Whole genome sequence analysis of blood lipid levels in >66,000 individuals
Authors: 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, Abe Namiko , Abecasis Gonçalo , Aguet Francois , Albert Christine , Almasy Laura , Alonso Alvaro , Ament Seth , Anderson Peter , Anugu Pramod , Applebaum-Bowden Deborah , Ardlie Kristin , Arking Dan , Ashley-Koch Allison , Assimes Tim , Auer Paul , Avramopoulos Dimitrios , Ayas Najib , Balasubramanian Adithya , Barnard John , Barnes Kathleen , Barr R. Graham , Barron-Casella Emily , Barwick Lucas , Beaty Terri , Beck Gerald , Becker Diane , Becker Lewis , Beer Rebecca , Beitelshees Amber , Benjamin Emelia , Benos Takis , Bezerra Marcos , Bielak Larry , Blackwell Thomas , Bowler Russell , Broeckel Ulrich , Broome Jai , Brown Deborah , Bunting Karen , Burchard Esteban , Bustamante Carlos , Buth Erin , Cardwell Jonathan , Carey Vincent , Carrier Julie , Carty Cara , Casaburi Richard , Romero Juan P. Casas , Casella James , Castaldi Peter , Chaffin Mark , Chang Christy , Chang Yi-Cheng , Chasman Daniel , Chavan Sameer , Chen Bo-Juen , Chen Wei-Min , Chen Yii-Der Ida , Cho Michael , Choi Seung Hoan , Chung Mina , Clish Clary , Comhair Suzy , Conomos Matthew , Cornell Elaine , Crandall Carolyn , Crapo James , Cupples L. Adrienne , Curtis Jeffrey , Custer Brian , Damcott Coleen , Darbar Dawood , David Sean , Davis Colleen , Daya Michelle , de Andrade Mariza , DeBaun Michael , Deka Ranjan , DeMeo Dawn , Devine Scott , Dinh Huyen , Doddapaneni Harsha , Duan Qing , Dugan-Perez Shannon , Duggirala Ravi , Durda Jon Peter , Eaton Charles , Ekunwe Lynette , Boueiz Adel El , Emery Leslie , Erzurum Serpil , Farber Charles , Farek Jesse , Fingerlin Tasha , Flickinger Matthew , Franceschini Nora , Frazar Chris , Fu Mao , Fullerton Stephanie M. , Fulton Lucinda , Gan Weiniu , Gao Shanshan , Gao Yan , Gass Margery , Geiger Heather , Gelb Bruce , Geraci Mark , Gerszten Robert , Ghosh Auyon , Gignoux Chris , Gladwin Mark , Glahn David , Gogarten Stephanie , Gong Da-Wei , Goring Harald , Graw Sharon , Gray Kathryn J. , Grine Daniel , Gross Colin , Gu C. Charles , Guan Yue , Gupta Namrata , Haas David M. , Haessler Jeff , Hall Michael , Han Yi , Hanly Patrick , Harris Daniel , Hawley Nicola L. , Heavner Ben , Heckbert Susan , Hernandez Ryan , Herrington David , Hersh Craig , Hidalgo Bertha , Hixson James , Hobbs Brian , Hokanson John , Hong Elliott , Hoth Karin , Hsiung Chao Agnes , Hu Jianhong , Hung Yi-Jen , Huston Haley , Hwu Chii Min , Jackson Rebecca , Jain Deepti , Jaquish Cashell , Johnsen Jill , Johnson Andrew , Johnson Craig , Johnston Rich , Jones Kimberly , Kang Hyun Min , Kelly Shannon , Kenny Eimear , Kessler Michael , Khan Alyna , Khan Ziad , Kim Wonji , Kimoff John , Kinney Greg , Konkle Barbara , Kramer Holly , Lange Christoph , Lange Ethan , Laurie Cathy , Laurie Cecelia , LeBoff Meryl , Lee Jiwon , Lee Sandra , Lee Wen-Jane , LeFaive Jonathon , Levine David , Levy Dan , Lewis Joshua , Li Yun , Lin Henry , Lin Honghuang , Liu Simin , Liu Yongmei , Liu Yu , Lunetta Kathryn , Luo James , Magalang Ulysses , Mahaney Michael , Make Barry , Manning Alisa , Manson JoAnn , Martin Lisa , Marton Melissa , Mathai Susan , May Susanne , McArdle Patrick , McDonald Merry-Lynn , McFarland Sean , McGoldrick Daniel , McHugh Caitlin , McNeil Becky , Mei Hao , Meigs James , Menon Vipin , Mestroni Luisa , Metcalf Ginger , Meyers Deborah A. , Mignot Emmanuel , Mikulla Julie , Min Nancy , Minear Mollie , Minster Ryan L. , Moll Matt , Momin Zeineen , Montgomery Courtney , Muzny Donna , Mychaleckyj Josyf C. , Nadkarni Girish , Naik Rakhi , Nekhai Sergei , Nelson Sarah C. , Neltner Bonnie , Nessner Caitlin , Nkechinyere Osuji , O’Connell Jeff , O’Connor Tim , Ochs-Balcom Heather , Okwuonu Geoffrey , Pack Allan , Paik David T. , Pankow James , Papanicolaou George , Parker Cora , Peralta Juan Manuel , Perez Marco , Perry James , Peters Ulrike , Phillips Lawrence S. , Pleiness Jacob , Pollin Toni , Post Wendy , Becker Julia Powers , Boorgula Meher Preethi , Preuss Michael , Qasba Pankaj , Qiao Dandi , Qin Zhaohui , Rafaels Nicholas , Raffield Laura , Rajendran Mahitha , Vasan Ramachandran S. , Rao D. C. , Rasmussen-Torvik Laura , Ratan Aakrosh , Reed Robert , Reeves Catherine , Regan Elizabeth , Reiner Alex , Rice Ken , Robillard Rebecca , Robine Nicolas , Roden Dan , Roselli Carolina , Ruczinski Ingo , Runnels Alexi , Russell Pamela , Ruuska Sarah , Ryan Kathleen , Sabino Ester Cerdeira , Saleheen Danish , Salimi Shabnam , Salvi Sejal , Salzberg Steven , Sandow Kevin , Sankaran Vijay G. , Santibanez Jireh , Schwander Karen , Schwartz David , Sciurba Frank , Seidman Christine , Seidman Jonathan , Sériès Frédéric , Sheehan Vivien , Sherman Stephanie L. , Shetty Amol , Shetty Aniket , Sheu Wayne Hui-Heng , Shoemaker M. Benjamin , Silver Brian , Silverman Edwin , Skomro Robert , Smith Albert Vernon , Smith Josh , Smith Nicholas , Smith Tanja , Smoller Sylvia , Snively Beverly , Snyder Michael , Sofer Tamar , Sotoodehnia Nona , Stilp Adrienne M. , Storm Garrett , Streeten Elizabeth , Su Jessica Lasky , Sung Yun Ju , Sylvia Jody , Szpiro Adam , Taliun Daniel , Tang Hua , Taub Margaret , Taylor Matthew , Taylor Simeon , Telen Marilyn , Thornton Timothy A. , Threlkeld Machiko , Tinker Lesley , Tirschwell David , Tishkoff Sarah , Tiwari Hemant , Tong Catherine , Vaidya Dhananjay , Berg David Van Den , VandeHaar Peter , Vrieze Scott , Walker Tarik , Wallace Robert , Walts Avram , Wang Fei Fei , Wang Heming , Wang Jiongming , Watson Karol , Watt Jennifer , Weeks Daniel E. , Weinstock Joshua , Weir Bruce , Weiss Scott T. , Weng Lu-Chen , Wessel Jennifer , Williams Kayleen , Williams L. Keoki , Wilson Carla , Wilson James , Winterkorn Lara , Wong Quenna , Wu Joseph , Xu Huichun , Yang Ivana , Yu Ketian , Zekavat Seyedeh Maryam , Zhang Yingze , Zhao Snow Xueyan , Zhao Wei , Zhu Xiaofeng , Zody Michael , Zoellner Sebastian , Peloso Gina M. , Natarajan Pradeep 
Published: October 2022

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.