Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries
Authors: Zekavat Seyedeh M. , Ruotsalainen Sanni , Handsaker Robert E. , Alver Maris , Bloom Jonathan , Poterba Timothy , Seed Cotton , Ernst Jason , Chaffin Mark , Engreitz Jesse , Peloso Gina M. , Manichaikul Ani , Yang Chaojie , Ryan Kathleen A. , Fu Mao , Johnson W. Craig , Tsai Michael , Budoff Matthew , Vasan Ramachandran S. , Cupples L. Adrienne , Rotter Jerome I. , Rich Stephen S. , Post Wendy , Mitchell Braxton D. , Correa Adolfo , Metspalu Andres , Wilson James G. , Salomaa Veikko , Kellis Manolis , Daly Mark J. , Neale Benjamin M. , McCarroll Steven , Surakka Ida , Esko Tonu , Ganna Andrea , Ripatti Samuli , Kathiresan Sekar , Natarajan Pradeep ,   NHLBI TOPMed Lipids Working Group, Abe Namiko , Abecasis Goncalo , Albert Christine , Allred Nicholette Palmer , Almasy Laura , Alonso Alvaro , Ament Seth , Anderson Peter , Anugu Pramod , Applebaum-Bowden Deborah , Arking Dan , Arnett Donna K , Ashley-Koch Allison , Aslibekyan Stella , Assimes Tim , Auer Paul , Avramopoulos Dimitrios , Barnard John , Barnes Kathleen , Barr R. Graham , Barron-Casella Emily , Beaty Terri , Becker Diane , Becker Lewis , Beer Rebecca , Begum Ferdouse , Beitelshees Amber , Benjamin Emelia , Bezerra Marcos , Bielak Larry , Bis Joshua , Blackwell Thomas , Blangero John , Boerwinkle Eric , Borecki Ingrid , Bowler Russell , Brody Jennifer , Broeckel Ulrich , Broome Jai , Bunting Karen , Burchard Esteban , Cardwell Jonathan , Carty Cara , Casaburi Richard , Casella James , Chang Christy , Chasman Daniel , Chavan Sameer , Chen Bo-Juen , Chen Wei-Min , Chen Yii-Der Ida , Cho Michael , Choi Seung Hoan , Chuang Lee-Ming , Chung Mina , Cornell Elaine , Crandall Carolyn , Crapo James , Curran Joanne , Curtis Jeffrey , Custer Brian , Damcott Coleen , Darbar Dawood , Das Sayantan , David Sean , Davis Colleen , Daya Michelle , Andrade Mariza de , DeBaun Michael , Deka Ranjan , DeMeo Dawn , Devine Scott , Do Ron , Duan Qing , Duggirala Ravi , Durda Peter , Dutcher Susan , Eaton Charles , Ekunwe Lynette , Ellinor Patrick , Emery Leslie , Farber Charles , Farnam Leanna , Fingerlin Tasha , Flickinger Matthew , Fornage Myriam , Franceschini Nora , Fullerton Stephanie M. , Fulton Lucinda , Gabriel Stacey , Gan Weiniu , Gao Yan , Gass Margery , Gelb Bruce , Geng Xiaoqi , Germer Soren , Gignoux Chris , Gladwin Mark , Glahn David , Gogarten Stephanie , Gong Da-Wei , Goring Harald , Gu C. Charles , Guan Yue , Guo Xiuqing , Haessler Jeff , Hall Michael , Harris Daniel , Hawley Nicola , He Jiang , Heavner Ben , Heckbert Susan , Hernandez Ryan , Herrington David , Hersh Craig , Hidalgo Bertha , Hixson James , Hokanson John , Hong Elliott , Hoth Karin , Hsiung Chao , Huston Haley , Hwu Chii Min , Irvin Marguerite Ryan , Jackson Rebecca , Jain Deepti , Jaquish Cashell , Jhun Min A , Johnsen Jill , Johnson Andrew , Johnston Rich , Jones Kimberly , Kang Hyun Min , Kaplan Robert , Kardia Sharon , Kaufman Laura , Kelly Shannon , Kenny Eimear , Kessler Michael , Khan Alyna , Kinney Greg , Konkle Barbara , Kooperberg Charles , Kramer Holly , Krauter Stephanie , Lange Christoph , Lange Ethan , Lange Leslie , Laurie Cathy , Laurie Cecelia , LeBoff Meryl , Lee Seunggeun Shawn , Lee Wen-Jane , LeFaive Jonathon , Levine David , Levy Dan , Lewis Joshua , Li Yun , Lin Honghuang , Lin Keng Han , Liu Simin , Liu Yongmei , Loos Ruth , Lubitz Steven , Lunetta Kathryn , Luo James , Mahaney Michael , Make Barry , Manson JoAnn , Margolin Lauren , Martin Lisa , Mathai Susan , Mathias Rasika , McArdle Patrick , McDonald Merry-Lynn , McFarland Sean , McGarvey Stephen , Mei Hao , Meyers Deborah A , Mikulla Julie , Min Nancy , Minear Mollie , Minster Ryan L , Montasser May E. , Musani Solomon , Mwasongwe Stanford , Mychaleckyj Josyf C , Nadkarni Girish , Naik Rakhi , Nekhai Sergei , Nickerson Deborah , North Kari , O’Connell Jeff , O’Connor Tim , Ochs-Balcom Heather , Pankow James , Papanicolaou George , Parker Margaret , Parsa Afshin , Penchev Sara , Peralta Juan Manuel , Perez Marco , Perry James , Peters Ulrike , Peyser Patricia , Phillips Larry , Phillips Sam , Pollin Toni , Becker Julia Powers , Boorgula Meher Preethi , Preuss Michael , Prokopenko Dmitry , Psaty Bruce , Qasba Pankaj , Qiao Dandi , Qin Zhaohui , Rafaels Nicholas , Raffield Laura , Rao D. C. , Rasmussen-Torvik Laura , Ratan Aakrosh , Redline Susan , Reed Robert , Regan Elizabeth , Reiner Alex , Rice Ken , Roden Dan , Roselli Carolina , Ruczinski Ingo , Russell Pamela , Ruuska Sarah , Sakornsakolpat Phuwanat , Salimi Shabnam , Salzberg Steven , Sandow Kevin , Sankaran Vijay , Scheller Christopher , Schmidt Ellen , Schwander Karen , Schwartz David , Sciurba Frank , Seidman Christine , Sheehan Vivien , Shetty Amol , Shetty Aniket , Sheu Wayne Hui-Heng , Shoemaker M. Benjamin , Silver Brian , Silverman Edwin , Smith Jennifer , Smith Josh , Smith Nicholas , Smith Tanja , Smoller Sylvia , Snively Beverly , Sofer Tamar , Sotoodehnia Nona , Stilp Adrienne , Streeten Elizabeth , Sung Yun Ju , Sylvia Jody , Szpiro Adam , Sztalryd Carole , Taliun Daniel , Tang Hua , Taub Margaret , Taylor Kent , Taylor Simeon , Telen Marilyn , Thornton Timothy A. , Tinker Lesley , Tirschwell David , Tiwari Hemant , Tracy Russell , Vaidya Dhananjay , VandeHaar Peter , Vrieze Scott , Walker Tarik , Wallace Robert , Walts Avram , Wan Emily , Wang Fei Fei , Watson Karol , Weeks Daniel E. , Weir Bruce , Weiss Scott , Weng Lu-Chen , Willer Cristen , Williams Kayleen , Williams L. Keoki , Wilson Carla , Wong Quenna , Xu Huichun , Yanek Lisa , Yang Ivana , Yang Rongze , Zaghloul Norann , Zhang Yingze , Zhao Snow Xueyan , Zhao Wei , Zheng Xiuwen , Zhi Degui , Zhou Xiang , Zody Michael , Zoellner Sebastian 
Published: June 2018

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.