Deep-coverage whole genome sequences and blood lipids among 16,324 individuals
Authors: Natarajan Pradeep , Peloso Gina M. , Zekavat Seyedeh Maryam , Montasser May , Ganna Andrea , Chaffin Mark , Khera Amit V. , Zhou Wei , Bloom Jonathan M. , Engreitz Jesse M. , Ernst Jason , O’Connell Jeffrey R. , Ruotsalainen Sanni E. , Alver Maris , Manichaikul Ani , Johnson W. Craig , Perry James A. , Poterba Timothy , Seed Cotton , Surakka Ida L. , Esko Tonu , Ripatti Samuli , Salomaa Veikko , Correa Adolfo , Vasan Ramachandran S. , Kellis Manolis , Neale Benjamin M. , Lander Eric S. , Abecasis Goncalo , Mitchell Braxton , Rich Stephen S. , Wilson James G. , Cupples L. Adrienne , Rotter Jerome I. , Willer Cristen J. , Kathiresan Sekar ,   NHLBI TOPMed Lipids Working Group, Abe Namiko , 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 , de Andrade Mariza , 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 , Fu Mao , Fullerton Malia , 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 , Musani Solomon , Mwasongwe Stanford , Mychaleckyj Josyf C , Nadkarni Girish , Naik Rakhi , Nekhai Sergei , Nickerson Deborah , North Kari , O’Connor Tim , Ochs-Balcom Heather , Pankow James , Papanicolaou George , Parker Margaret , Parsa Afshin , Penchev Sara , Peralta Juan Manuel , Perez Marco , Peters Ulrike , Peyser Patricia , Phillips Larry , Phillips Sam , Pollin Toni , Post Wendy , 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 , Ryan Kathleen , Sakornsakolpat Phuwanat , Salimi Shabnam , Salzberg Steven , Sandow Kevin , Sankaran Vijay , 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 , Tsai Michael , 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 , Zheng Xiuwen , Zhi Degui , Zhou Xiang , Zody Michael , Zoellner Sebastian 
Published: August 2018

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits—plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.