Rare coding variants in 35 genes associate with circulating lipid levels – a multi-ancestry analysis of 170,000 exomes
Authors: Hindy George , Dornbos Peter , Chaffin Mark D. , Liu Dajiang J. , Wang Minxian X. , Selvaraj Margaret Sunitha , Zhang David , Park Joseph , Aguilar-Salinas Carlos A. , Antonacci-Fulton Lucinda , Ardissino Diego , Arnett Donna K. , Aslibekyan Stella , Atzmon Gil , Ballantyne Christie M. , Barajas-Olmos Francisco , Barzilai Nir , Becker Lewis C. , Bielak Lawrence F. , Bis Joshua C. , Blangero John , Boerwinkle Eric , Bonnycastle Lori L. , Bottinger Erwin , Bowden Donald W. , Bown Matthew J. , Brody Jennifer A. , Broome Jai G. , Burtt Noël P. , Cade Brian E. , Centeno-Cruz Federico , Chan Edmund , Chang Yi-Cheng , Chen Yii-Der I. , Cheng Ching-Yu , Choi Won Jung , Chowdhury Rajiv , Contreras-Cubas Cecilia , Córdova Emilio J. , Correa Adolfo , Cupples L Adrienne , Curran Joanne E. , Danesh John , de Vries Paul S. , DeFronzo Ralph A. , Doddapaneni Harsha , Duggirala Ravindranath , Dutcher Susan K. , Ellinor Patrick T. , Emery Leslie S. , Florez Jose C. , Fornage Myriam , Freedman Barry I. , Fuster Valentin , Garay-Sevilla Ma. Eugenia , García-Ortiz Humberto , Germer Soren , Gibbs Richard A. , Gieger Christian , Glaser Benjamin , Gonzalez Clicerio , Gonzalez-Villalpando Maria Elena , Graff Mariaelisa , Graham Sarah E , Grarup Niels , Groop Leif C. , Guo Xiuqing , Gupta Namrata , Han Sohee , Hanis Craig L. , Hansen Torben , He Jiang , Heard-Costa Nancy L. , Hung Yi-Jen , Hwang Mi Yeong , Irvin Marguerite R. , Islas-Andrade Sergio , Jarvik Gail P. , Kang Hyun Min , Kardia Sharon L.R. , Kelly Tanika , Kenny Eimear E. , Khan Alyna T. , Kim Bong-Jo , Kim Ryan W. , Kim Young Jin , Koistinen Heikki A. , Kooperberg Charles , Kuusisto Johanna , Kwak Soo Heon , Laakso Markku , Lange Leslie A. , Lee Jiwon , Lee Juyoung , Lee Seonwook , Lehman Donna M. , Lemaitre Rozenn N. , Linneberg Allan , Liu Jianjun , Loos Ruth J.F. , Lubitz Steven A. , Lyssenko Valeriya , Ma Ronald C.W. , Martin Lisa Warsinger , Martínez-Hernández Angélica , Mathias Rasika A. , McGarvey Stephen T. , McPherson Ruth , Meigs James B. , Meitinger Thomas , Melander Olle , Mendoza-Caamal Elvia , Metcalf Ginger A. , Mi Xuenan , Mohlke Karen L. , Montasser May E. , Moon Jee-Young , Moreno-Macías Hortensia , Morrison Alanna C. , Muzny Donna M. , Nelson Sarah C. , Nilsson Peter M. , O’Connell Jeffrey R. , Orho-Melander Marju , Orozco Lorena , Palmer Colin N.A. , Palmer Nicholette D. , Park Cheol Joo , Park Kyong Soo , Pedersen Oluf , Peralta Juan M. , Peyser Patricia A. , Post Wendy S. , Preuss Michael , Psaty Bruce M. , Qi Qibin , Rao DC , Redline Susan , Reiner Alexander P. , Revilla-Monsalve Cristina , Rich Stephen S. , Samani Nilesh , Schunkert Heribert , Schurmann Claudia , Seo Daekwan , Seo Jeong-Sun , Sim Xueling , Sladek Rob , Small Kerrin S. , So Wing Yee , Stilp Adrienne M. , Tai E Shyong , Tam Claudia H.T. , Taylor Kent D. , Teo Yik Ying , Thameem Farook , Tomlinson Brian , Tsai Michael Y. , Tuomi Tiinamaija , Tuomilehto Jaakko , Tusié-Luna Teresa , van Dam Rob M. , Vasan Ramachandran S. , Viaud Martinez Karine A. , Wang Fei Fei , Wang Xuzhi , Watkins Hugh , Weeks Daniel E. , Wilson James G. , Witte Daniel R. , Wong Tien-Yin , Yanek Lisa R. ,   AMP-T2D-GENES,   Myocardial Infarction Genetics Consortium,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,   NHLBI TOPMed Lipids Working Group, Kathiresan Sekar , Rader Daniel J. , Rotter Jerome I. , Boehnke Michael , McCarthy Mark I. , Willer Cristen J. , Natarajan Pradeep , Flannick Jason A. , Khera Amit V. , Peloso Gina M. 
Published: December 2020

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency<1%) predicted damaging coding variation using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these:ALB,SRSF2,JAK2, CREB3L3,TMEM136,VARS,NR1H3,PLA2G12A,PPARGandSTAB1have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three:EVI5, SH2B3, andPLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.