Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices
Authors: Natarajan Pradeep , Pampana Akhil , Graham Sarah E. , Ruotsalainen Sanni E. , Perry James A. , de Vries Paul S. , Broome Jai G. , Pirruccello James P. , Honigberg Michael C. , Aragam Krishna , Wolford Brooke , Brody Jennifer A. , Antonacci-Fulton Lucinda , Arden Moscati , Aslibekyan Stella , Assimes Themistocles L. , Ballantyne Christie M. , Bielak Lawrence F. , Bis Joshua C. , Cade Brian E. , Do Ron , Doddapaneni Harsha , Emery Leslie S. , Hung Yi-Jen , Irvin Marguerite R. , Khan Alyna T. , Lange Leslie , Lee Jiwon , Lemaitre Rozenn N. , Martin Lisa W. , Metcalf Ginger , Montasser May E. , Moon Jee-Young , Muzny Donna , O’Connell Jeffrey R. , Palmer Nicholette D. , Peralta Juan M. , Peyser Patricia A. , Stilp Adrienne M. , Tsai Michael , Wang Fei Fei , Weeks Daniel E. , Yanek Lisa R. , Wilson James G. , Abecasis Goncalo , Arnett Donna K. , Becker Lewis C. , Blangero John , Boerwinkle Eric , Bowden Donald W. , Chang Yi-Cheng , Chen Yii-Der I. , Choi Won Jung , Correa Adolfo , Curran Joanne E. , Daly Mark J. , Dutcher Susan K. , Ellinor Patrick T. , Fornage Myriam , Freedman Barry I. , Gabriel Stacey , Germer Soren , Gibbs Richard A. , He Jiang , Hveem Kristian , Jarvik Gail P. , Kaplan Robert C. , Kardia Sharon L. R. , Kenny Eimear , Kim Ryan W. , Kooperberg Charles , Laurie Cathy C. , Lee Seonwook , Lloyd-Jones Don M. , Loos Ruth J. F. , Lubitz Steven A. , Mathias Rasika A. , Martinez Karine A. Viaud , McGarvey Stephen T. , Mitchell Braxton D. , Nickerson Deborah A. , North Kari E. , Palotie Aarno , Park Cheol Joo , Psaty Bruce M. , Rao D. C. , Redline Susan , Reiner Alexander P. , Seo Daekwan , Seo Jeong-Sun , Smith Albert V. , Tracy Russell P. , Vasan Ramachandran S. , Kathiresan Sekar , Cupples L. Adrienne , Rotter Jerome I. , Morrison Alanna C. , Rich Stephen S. , Ripatti Samuli , Willer Cristen ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Abe Namiko , Albert Christine , Almasy Laura , Alonso Alvaro , Ament Seth , Anderson Peter , Anugu Pramod , Applebaum-Bowden Deborah , Arking Dan , Ashley-Koch Allison , Auer Paul , Avramopoulos Dimitrios , Barnard John , Barnes Kathleen , Barr R. Graham , Barron-Casella Emily , Beaty Terri , Becker Diane , Beer Rebecca , Begum Ferdouse , Beitelshees Amber , Benjamin Emelia , Bezerra Marcos , Bielak Larry , Blackwell Thomas , Bowler Russell , Broeckel Ulrich , Bunting Karen , Burchard Esteban , Buth Erin , Cardwell Jonathan , Carty Cara , Casaburi Richard , Casella James , Chaffin Mark , Chang Christy , Chasman Daniel , Chavan Sameer , Chen Bo-Juen , Chen Wei-Min , Cho Michael , Choi Seung Hoan , Chuang Lee-Ming , Chung Mina , Conomos Matthew P. , Cornell Elaine , Crandall Carolyn , Crapo James , 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 , Duan Qing , Duggirala Ravi , Durda Jon Peter , Dutcher Susan , Eaton Charles , Ekunwe Lynette , Farber Charles , Farnam Leanna , Fingerlin Tasha , Flickinger Matthew , Franceschini Nora , Fu Mao , Fullerton Stephanie M. , Fulton Lucinda , Gan Weiniu , Gao Yan , Gass Margery , Gelb Bruce , Geng Xiaoqi , 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 , 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 , Jackson