Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study

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Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study. / Wang, Yuxuan; Selvaraj, Margaret Sunitha; Li, Xihao; Li, Zilin; Holdcraft, Jacob A.; Arnett, Donna K.; Bis, Joshua C.; Blangero, John; Boerwinkle, Eric; Bowden, Donald W.; Cade, Brian E.; Carlson, Jenna C.; Carson, April P.; Chen, Yii Der Ida; Curran, Joanne E.; de Vries, Paul S.; Dutcher, Susan K.; Ellinor, Patrick T.; Floyd, James S.; Fornage, Myriam; Freedman, Barry I.; Gabriel, Stacey; Germer, Soren; Gibbs, Richard A.; Guo, Xiuqing; He, Jiang; Heard-Costa, Nancy; Hildalgo, Bertha; Hou, Lifang; Irvin, Marguerite R.; Joehanes, Roby; Kaplan, Robert C.; Kardia, Sharon LR; Kelly, Tanika N.; Kim, Ryan; Kooperberg, Charles; Kral, Brian G.; Levy, Daniel; Li, Changwei; Liu, Chunyu; Lloyd-Jone, Don; Loos, Ruth J.F.; Mahaney, Michael C.; Martin, Lisa W.; Mathias, Rasika A.; Minster, Ryan L.; Mitchell, Braxton D.; Montasser, May E.; Morrison, Alanna C.; Murabito, Joanne M.; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium.

In: American Journal of Human Genetics, Vol. 110, No. 10, 2023, p. 1704-1717.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Wang, Y, Selvaraj, MS, Li, X, Li, Z, Holdcraft, JA, Arnett, DK, Bis, JC, Blangero, J, Boerwinkle, E, Bowden, DW, Cade, BE, Carlson, JC, Carson, AP, Chen, YDI, Curran, JE, de Vries, PS, Dutcher, SK, Ellinor, PT, Floyd, JS, Fornage, M, Freedman, BI, Gabriel, S, Germer, S, Gibbs, RA, Guo, X, He, J, Heard-Costa, N, Hildalgo, B, Hou, L, Irvin, MR, Joehanes, R, Kaplan, RC, Kardia, SLR, Kelly, TN, Kim, R, Kooperberg, C, Kral, BG, Levy, D, Li, C, Liu, C, Lloyd-Jone, D, Loos, RJF, Mahaney, MC, Martin, LW, Mathias, RA, Minster, RL, Mitchell, BD, Montasser, ME, Morrison, AC, Murabito, JM & NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium 2023, 'Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study', American Journal of Human Genetics, vol. 110, no. 10, pp. 1704-1717. https://doi.org/10.1016/j.ajhg.2023.09.003

APA

Wang, Y., Selvaraj, M. S., Li, X., Li, Z., Holdcraft, J. A., Arnett, D. K., Bis, J. C., Blangero, J., Boerwinkle, E., Bowden, D. W., Cade, B. E., Carlson, J. C., Carson, A. P., Chen, Y. D. I., Curran, J. E., de Vries, P. S., Dutcher, S. K., Ellinor, P. T., Floyd, J. S., ... NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium (2023). Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study. American Journal of Human Genetics, 110(10), 1704-1717. https://doi.org/10.1016/j.ajhg.2023.09.003

Vancouver

Wang Y, Selvaraj MS, Li X, Li Z, Holdcraft JA, Arnett DK et al. Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study. American Journal of Human Genetics. 2023;110(10):1704-1717. https://doi.org/10.1016/j.ajhg.2023.09.003

Author

Wang, Yuxuan ; Selvaraj, Margaret Sunitha ; Li, Xihao ; Li, Zilin ; Holdcraft, Jacob A. ; Arnett, Donna K. ; Bis, Joshua C. ; Blangero, John ; Boerwinkle, Eric ; Bowden, Donald W. ; Cade, Brian E. ; Carlson, Jenna C. ; Carson, April P. ; Chen, Yii Der Ida ; Curran, Joanne E. ; de Vries, Paul S. ; Dutcher, Susan K. ; Ellinor, Patrick T. ; Floyd, James S. ; Fornage, Myriam ; Freedman, Barry I. ; Gabriel, Stacey ; Germer, Soren ; Gibbs, Richard A. ; Guo, Xiuqing ; He, Jiang ; Heard-Costa, Nancy ; Hildalgo, Bertha ; Hou, Lifang ; Irvin, Marguerite R. ; Joehanes, Roby ; Kaplan, Robert C. ; Kardia, Sharon LR ; Kelly, Tanika N. ; Kim, Ryan ; Kooperberg, Charles ; Kral, Brian G. ; Levy, Daniel ; Li, Changwei ; Liu, Chunyu ; Lloyd-Jone, Don ; Loos, Ruth J.F. ; Mahaney, Michael C. ; Martin, Lisa W. ; Mathias, Rasika A. ; Minster, Ryan L. ; Mitchell, Braxton D. ; Montasser, May E. ; Morrison, Alanna C. ; Murabito, Joanne M. ; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium. / Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study. In: American Journal of Human Genetics. 2023 ; Vol. 110, No. 10. pp. 1704-1717.

