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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.
Abstract

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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