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

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.

• Authors: Pradeep Natarajan, Akhil Pampana, Sarah E Graham, Sanni E Ruotsalainen, James A Perry, Paul S de Vries, Jai G Broome, James P Pirruccello, Michael C Honigberg, Krishna Aragam, Brooke Wolford, Jennifer A Brody, Lucinda Antonacci-Fulton, Moscati Arden, Stella Aslibekyan, Themistocles L Assimes, Christie M Ballantyne, Lawrence F Bielak, Joshua C Bis, Brian E Cade, Ron Do, Harsha Doddapaneni, Leslie S Emery, Yi-Jen Hung, Marguerite R Irvin, Alyna T Khan, Leslie Lange, Jiwon Lee, Rozenn N Lemaitre, Lisa W Martin, Ginger Metcalf, May E Montasser, Jee-Young Moon, Donna Muzny, Jeffrey R O'Connell, Nicholette D Palmer, Juan M Peralta, Patricia A Peyser, Adrienne M Stilp, Michael Tsai, Fei Fei Wang, Daniel E Weeks, Lisa R Yanek, James G Wilson, Goncalo Abecasis, Donna K Arnett, Lewis C Becker, John Blangero, Eric Boerwinkle, Donald W Bowden, Yi-Cheng Chang, Yii-Der I Chen, Won Jung Choi, Adolfo Correa, Joanne E Curran, Mark J Daly, Susan K Dutcher, Patrick T Ellinor, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Soren Germer, Richard A Gibbs, Jiang He, Kristian Hveem, Gail P Jarvik, Robert C Kaplan, Sharon L R Kardia, Eimear Kenny, Ryan W Kim, Charles Kooperberg, Cathy C Laurie, Seonwook Lee, Don M Lloyd-Jones, Ruth J F Loos, Steven A Lubitz, Rasika A Mathias, Karine A Viaud Martinez, Stephen T McGarvey, Braxton D Mitchell, Deborah A Nickerson, Kari E North, Aarno Palotie, Cheol Joo Park, Bruce M Psaty, D C Rao, Susan Redline, Alexander P Reiner, Daekwan Seo, Jeong-Sun Seo, Albert V Smith, Russell P Tracy, Ramachandran S Vasan, Sekar Kathiresan, L Adrienne Cupples, Jerome I Rotter, Alanna C Morrison, Stephen S Rich, Samuli Ripatti, Cristen Willer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, FinnGen, Gina M Peloso
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2182 (04 12 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33846329 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CHRDL1 protein, human
• Eye Proteins
• Lipids
• Nerve Tissue Proteins

Topics

• Cardiometabolic Risk Factors
• Chromosomes, Human, X (genetics)
• Eye Proteins (metabolism)
• Female
• Gene Expression Regulation
• Genetic Association Studies
• Genetic Loci
• Genetic Predisposition to Disease
• Genotype
• Humans
• Lipids (blood)
• Male
• Middle Aged
• Nerve Tissue Proteins (metabolism)
• Phenomics
• Polymorphism, Single Nucleotide (genetics)
• Subcutaneous Tissue (metabolism)
• Whole Genome Sequencing