Bibtex

@article{a1c0678345bf45e88b877d68756a2d58,
title = "Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study",
abstract = "Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.",
keywords = "association, blood lipid, cholesterol, lncRNA, rare variants, whole-genome sequencing",
author = "Yuxuan Wang and Selvaraj, {Margaret Sunitha} and Xihao Li and Zilin Li and Holdcraft, {Jacob A.} and Arnett, {Donna K.} and Bis, {Joshua C.} and John Blangero and Eric Boerwinkle and Bowden, {Donald W.} and Cade, {Brian E.} and Carlson, {Jenna C.} and Carson, {April P.} and Chen, {Yii Der Ida} and Curran, {Joanne E.} and {de Vries}, {Paul S.} and Dutcher, {Susan K.} and Ellinor, {Patrick T.} and Floyd, {James S.} and Myriam Fornage and Freedman, {Barry I.} and Stacey Gabriel and Soren Germer and Gibbs, {Richard A.} and Xiuqing Guo and Jiang He and Nancy Heard-Costa and Bertha Hildalgo and Lifang Hou and Irvin, {Marguerite R.} and Roby Joehanes and Kaplan, {Robert C.} and Kardia, {Sharon LR} and Kelly, {Tanika N.} and Ryan Kim and Charles Kooperberg and Kral, {Brian G.} and Daniel Levy and Changwei Li and Chunyu Liu and Don Lloyd-Jone and Loos, {Ruth J.F.} and Mahaney, {Michael C.} and Martin, {Lisa W.} and Mathias, {Rasika A.} and Minster, {Ryan L.} and Mitchell, {Braxton D.} and Montasser, {May E.} and Morrison, {Alanna C.} and Murabito, {Joanne M.} and {NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium}",
note = "Publisher Copyright: {\textcopyright} 2023 American Society of Human Genetics",
year = "2023",
doi = "10.1016/j.ajhg.2023.09.003",
language = "English",
volume = "110",
pages = "1704--1717",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "10",

}

RIS

TY - JOUR

T1 - Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed whole-genome sequencing study

AU - Wang, Yuxuan

AU - Selvaraj, Margaret Sunitha

AU - Li, Xihao

AU - Li, Zilin

AU - Holdcraft, Jacob A.

AU - Arnett, Donna K.

AU - Bis, Joshua C.

AU - Blangero, John

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

AU - Cade, Brian E.

AU - Carlson, Jenna C.

AU - Carson, April P.

AU - Chen, Yii Der Ida

AU - Curran, Joanne E.

AU - de Vries, Paul S.

AU - Dutcher, Susan K.

AU - Ellinor, Patrick T.

AU - Floyd, James S.

AU - Fornage, Myriam

AU - Freedman, Barry I.

AU - Gabriel, Stacey

AU - Germer, Soren

AU - Gibbs, Richard A.

AU - Guo, Xiuqing

AU - He, Jiang

AU - Heard-Costa, Nancy

AU - Hildalgo, Bertha

AU - Hou, Lifang

AU - Irvin, Marguerite R.

AU - Joehanes, Roby

AU - Kaplan, Robert C.

AU - Kardia, Sharon LR

AU - Kelly, Tanika N.

AU - Kim, Ryan

AU - Kooperberg, Charles

AU - Kral, Brian G.

AU - Levy, Daniel

AU - Li, Changwei

AU - Liu, Chunyu

AU - Lloyd-Jone, Don

AU - Loos, Ruth J.F.

AU - Mahaney, Michael C.

AU - Martin, Lisa W.

AU - Mathias, Rasika A.

AU - Minster, Ryan L.

AU - Mitchell, Braxton D.

AU - Montasser, May E.

AU - Morrison, Alanna C.

AU - Murabito, Joanne M.

AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

N1 - Publisher Copyright: © 2023 American Society of Human Genetics

PY - 2023

Y1 - 2023

N2 - Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

AB - Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions in lipid metabolism. Large-scale whole-genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess more associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with measurement of blood lipids and lipoproteins (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare-variant aggregate association tests using the STAAR (variant-set test for association using annotation information) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare-coding variants in nearby protein-coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500-kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variation and rare protein-coding variation at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNAs.

KW - association

KW - blood lipid

KW - cholesterol

KW - lncRNA

KW - rare variants

KW - whole-genome sequencing

U2 - 10.1016/j.ajhg.2023.09.003

DO - 10.1016/j.ajhg.2023.09.003

M3 - Journal article

C2 - 37802043

AN - SCOPUS:85173464923

VL - 110

SP - 1704

EP - 1717

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 10

ER -

ID: 372823537