Journal article
Whole genome sequence analysis of blood lipid levels in >66,000 individuals
Nature communications, Vol.13(1), pp.5995-5995
10/11/2022
DOI: 10.1038/s41467-022-33510-7
PMCID: PMC9553944
PMID: 36220816
Abstract
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.
Details
- Title: Subtitle
- Whole genome sequence analysis of blood lipid levels in >66,000 individuals
- Creators
- Margaret Sunitha Selvaraj - Massachusetts General HospitalXihao Li - Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USAZilin Li - Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USAAkhil Pampana - Broad InstituteDavid Y Zhang - University of PennsylvaniaJoseph Park - University of PennsylvaniaStella Aslibekyan - University of Alabama at BirminghamJoshua C Bis - University of WashingtonJennifer A Brody - University of WashingtonBrian E Cade - Brigham and Women's HospitalLee-Ming Chuang - National Taiwan University HospitalRen-Hua Chung - National Health Research InstitutesJoanne E Curran - The University of Texas Rio Grande ValleyLisa de Las Fuentes - Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USAPaul S de Vries - The University of Texas Health Science Center at HoustonRavindranath Duggirala - The University of Texas Rio Grande ValleyBarry I Freedman - Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USAMariaelisa Graff - University of North Carolina at Chapel HillXiuqing Guo - Harbor–UCLA Medical CenterNancy Heard-Costa - Boston University School of MedicineBertha Hidalgo - University of Alabama at BirminghamChii-Min Hwu - Taipei Veterans General HospitalMarguerite R Irvin - University of Alabama at BirminghamTanika N Kelly - Tulane UniversityBrian G Kral - Johns Hopkins University School of MedicineLeslie Lange - University of Colorado Anschutz Medical CampusXiaohui Li - Harbor–UCLA Medical CenterLisa Martin - George Washington UniversitySteven A Lubitz - Broad InstituteAni W Manichaikul - University of VirginiaMichael Preuss - Icahn School of Medicine at Mount SinaiMay E Montasser - Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USAAlanna C Morrison - The University of Texas Health Science Center at HoustonTake Naseri - Ministry of Health, Government of Samoa, Samoa, USAJeffrey R O'Connell - Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USANicholette D Palmer - Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USAPatricia A Peyser - University of MichiganMuagututia S Reupena - Lutia i Puava ae Mapu i Fagalele, Apia, SamoaJennifer A Smith - University of MichiganXiao Sun - Tulane UniversityKent D Taylor - Harbor–UCLA Medical CenterRussell P Tracy - University of VermontMichael Y Tsai - Department of Laboratory Medicine and Pathology, University of Minneosta, Minneapolis, MN, USAZhe Wang - Icahn School of Medicine at Mount SinaiYuxuan Wang - Boston UniversityWei Bao - Institute of Public Health, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230026, ChinaJohn T Wilkins - Northwestern UniversityLisa R Yanek - Johns Hopkins University School of MedicineWei Zhao - University of MichiganDonna K Arnett - University of KentuckyJohn Blangero - The University of Texas Rio Grande ValleyEric Boerwinkle - The University of Texas Health Science Center at HoustonDonald W Bowden - Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USAYii-Der Ida Chen - Harbor–UCLA Medical CenterAdolfo Correa - University of Mississippi Medical CenterL Adrienne Cupples - Boston UniversitySusan K Dutcher - The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USAPatrick T Ellinor - Broad InstituteMyriam Fornage - The University of Texas Health Science Center at HoustonStacey Gabriel - Broad InstituteSoren Germer - New York Genome CenterRichard Gibbs - Baylor College of MedicineJiang He - Tulane UniversityRobert C Kaplan - Fred Hutch Cancer CenterSharon L R Kardia - University of MichiganRyan Kim - Macrogen (South Korea)Charles Kooperberg - Fred Hutch Cancer CenterRuth J F Loos - University of CopenhagenKarine A Viaud-Martinez - Illumina (United States)Rasika A Mathias - Johns Hopkins University School of MedicineStephen T McGarvey - Brown UniversityBraxton D Mitchell - Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USADeborah Nickerson - University of WashingtonKari E North - University of North Carolina at Chapel HillBruce M Psaty - University of WashingtonSusan Redline - Brigham and Women's HospitalAlexander P Reiner - University of WashingtonRamachandran S Vasan - Framingham Heart StudyStephen S Rich - University of VirginiaCristen Willer - University of Michigan, Internal Medicine, Ann Arbor, MI, 48109, USAJerome I Rotter - Harbor–UCLA Medical CenterDaniel J Rader - University of PennsylvaniaXihong Lin - Harvard UniversityGina M Peloso - Boston UniversityPradeep Natarajan - Harvard Medical SchoolNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Contributors
- Robert Wallace (Contributor) - University of Iowa, Internal Medicine
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.13(1), pp.5995-5995
- DOI
- 10.1038/s41467-022-33510-7
- PMID
- 36220816
- PMCID
- PMC9553944
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Grant note
- K01 HL135405 / NHLBI NIH HHS U01 DK085524 / NIDDK NIH HHS R01 HL121007 / NHLBI NIH HHS K01 AG059898 / NIA NIH HHS R01 HL148565 / NHLBI NIH HHS R01 HL093093 / NHLBI NIH HHS R01 HL148050 / NHLBI NIH HHS R01 HL140570 / NHLBI NIH HHS R01 MH083824 / NIMH NIH HHS R01 HL135242 / NHLBI NIH HHS R01 HL139731 / NHLBI NIH HHS R03 HL154284 / NHLBI NIH HHS R01 HL157635 / NHLBI NIH HHS R01 HL142711 / NHLBI NIH HHS R01 HL151152 / NHLBI NIH HHS P30 DK020541 / NIDDK NIH HHS R01 HL087263 / NHLBI NIH HHS R35 HL135818 / NHLBI NIH HHS R35 CA197449 / NCI NIH HHS R01 HL113323 / NHLBI NIH HHS U01 HL072515 / NHLBI NIH HHS U01 HL072507 / NHLBI NIH HHS U01 HG009088 / NHGRI NIH HHS R01 HL127564 / NHLBI NIH HHS P01 HL045522 / NHLBI NIH HHS R01 HL151283 / NHLBI NIH HHS R01 HL105756 / NHLBI NIH HHS R01 MH078111 / NIMH NIH HHS R01 HL090682 / NHLBI NIH HHS R01 MH078143 / NIMH NIH HHS U19 CA203654 / NCI NIH HHS R01 HL153805 / NHLBI NIH HHS R01 HL113338 / NHLBI NIH HHS
- Language
- English
- Date published
- 10/11/2022
- Academic Unit
- Epidemiology; Injury Prevention Research Center; Internal Medicine
- Record Identifier
- 9984364435002771
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