Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.
Pradeep NatarajanAkhil PampanaSarah E GrahamSanni E RuotsalainenJames A PerryPaul S de VriesJai G BroomeJames Paul PirruccelloMichael C HonigbergKrishna AragamBrooke N WolfordJennifer A BrodyLucinda Antonacci-FultonMoscati ArdenStella AslibekyanThemistocles L AssimesChristie M BallantyneLawrence F BielakJoshua C BisBrian E CadeRon DoHarsha Vardhan DoddapaneniLeslie S EmeryYi-Jen HungMarguerite R IrvinAlyna T KhanLeslie LangeJiwon LeeRozenn N LemaitreLisa Warsinger MartinGinger MetcalfMay E MontasserJee-Young MoonDonna MuznyJeffrey R O'ConnellNicholette D D AllredJuan M PeraltaPatricia A PeyserAdrienne M StilpMichael TsaiFei Fei WangDaniel E WeeksLisa R YanekJames G WilsonGonçalo R AbecasisDonna K ArnettLewis C BeckerJohn E BlangeroEric BoerwinkleDonald W BowdenYi-Cheng ChangYii-Der I ChenWon Jung ChoiAdolfo CorreaJoanne E CurranMark J DalySusan K DutcherPatrick T EllinorMyriam FornageBarry I FreedmanStacey GabrielSoren GermerRichard A GibbsJiang HeKristian HveemDavid L VeenstraRobert C KaplanSharon L R KardiaEimear KennyRyan W KimCharles KooperbergCathy C LaurieSeonwook LeeDon M Lloyd-JonesRuth J F LoosSteven A LubitzRasika A MathiasKarine A Viaud MartinezStephen T McGarveyBraxton D MitchellDeborah A NickersonKari E NorthAarno PalotieCheol Joo ParkBruce M PsatyD C RaoSusan RedlineAlexander P ReinerDaekwan SeoJeong-Sun SeoAlbert Vernon SmithRussell P TracyRamachandran S VasanSekar KathiresanL Adrienne CupplesJerome I RotterAlanna C MorrisonStephen S RichSamuli RipattiCristen J Willernull nullnull nullGina M PelosoPublished in: Nature communications (2021)
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.