%0 Journal Article %J Nat Commun %D 2021 %T Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. %A Natarajan, Pradeep %A Pampana, Akhil %A Graham, Sarah E %A Ruotsalainen, Sanni E %A Perry, James A %A de Vries, Paul S %A Broome, Jai G %A Pirruccello, James P %A Honigberg, Michael C %A Aragam, Krishna %A Wolford, Brooke %A Brody, Jennifer A %A Antonacci-Fulton, Lucinda %A Arden, Moscati %A Aslibekyan, Stella %A Assimes, Themistocles L %A Ballantyne, Christie M %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Do, Ron %A Doddapaneni, Harsha %A Emery, Leslie S %A Hung, Yi-Jen %A Irvin, Marguerite R %A Khan, Alyna T %A Lange, Leslie %A Lee, Jiwon %A Lemaitre, Rozenn N %A Martin, Lisa W %A Metcalf, Ginger %A Montasser, May E %A Moon, Jee-Young %A Muzny, Donna %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peralta, Juan M %A Peyser, Patricia A %A Stilp, Adrienne M %A Tsai, Michael %A Wang, Fei Fei %A Weeks, Daniel E %A Yanek, Lisa R %A Wilson, James G %A Abecasis, Goncalo %A Arnett, Donna K %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Chang, Yi-Cheng %A Chen, Yii-der I %A Choi, Won Jung %A Correa, Adolfo %A Curran, Joanne E %A Daly, Mark J %A Dutcher, Susan K %A Ellinor, Patrick T %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A He, Jiang %A Hveem, Kristian %A Jarvik, Gail P %A Kaplan, Robert C %A Kardia, Sharon L R %A Kenny, Eimear %A Kim, Ryan W %A Kooperberg, Charles %A Laurie, Cathy C %A Lee, Seonwook %A Lloyd-Jones, Don M %A Loos, Ruth J F %A Lubitz, Steven A %A Mathias, Rasika A %A Martinez, Karine A Viaud %A McGarvey, Stephen T %A Mitchell, Braxton D %A Nickerson, Deborah A %A North, Kari E %A Palotie, Aarno %A Park, Cheol Joo %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Seo, Daekwan %A Seo, Jeong-Sun %A Smith, Albert V %A Tracy, Russell P %A Vasan, Ramachandran S %A Kathiresan, Sekar %A Cupples, L Adrienne %A Rotter, Jerome I %A Morrison, Alanna C %A Rich, Stephen S %A Ripatti, Samuli %A Willer, Cristen %A Peloso, Gina M %X

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), 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), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10). 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.

%B Nat Commun %V 12 %P 2182 %8 2021 04 12 %G eng %N 1 %R 10.1038/s41467-021-22339-1