Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.
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.
Natarajan, P; Pampana, A; Graham, SE; Ruotsalainen, SE; Perry, JA; de Vries, PS; Broome, JG; Pirruccello, JP; Honigberg, MC; Aragam, K; Wolford, B; Brody, JA; Antonacci-Fulton, L; Arden, M; Aslibekyan, S; Assimes, TL; Ballantyne, CM; Bielak, LF; Bis, JC; Cade, BE; Do, R; Doddapaneni, H; Emery, LS; Hung, Y-J; Irvin, MR; Khan, AT; Lange, L; Lee, J; Lemaitre, RN; Martin, LW; Metcalf, G; Montasser, ME; Moon, J-Y; Muzny, D; O'Connell, JR; Palmer, ND; Peralta, JM; Peyser, PA; Stilp, AM; Tsai, M; Wang, FF; Weeks, DE; Yanek, LR; Wilson, JG; Abecasis, G; Arnett, DK; Becker, LC; Blangero, J; Boerwinkle, E; Bowden, DW; Chang, Y-C; Chen, Y-DI; Choi, WJ; Correa, A; Curran, JE; Daly, MJ; Dutcher, SK; Ellinor, PT; Fornage, M; Freedman, BI; Gabriel, S; Germer, S; Gibbs, RA; He, J; Hveem, K; Jarvik, GP; Kaplan, RC; Kardia, SLR; Kenny, E; Kim, RW; Kooperberg, C; Laurie, CC; Lee, S; Lloyd-Jones, DM; Loos, RJF; Lubitz, SA; Mathias, RA; Martinez, KAV; McGarvey, ST; Mitchell, BD; Nickerson, DA; North, KE; Palotie, A; Park, CJ; Psaty, BM; Rao, DC; Redline, S; Reiner, AP; Seo, D; Seo, J-S; Smith, AV; Tracy, RP; Vasan, RS; Kathiresan, S; Cupples, LA; Rotter, JI; Morrison, AC; Rich, SS; Ripatti, S; Willer, C; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, ; FinnGen, ; Peloso, GM
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