Rebecca , Jain Deepti , Jaquish Cashell , Jhun Min A. , Johnsen Jill , Johnson Andrew , Johnson Craig , Johnston Rich , Jones Kimberly , Kang Hyun Min , Kaufman Laura , Kelly Shannon , Kessler Michael , Kinney Greg , Konkle Barbara , Kramer Holly , Krauter Stephanie , Lange Christoph , Lange Ethan , 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 , Lin Xihong , Liu Simin , Liu Yongmei , Lunetta Kathryn , Luo James , Mahaney Michael , Make Barry , Manichaikul Ani , Manson JoAnn , Margolin Lauren , Mathai Susan , McArdle Patrick , McDonald Merry-Lynn , McFarland Sean , McHugh Caitlin , 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 , Naseri Take , Nekhai Sergei , Nelson Sarah C. , Nickerson Deborah , O’Connell Jeff , O’Connor Tim , Ochs-Balcom Heather , Pankow James , Papanicolaou George , Parker Margaret , Parsa Afshin , Penchev Sara , Perez Marco , Peters Ulrike , Phillips Lawrence S. , Phillips Sam , Pollin Toni , Post Wendy , Becker Julia Powers , Boorgula Meher Preethi , Preuss Michael , Prokopenko Dmitry , Qasba Pankaj , Qiao Dandi , Qin Zhaohui , Rafaels Nicholas , Raffield Laura , Rasmussen-Torvik Laura , Ratan Aakrosh , Reed Robert , Regan Elizabeth , Reupena Muagututi‘a Sefuiva , Rice Ken , Roden Dan , Roselli Carolina , Ruczinski Ingo , Russell Pamela , Ruuska Sarah , Ryan Kathleen , Sabino Ester Cerdeira , Sakornsakolpat Phuwanat , Salimi Shabnam , Salzberg Steven , Sandow Kevin , Sankaran Vijay G. , Scheller Christopher , Schmidt Ellen , Schwander Karen , Schwartz David , Sciurba Frank , Seidman Christine , Seidman Jonathan , 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 , Streeten Elizabeth , Su Jessica Lasky , Sung Yun Ju , Sylvia Jody , Szpiro Adam , Sztalryd Carole , Taliun Daniel , Tang Hua , Taub Margaret , Taylor Kent D. , Taylor Simeon , Telen Marilyn , Thornton Timothy A. , Tinker Lesley , Tirschwell David , Tiwari Hemant , Vaidya Dhananjay , VandeHaar Peter , Vrieze Scott , Walker Tarik , Wallace Robert , Walts Avram , Wan Emily , Wang Heming , Watson Karol , Weir Bruce , Weiss Scott , Weng Lu-Chen , Williams Kayleen , Williams L. Keoki , Wilson Carla , Wong Quenna , Xu Huichun , Yang Ivana , Yang Rongze , Zaghloul Norann , Zekavat Maryam , Zhang Yingze , Zhao Snow Xueyan , Zhao Wei , Zhi Degui , Zhou Xiang , Zhu Xiaofeng , Zody Michael , Zoellner Sebastian ,   FinnGen, Palotie Aarno , Daly Mark , Jacob Howard , Matakidou Athena , Runz Heiko , John Sally , Plenge Robert , McCarthy Mark , Hunkapiller Julie , Ehm Meg , Waterworth Dawn , Fox Caroline , Malarstig Anders , Klinger Kathy , Call Kathy , Mkel Tomi , Kaprio Jaakko , Virolainen Petri , Pulkki Kari , Kilpi Terhi , Perola Markus , Partanen Jukka , Pitkranta Anne , Kaarteenaho Riitta , Vainio Seppo , Savinainen Kimmo , Kosma Veli-Matti , Kujala Urho , Tuovila Outi , Hendolin Minna , Pakkanen Raimo , Waring Jeff , Riley-Gillis Bridget , Liu Jimmy , Biswas Shameek , Diogo Dorothee , Marshall Catherine , Hu Xinli , Gossel Matthias , Ripatti Samuli , Schleutker Johanna , Arvas Mikko , Carpen Olli , Hinttala Reetta , Kettunen Johannes , Laaksonen Reijo , Mannermaa Arto , Paloneva Juha , Soininen Hilkka , Julkunen Valtteri , Remes Anne , Klviinen Reetta , Hiltunen Mikko , Peltola Jukka , Tienari