Abstract
Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
Original language | English |
---|---|
Article number | 2606 |
Journal | Nature Communications |
Volume | 9 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2018 |
Bibliographical note
Publisher Copyright:© 2018 The Author(s).
Funding
Funders | Funder number |
---|---|
National Institute of General Medical Sciences | T32GM007205 |
National Institute of General Medical Sciences |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
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In: Nature Communications, Vol. 9, No. 1, 2606, 01.12.2018.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries
AU - Zekavat, Seyedeh M.
AU - Ruotsalainen, Sanni
AU - Handsaker, Robert E.
AU - Alver, Maris
AU - Bloom, Jonathan
AU - Poterba, Timothy
AU - Seed, Cotton
AU - Ernst, Jason
AU - Chaffin, Mark
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AU - Surakka, Ida
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AU - Ganna, Andrea
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AU - Albert, Christine
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AU - Almasy, Laura
AU - Alonso, Alvaro
AU - Ament, Seth
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AU - Anugu, Pramod
AU - Applebaum-Bowden, Deborah
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AU - Assimes, Tim
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AU - Barnard, John
AU - Barnes, Kathleen
AU - Barr, R. Graham
AU - Barron-Casella, Emily
AU - Beaty, Terri
AU - Becker, Diane
AU - Becker, Lewis
AU - Beer, Rebecca
AU - Begum, Ferdouse
AU - Beitelshees, Amber
AU - Benjamin, Emelia
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AU - Bis, Joshua
AU - Blackwell, Thomas
AU - Blangero, John
AU - Boerwinkle, Eric
AU - Borecki, Ingrid
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AU - Brody, Jennifer
AU - Broeckel, Ulrich
AU - Broome, Jai
AU - Bunting, Karen
AU - Burchard, Esteban
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AU - Casaburi, Richard
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AU - Chang, Christy
AU - Chasman, Daniel
AU - Chavan, Sameer
AU - Chen, Bo Juen
AU - Chen, Wei Min
AU - Chen, Yii Der Ida
AU - Cho, Michael
AU - Choi, Seung Hoan
AU - Chuang, Lee Ming
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AU - Curran, Joanne
AU - Curtis, Jeffrey
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AU - Damcott, Coleen
AU - Darbar, Dawood
AU - Das, Sayantan
AU - David, Sean
AU - Davis, Colleen
AU - Daya, Michelle
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AU - Debaun, Michael
AU - Deka, Ranjan
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AU - Devine, Scott
AU - Do, Ron
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AU - Duggirala, Ravi
AU - Durda, Peter
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AU - Ekunwe, Lynette
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AU - Farber, Charles
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AU - Fingerlin, Tasha
AU - Flickinger, Matthew
AU - Fornage, Myriam
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AU - Fullerton, Stephanie M.
AU - Fulton, Lucinda
AU - Gabriel, Stacey
AU - Gan, Weiniu
AU - Gao, Yan
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AU - Gelb, Bruce
AU - Geng, Xiaoqi
AU - Germer, Soren
AU - Gignoux, Chris
AU - Gladwin, Mark
AU - Glahn, David
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AU - Gong, Da Wei
AU - Goring, Harald
AU - Gu, C. Charles
AU - Guan, Yue
AU - Guo, Xiuqing
AU - Haessler, Jeff
AU - Hall, Michael
AU - Harris, Daniel
AU - Hawley, Nicola
AU - He, Jiang
AU - Heavner, Ben
AU - Heckbert, Susan
AU - Hernandez, Ryan
AU - Herrington, David
AU - Hersh, Craig
AU - Hidalgo, Bertha
AU - Hixson, James
AU - Hokanson, John
AU - Hong, Elliott
AU - Hoth, Karin
AU - Hsiung, Chao
AU - Huston, Haley
AU - Hwu, Chii Min
AU - Irvin, Marguerite Ryan
AU - Jackson, Rebecca
AU - Jain, Deepti
AU - Jaquish, Cashell
AU - Jhun, Min A.
AU - Johnsen, Jill
AU - Johnson, Andrew
AU - Johnston, Rich
AU - Jones, Kimberly
AU - Kang, Hyun Min
AU - Kaplan, Robert
AU - Kardia, Sharon
AU - Kaufman, Laura
AU - Kelly, Shannon
AU - Kenny, Eimear
AU - Kessler, Michael
AU - Khan, Alyna
AU - Kinney, Greg
AU - Konkle, Barbara
AU - Kooperberg, Charles
AU - Kramer, Holly
AU - Krauter, Stephanie
AU - Lange, Christoph
AU - Lange, Ethan
AU - Lange, Leslie
AU - Laurie, Cathy
AU - Laurie, Cecelia
AU - Leboff, Meryl
AU - Lee, Seunggeun Shawn
AU - Lee, Wen Jane
AU - Lefaive, Jonathon
AU - Levine, David
AU - Levy, Dan
AU - Lewis, Joshua
AU - Li, Yun
AU - Lin, Honghuang
AU - Lin, Keng Han
AU - Liu, Simin
AU - Liu, Yongmei
AU - Loos, Ruth
AU - Lubitz, Steven
AU - Lunetta, Kathryn
AU - Luo, James
AU - Mahaney, Michael
AU - Make, Barry
AU - Manson, Jo Ann
AU - Margolin, Lauren
AU - Martin, Lisa
AU - Mathai, Susan
AU - Mathias, Rasika
AU - McArdle, Patrick
AU - McDonald, Merry Lynn
AU - McFarland, Sean
AU - McGarvey, Stephen
AU - Mei, Hao
AU - Meyers, Deborah A.
