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

Whole genome sequence analysis of blood lipid levels in >66,000 individuals. Selvaraj, M. S., Li, X., Li, Z., Pampana, A., Zhang, D. Y, Park, J., Aslibekyan, S., Bis, J. C, Brody, J. A, Cade, B. E, Chuang, L., Chung, R., Curran, J. E, de Las Fuentes, L., de Vries, P. S, Duggirala, R., Freedman, B. I, Graff, M., Guo, X., Heard-Costa, N., Hidalgo, B., Hwu, C., Irvin, M. R, Kelly, T. N, Kral, B. G, Lange, L., Li, X., Lisa, M., Lubitz, S. A, Manichaikul, A. W, Michael, P., Montasser, M. E, Morrison, A. C, Naseri, T., O'Connell, J. R, Palmer, N. D, Peyser, P. A, Reupena, M. S, Smith, J. A, Sun, X., Taylor, K. D, Tracy, R. P, Tsai, M. Y, Wang, Z., Wang, Y., Bao, W., Wilkins, J. T, Yanek, L. R, Zhao, W., Arnett, D. K, Blangero, J., Boerwinkle, E., Bowden, D. W, Chen, Y. I., Correa, A., Cupples, L A., Dutcher, S. K, Ellinor, P. T, Fornage, M., Gabriel, S., Germer, S., Gibbs, R., He, J., Kaplan, R. C, Kardia, S. L R, Kim, R., Kooperberg, C., Loos, R. J F, Viaud-Martinez, K. A, Mathias, R. A, McGarvey, S. T, Mitchell, B. D, Nickerson, D., North, K. E, Psaty, B. M, Redline, S., Reiner, A. P, Vasan, R. S, Rich, S. S, Willer, C., Rotter, J. I, Rader, D. J, Lin, X., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Peloso, G. M, & Natarajan, P. Nat Commun, 13(1):5995, Oct, 2022.

Paper doi abstract bibtex

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.

@article{Selvaraj:2022ab,
	abstract = {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.},
	author = {Selvaraj, Margaret Sunitha and Li, Xihao and Li, Zilin and Pampana, Akhil and Zhang, David Y and Park, Joseph and Aslibekyan, Stella and Bis, Joshua C and Brody, Jennifer A and Cade, Brian E and Chuang, Lee-Ming and Chung, Ren-Hua and Curran, Joanne E and de Las Fuentes, Lisa and de Vries, Paul S and Duggirala, Ravindranath and Freedman, Barry I and Graff, Mariaelisa and Guo, Xiuqing and Heard-Costa, Nancy and Hidalgo, Bertha and Hwu, Chii-Min and Irvin, Marguerite R and Kelly, Tanika N and Kral, Brian G and Lange, Leslie and Li, Xiaohui and Lisa, Martin and Lubitz, Steven A and Manichaikul, Ani W and Michael, Preuss and Montasser, May E and Morrison, Alanna C and Naseri, Take and O'Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Reupena, Muagututia S and Smith, Jennifer A and Sun, Xiao and Taylor, Kent D and Tracy, Russell P and Tsai, Michael Y and Wang, Zhe and Wang, Yuxuan and Bao, Wei and Wilkins, John T and Yanek, Lisa R and Zhao, Wei and Arnett, Donna K and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Chen, Yii-Der Ida and Correa, Adolfo and Cupples, L Adrienne and Dutcher, Susan K and Ellinor, Patrick T and Fornage, Myriam and Gabriel, Stacey and Germer, Soren and Gibbs, Richard and He, Jiang and Kaplan, Robert C and Kardia, Sharon L R and Kim, Ryan and Kooperberg, Charles and Loos, Ruth J F and Viaud-Martinez, Karine A and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Nickerson, Deborah and North, Kari E and Psaty, Bruce M and Redline, Susan and Reiner, Alexander P and Vasan, Ramachandran S and Rich, Stephen S and Willer, Cristen and Rotter, Jerome I and Rader, Daniel J and Lin, Xihong and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Peloso, Gina M and Natarajan, Pradeep},
	date-added = {2024-05-19 20:58:18 -0400},
	date-modified = {2024-05-19 20:58:18 -0400},
	doi = {10.1038/s41467-022-33510-7},
	journal = {Nat Commun},
	journal-full = {Nature communications},
	mesh = {Alleles; Cholesterol, LDL; Genome-Wide Association Study; Humans; Lipids; Whole Genome Sequencing},
	month = {Oct},
	number = {1},
	pages = {5995},
	pmc = {PMC9553944},
	pmid = {36220816},
	url = {https://pubmed.ncbi.nlm.nih.gov/36220816/},
	pst = {epublish},
	title = {Whole genome sequence analysis of blood lipid levels in >66,000 individuals},
	volume = {13},
	year = {2022},
	bdsk-url-1 = {https://doi.org/10.1038/s41467-022-33510-7}}

Downloads: 0