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Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.

  • Author(s): 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 LR;
  • Kenny, Eimear;
  • Kim, Ryan W;
  • Kooperberg, Charles;
  • Laurie, Cathy C;
  • Lee, Seonwook;
  • Lloyd-Jones, Don M;
  • Loos, Ruth JF;
  • 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, DC;
  • 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;
  • FinnGen;
  • Peloso, Gina M
  • et al.

Autosomal 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.

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