AU - Mikulla, Julie
AU - Min, Nancy
AU - Minear, Mollie
AU - Minster, Ryan L.
AU - Montasser, May E.
AU - Musani, Solomon
AU - Mwasongwe, Stanford
AU - Mychaleckyj, Josyf C.
AU - Nadkarni, Girish
AU - Naik, Rakhi
AU - Nekhai, Sergei
AU - Nickerson, Deborah
AU - North, Kari
AU - O'connell, Jeff
AU - O'connor, Tim
AU - Ochs-Balcom, Heather
AU - Pankow, James
AU - Papanicolaou, George
AU - Parker, Margaret
AU - Parsa, Afshin
AU - Penchev, Sara
AU - Peralta, Juan Manuel
AU - Perez, Marco
AU - Perry, James
AU - Peters, Ulrike
AU - Peyser, Patricia
AU - Phillips, Larry
AU - Phillips, Sam
AU - Pollin, Toni
AU - Becker, Julia Powers
AU - Boorgula, Meher Preethi
AU - Preuss, Michael
AU - Prokopenko, Dmitry
AU - Psaty, Bruce
AU - Qasba, Pankaj
AU - Qiao, Dandi
AU - Qin, Zhaohui
AU - Rafaels, Nicholas
AU - Raffield, Laura
AU - Rao, D. C.
AU - Rasmussen-Torvik, Laura
AU - Ratan, Aakrosh
AU - Redline, Susan
AU - Reed, Robert
AU - Regan, Elizabeth
AU - Reiner, Alex
AU - Rice, Ken
AU - Roden, Dan
AU - Roselli, Carolina
AU - Ruczinski, Ingo
AU - Russell, Pamela
AU - Ruuska, Sarah
AU - Sakornsakolpat, Phuwanat
AU - Salimi, Shabnam
AU - Salzberg, Steven
AU - Sandow, Kevin
AU - Sankaran, Vijay
AU - Scheller, Christopher
AU - Schmidt, Ellen
AU - Schwander, Karen
AU - Schwartz, David
AU - Sciurba, Frank
AU - Seidman, Christine
AU - Sheehan, Vivien
AU - Shetty, Amol
AU - Shetty, Aniket
AU - Sheu, Wayne Hui Heng
AU - Shoemaker, M. Benjamin
AU - Silver, Brian
AU - Silverman, Edwin
AU - Smith, Jennifer
AU - Smith, Josh
AU - Smith, Nicholas
AU - Smith, Tanja
AU - Smoller, Sylvia
AU - Snively, Beverly
AU - Sofer, Tamar
AU - Sotoodehnia, Nona
AU - Stilp, Adrienne
AU - Streeten, Elizabeth
AU - Sung, Yun Ju
AU - Sylvia, Jody
AU - Szpiro, Adam
AU - Sztalryd, Carole
AU - Taliun, Daniel
AU - Tang, Hua
AU - Taub, Margaret
AU - Taylor, Kent
AU - Taylor, Simeon
AU - Telen, Marilyn
AU - Thornton, Timothy A.
AU - Tinker, Lesley
AU - Tirschwell, David
AU - Tiwari, Hemant
AU - Tracy, Russell
AU - Vaidya, Dhananjay
AU - Vandehaar, Peter
AU - Vrieze, Scott
AU - Walker, Tarik
AU - Wallace, Robert
AU - Walts, Avram
AU - Wan, Emily
AU - Wang, Fei Fei
AU - Watson, Karol
AU - Weeks, Daniel E.
AU - Weir, Bruce
AU - Weiss, Scott
AU - Weng, Lu Chen
AU - Willer, Cristen
AU - Williams, Kayleen
AU - Williams, L. Keoki
AU - Wilson, Carla
AU - Wong, Quenna
AU - Xu, Huichun
AU - Yanek, Lisa
AU - Yang, Ivana
AU - Yang, Rongze
AU - Zaghloul, Norann
AU - Zhang, Yingze
AU - Zhao, Snow Xueyan
AU - Zhao, Wei
AU - Zheng, Xiuwen
AU - Zhi, Degui
AU - Zhou, Xiang
AU - Zody, Michael
AU - Zoellner, Sebastian
N1 - Publisher Copyright: © 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
AB - Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
UR - http://www.scopus.com/inward/record.url?scp=85049751193&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049751193&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04668-w
DO - 10.1038/s41467-018-04668-w
M3 - Article
C2 - 29973585
AN - SCOPUS:85049751193
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2606
ER -