A multi-ancestry analysis of 170,000 exomes ', American Journal of Human Genetics, vol. 109, no. 1, pp. 81-96 . https://doi.org/10.1016/j.ajhg.2021.11.021 Hindy, G, Dornbos, P, Chaffin, M D, Liu, D J, Wang, M, Selvaraj, M S, Zhang, D, Park, J, Aguilar-Salinas, C A, Antonacci-Fulton, L, Ardissino, D, Arnett, D K, Aslibekyan, S, Atzmon, G, Ballantyne, C M, Barajas-Olmos, F, Barzilai, N, Becker, L C, Bielak, L F, Bis, J C, Blangero, J, Boerwinkle, E, Bonnycastle, L L, Bottinger, E, Bowden, D W, Bown, M J, Brody, J A, Broome, J G, Burtt, N P, Cade, B E, Centeno-Cruz, F, Chan, E, Chang, Y-C, Chen, Y-D I, Cheng, C-Y, Choi, W J, Chowdhury, R, Contreras-Cubas, C, Córdova, E J, Correa, A, Cupples, L A, Curran, J E, Danesh, J, de Vries, P S, DeFronzo, R A, Doddapaneni, H, Duggirala, R, Dutcher, S K, Ellinor, P T, Grarup, N, Hansen, T, Pedersen, O, Linneberg, A, Witte, D R & AMP-T2D-GENES, Myocardial Infarction Genetics Consortium 2022, ' Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes ', American Journal of Human Genetics, vol. 109, no. 1, pp. 81-96 . https://doi.org/10.1016/j.ajhg.2021.11.021 |
| بيانات النشر: | American Society of Human Genetics, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | APOC3, Blood Glucose, Multifactorial Inheritance, gene-based association, Polymorphism, Single Nucleotide, Article, Open Reading Frames, ANGPTL3, lipid, OF-FUNCTION MUTATIONS, BINDING, Databases, Genetic, SEQUENCE VARIANTS, Genetics, Humans, Exome, Genetic Predisposition to Disease, SINUSOIDAL ENDOTHELIAL-CELLS, Genetics (clinical), Alleles, RISK, IDENTIFICATION, 1184 Genetics, developmental biology, physiology, association, cholesterol, Genetic Variation, Computational Biology, Molecular Sequence Annotation, PERILIPIN, Lipid Metabolism, Lipids, Genetics, Population, Phenotype, Diabetes Mellitus, Type 2, Liver, Case-Control Studies, exome sequencing, TRIGLYCERIDES, Genome-Wide Association Study |
| الوصف: | 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. This work was supported by a grant from the Swedish Research Council (2016-06830) and grants from the National Heart, Lung, and Blood Institute (NHLBI): R01HL142711 and R01HL127564. Please refer to the supplemental information for the full acknowledgements. Sí |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1016/j.ajhg.2021.11.021 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d53d518c5a9781ccf6a21517fa2887b9 https://hdl.handle.net/20.500.12105/15626 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d53d518c5a9781ccf6a21517fa2887b9 |
| قاعدة البيانات: | OpenAIRE |
| DOI: | 10.1016/j.ajhg.2021.11.021 |
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