Whole genome sequence analysis of blood lipid levels in >66,000 individuals.
Margaret Sunitha SelvarajXihao LiZilin LiAkhil PampanaDavid Y ZhangJoseph ParkStella AslibekyanJoshua C BisJennifer A BrodyBrian E CadeLee-Ming ChuangRen-Hua ChungJoanne E CurranLisa de Las FuentesPaul S de VriesRavindranath DuggiralaBarry I FreedmanMariaelisa GraffXiuqing GuoNancy Heard- CostaBertha HidalgoChii-Min HwaMarguerite R IrvinTanika N KellyBrian G KralLeslie LangeXiaohui LiLisa Warsinger MartinSteven A LubitzAni W ManichaikulMichael H PreussMay E MontasserAlanna C MorrisonTake NaseriJeffrey R O'ConnellNicholette D D AllredPatricia A PeyserMuagututia S ReupenaJennifer A SmithXiao SunKent D TaylorRussell P TracyMichael Y TsaiZhe WangYuxuan WangWei BaoJohn T WilkinsLisa R YanekWei ZhaoDonna K ArnettJohn E BlangeroEric BoerwinkleDonald W BowdenYii-Der Ida ChenAdolfo CorreaL Adrienne CupplesSusan K DutcherPatrick T EllinorMyriam FornageStacey GabrielSoren GermerRichard GibbsJiang HeRobert C KaplanSharon L R KardiaRyan KimCharles KooperbergRuth J F LoosKarine A Viaud-MartinezRasika A MathiasStephen T McGarveyBraxton D MitchellDeborah NickersonKari E NorthBruce M PsatySusan RedlineAlexander P ReinerRamachandran S VasanStephen S RichCristen J WillerJerome I RotterDaniel James RaderXihong Linnull nullGina M PelosoPradeep NatarajanPublished in: Nature communications (2022)
Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.