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DOI 10.1038/s41467-022-33510-7

Медицинская библиотека · Nature communications · 2022

Whole genome sequence analysis of blood lipid levels in >66,000 individuals.

Selvaraj Margaret Sunitha, Li Xihao, Li Zilin, Pampana Akhil, Zhang David Y, Park Joseph, Aslibekyan Stella, Bis Joshua C, Brody Jennifer A, Cade Brian E, Chuang Lee-Ming, Chung Ren-Hua, Curran Joanne E, de las Fuentes Lisa, de Vries Paul S, Duggirala Ravindranath, Freedman Barry I, Graff Mariaelisa, Guo Xiuqing, Heard-Costa Nancy, Hidalgo Bertha, Hwu Chii-Min, Irvin Marguerite R, Kelly Tanika N, Kral Brian G, Lange Leslie, Li Xiaohui, Lisa Martin, Lubitz Steven A, Manichaikul Ani W, Michael Preuss, Montasser May E, Morrison Alanna C, Naseri Take, O'Connell Jeffrey R, Palmer Nicholette D, Peyser Patricia A, Reupena Muagututia S, Smith Jennifer A, Sun Xiao, Taylor Kent D, Tracy Russell P, Tsai Michael Y, Wang Zhe, Wang Yuxuan, Bao Wei, Wilkins John T, Yanek Lisa R, Zhao Wei, Arnett Donna K, Blangero John, Boerwinkle Eric, Bowden Donald W, Chen Yii-Der Ida, Correa Adolfo, Cupples L Adrienne, Dutcher Susan K, Ellinor Patrick T, Fornage Myriam, Gabriel Stacey, Germer Soren, Gibbs Richard, He Jiang, Kaplan Robert C, Kardia Sharon L R, Kim Ryan, Kooperberg Charles, Loos Ruth J F, Viaud-Martinez Karine A, Mathias Rasika A, McGarvey Stephen T, Mitchell Braxton D, Nickerson Deborah, North Kari E, Psaty Bruce M, Redline Susan, Reiner Alexander P, Vasan Ramachandran S, Rich Stephen S, Willer Cristen, Rotter Jerome I, Rader Daniel J, Lin Xihong, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Peloso Gina M, Natarajan Pradeep

СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаПеревод пока не подготовлен

Аннотация

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

Для цитирования: Selvaraj Margaret Sunitha, Li Xihao, Li Zilin, Pampana Akhil, Zhang David Y, Park Joseph, Aslibekyan Stella, Bis Joshua C, Brody Jennifer A, Cade Brian E, Chuang Lee-Ming, Chung Ren-Hua, Curran Joanne E, de las Fuentes Lisa, de Vries Paul S, Duggirala Ravindranath, Freedman Barry I, Graff Mariaelisa, Guo Xiuqing, Heard-Costa Nancy, Hidalgo Bertha, Hwu Chii-Min, Irvin Marguerite R, Kelly Tanika N, Kral Brian G, Lange Leslie, Li Xiaohui, Lisa Martin, Lubitz Steven A, Manichaikul Ani W, Michael Preuss, Montasser May E, Morrison Alanna C, Naseri Take, O'Connell Jeffrey R, Palmer Nicholette D, Peyser Patricia A, Reupena Muagututia S, Smith Jennifer A, Sun Xiao, Taylor Kent D, Tracy Russell P, Tsai Michael Y, Wang Zhe, Wang Yuxuan, Bao Wei, Wilkins John T, Yanek Lisa R, Zhao Wei, Arnett Donna K, Blangero John, Boerwinkle Eric, Bowden Donald W, Chen Yii-Der Ida, Correa Adolfo, Cupples L Adrienne, Dutcher Susan K, Ellinor Patrick T, Fornage Myriam, Gabriel Stacey, Germer Soren, Gibbs Richard, He Jiang, Kaplan Robert C, Kardia Sharon L R, Kim Ryan, Kooperberg Charles, Loos Ruth J F, Viaud-Martinez Karine A, Mathias Rasika A, McGarvey Stephen T, Mitchell Braxton D, Nickerson Deborah, North Kari E, Psaty Bruce M, Redline Susan, Reiner Alexander P, Vasan Ramachandran S, Rich Stephen S, Willer Cristen, Rotter Jerome I, Rader Daniel J, Lin Xihong, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Peloso Gina M, Natarajan Pradeep. Whole genome sequence analysis of blood lipid levels in >66,000 individuals.. Nature communications. 2022. DOI: 10.1038/s41467-022-33510-7.

Предметные рубрики MeSH

AllelesCholesterol, LDLGenome-Wide Association StudyHumansLipidsWhole Genome Sequencing
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