Pentti , Rinne Juha , Ziemann Adam , Waring Jeffrey , Esmaeeli Sahar , Smaoui Nizar , Lehtonen Anne , Eaton Susan , Lahdenper Sanni , Michon John , Kerchner Geoff , Bowers Natalie , Teng Edmond , Eicher John , Mehta Vinay , Gormley Padhraig , Linden Kari , Whelan Christopher , Xu Fanli , Pulford David , Frkkil Martti , Pikkarainen Sampsa , Jussila Airi , Blomster Timo , Kiviniemi Mikko , Voutilainen Markku , Georgantas Bob , Heap Graham , Rahimov Fedik , Usiskin Keith , Maranville Joseph , Lu Tim , Oh Danny , Kalpala Kirsi , Miller Melissa , McCarthy Linda , Eklund Kari , Palomki Antti , Isomki Pia , Piril Laura , Kaipiainen-Seppnen Oili , Huhtakangas Johanna , Lertratanakul Apinya , Close David , Hochfeld Marla , Bing Nan , Gordillo Jorge Esparza , Mars Nina , Laitinen Tarja , Pelkonen Margit , Kauppi Paula , Kankaanranta Hannu , Harju Terttu , Greenberg Steven , Chen Hubert , Betts Jo , Ghosh Soumitra , Salomaa Veikko , Niiranen Teemu , Juonala Markus , Metsrinne Kaj , Khnen Mika , Junttila Juhani , Laakso Markku , Pihlajamki Jussi , Sinisalo Juha , Taskinen Marja-Riitta , Tuomi Tiinamaija , Laukkanen Jari , Challis Ben , Peterson Andrew , Chu Audrey , Parkkinen Jaakko , Muslin Anthony , Joensuu Heikki , Meretoja Tuomo , Aaltonen Lauri , Auranen Annika , Karihtala Peeter , Kauppila Saila , Auvinen Pivi , Elenius Klaus , Popovic Relja , Schutzman Jennifer , Loboda Andrey , Chhibber Aparna , Lehtonen Heli , McDonough Stefan , Crohns Marika , Kulkarni Diptee , Kaarniranta Kai , Turunen Joni , Ollila Terhi , Seitsonen Sanna , Uusitalo Hannu , Aaltonen Vesa , Uusitalo-Jrvinen Hannele , Luodonp Marja , Hautala Nina , Strauss Erich , Chen Hao , Podgornaia Anna , Hoffman Joshua , Tasanen Kaisa , Huilaja Laura , Hannula-Jouppi Katariina , Salmi Teea , Peltonen Sirkku , Koulu Leena , Harvima Ilkka , Wu Ying , Choy David , Jalanko Anu , Kajanne Risto , Lyhs Ulrike , Kaunisto Mari , Davis Justin Wade , Quarless Danjuma , Petrovski Slav , Chen Chia-Yen , Bronson Paola , Yang Robert , Chang Diana , Bhangale Tushar , Holzinger Emily , Wang Xulong , Chen Xing , Hedman sa , Auro Kirsi , Wang Clarence , Xu Ethan , Auge Franck , Chatelain Clement , Kurki Mitja , Karjalainen Juha , Havulinna Aki , Palin Kimmo , Palta Priit , Parolo Pietro Della Briotta , Zhou Wei , Lemmel Susanna , Rivas Manuel , Harju Jarmo , Lehisto Arto , Ganna Andrea , Llorens Vincent , Karlsson Antti , Kristiansson Kati , Hyvrinen Kati , Ritari Jarmo , Wahlfors Tiina , Koskinen Miika , Pylks Katri , Kalaoja Marita , Karjalainen Minna , Mantere Tuomo , Kangasniemi Eeva , Heikkinen Sami , Laakkonen Eija , Kononen Juha , Loukola Anu , Laiho Pivi , Sistonen Tuuli , Kaiharju Essi , Laukkanen Markku , Jrvensivu Elina , Lhteenmki Sini , Mnnikk Lotta , Wong Regis , Mattsson Hannele , Hiekkalinna Tero , Jimnez Manuel Gonzlez , Donner Kati , Prn Kalle , Nunez-Fontarnau Javier , Kilpelinen Elina , Sipil Timo P. , Brein Georg , Dada Alexander , Awaisa Ghazal , Shcherban Anastasia , Sipil Tuomas , Laivuori Hannele , Kiiskinen Tuomo , Siirtola Harri , Tabuenca Javier Gracia , Kallio Lila , Soini Sirpa , Pitknen Kimmo , Kuopio Teijo , Peloso Gina M. 
Published: April 2021

AbstractAutosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.