Whole genome sequence analysis of blood lipid levels in >66,000 individuals.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 10 2022
11 10 2022
Historique:
received:
27
09
2021
accepted:
21
09
2022
entrez:
11
10
2022
pubmed:
12
10
2022
medline:
14
10
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36220816
doi: 10.1038/s41467-022-33510-7
pii: 10.1038/s41467-022-33510-7
pmc: PMC9553944
doi:
Substances chimiques
Cholesterol, LDL
0
Lipids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
5995Subventions
Organisme : NIA NIH HHS
ID : K01 AG059898
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148565
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135818
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197449
Pays : United States
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ID : R01 MH078143
Pays : United States
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ID : R01 HL087263
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151152
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK085524
Pays : United States
Organisme : CSRD VA
ID : I01 CX001737
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL135405
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL140570
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL072515
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH083824
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA154274
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG009088
Pays : United States
Organisme : BLRD VA
ID : I01 BX005831
Pays : United States
Investigateurs
Namiko Abe
(N)
Gonçalo Abecasis
(G)
Francois Aguet
(F)
Christine Albert
(C)
Laura Almasy
(L)
Alvaro Alonso
(A)
Seth Ament
(S)
Peter Anderson
(P)
Pramod Anugu
(P)
Deborah Applebaum-Bowden
(D)
Kristin Ardlie
(K)
Dan Arking
(D)
Allison Ashley-Koch
(A)
Tim Assimes
(T)
Paul Auer
(P)
Dimitrios Avramopoulos
(D)
Najib Ayas
(N)
Adithya Balasubramanian
(A)
John Barnard
(J)
Kathleen Barnes
(K)
R Graham Barr
(RG)
Emily Barron-Casella
(E)
Lucas Barwick
(L)
Terri Beaty
(T)
Gerald Beck
(G)
Diane Becker
(D)
Lewis Becker
(L)
Rebecca Beer
(R)
Amber Beitelshees
(A)
Emelia Benjamin
(E)
Takis Benos
(T)
Marcos Bezerra
(M)
Larry Bielak
(L)
Thomas Blackwell
(T)
Russell Bowler
(R)
Ulrich Broeckel
(U)
Jai Broome
(J)
Deborah Brown
(D)
Karen Bunting
(K)
Esteban Burchard
(E)
Carlos Bustamante
(C)
Erin Buth
(E)
Jonathan Cardwell
(J)
Vincent Carey
(V)
Julie Carrier
(J)
Cara Carty
(C)
Richard Casaburi
(R)
Juan P Casas Romero
(JPC)
James Casella
(J)
Peter Castaldi
(P)
Mark Chaffin
(M)
Christy Chang
(C)
Yi-Cheng Chang
(YC)
Daniel Chasman
(D)
Sameer Chavan
(S)
Bo-Juen Chen
(BJ)
Wei-Min Chen
(WM)
Yii-Der Ida Chen
(YI)
Michael Cho
(M)
Seung Hoan Choi
(SH)
Mina Chung
(M)
Clary Clish
(C)
Suzy Comhair
(S)
Matthew Conomos
(M)
Elaine Cornell
(E)
Carolyn Crandall
(C)
James Crapo
(J)
L Adrienne Cupples
(LA)
Jeffrey Curtis
(J)
Brian Custer
(B)
Coleen Damcott
(C)
Dawood Darbar
(D)
Sean David
(S)
Colleen Davis
(C)
Michelle Daya
(M)
Mariza de Andrade
(M)
Michael DeBaun
(M)
Ranjan Deka
(R)
Dawn DeMeo
(D)
Scott Devine
(S)
Huyen Dinh
(H)
Harsha Doddapaneni
(H)
Qing Duan
(Q)
Shannon Dugan-Perez
(S)
Ravi Duggirala
(R)
Jon Peter Durda
(JP)
Charles Eaton
(C)
Lynette Ekunwe
(L)
Adel El Boueiz
(AE)
Leslie Emery
(L)
Serpil Erzurum
(S)
Charles Farber
(C)
Jesse Farek
(J)
Tasha Fingerlin
(T)
Matthew Flickinger
(M)
Nora Franceschini
(N)
Chris Frazar
(C)
Mao Fu
(M)
Stephanie M Fullerton
(SM)
Lucinda Fulton
(L)
Weiniu Gan
(W)
Shanshan Gao
(S)
Yan Gao
(Y)
Margery Gass
(M)
Heather Geiger
(H)
Bruce Gelb
(B)
Mark Geraci
(M)
Robert Gerszten
(R)
Auyon Ghosh
(A)
Chris Gignoux
(C)
Mark Gladwin
(M)
David Glahn
(D)
Stephanie Gogarten
(S)
Da-Wei Gong
(DW)
Harald Goring
(H)
Sharon Graw
(S)
Kathryn J Gray
(KJ)
Daniel Grine
(D)
Colin Gross
(C)
C Charles Gu
(CC)
Yue Guan
(Y)
Namrata Gupta
(N)
David M Haas
(DM)
Jeff Haessler
(J)
Michael Hall
(M)
Yi Han
(Y)
Patrick Hanly
(P)
Daniel Harris
(D)
Nicola L Hawley
(NL)
Ben Heavner
(B)
Susan Heckbert
(S)
Ryan Hernandez
(R)
David Herrington
(D)
Craig Hersh
(C)
Bertha Hidalgo
(B)
James Hixson
(J)
Brian Hobbs
(B)
John Hokanson
(J)
Elliott Hong
(E)
Karin Hoth
(K)
Chao Agnes Hsiung
(CA)
Jianhong Hu
(J)
Yi-Jen Hung
(YJ)
Haley Huston
(H)
Chii Min Hwu
(CM)
Rebecca Jackson
(R)
Deepti Jain
(D)
Cashell Jaquish
(C)
Jill Johnsen
(J)
Andrew Johnson
(A)
Craig Johnson
(C)
Rich Johnston
(R)
Kimberly Jones
(K)
Hyun Min Kang
(HM)
Shannon Kelly
(S)
Eimear Kenny
(E)
Michael Kessler
(M)
Alyna Khan
(A)
Ziad Khan
(Z)
Wonji Kim
(W)
John Kimoff
(J)
Greg Kinney
(G)
Barbara Konkle
(B)
Holly Kramer
(H)
Christoph Lange
(C)
Ethan Lange
(E)
Cathy Laurie
(C)
Cecelia Laurie
(C)
Meryl LeBoff
(M)
Jiwon Lee
(J)
Sandra Lee
(S)
Wen-Jane Lee
(WJ)
Jonathon LeFaive
(J)
David Levine
(D)
Dan Levy
(D)
Joshua Lewis
(J)
Yun Li
(Y)
Henry Lin
(H)
Honghuang Lin
(H)
Simin Liu
(S)
Yongmei Liu
(Y)
Yu Liu
(Y)
Kathryn Lunetta
(K)
James Luo
(J)
Ulysses Magalang
(U)
Michael Mahaney
(M)
Barry Make
(B)
Alisa Manning
(A)
JoAnn Manson
(J)
Lisa Martin
(L)
Melissa Marton
(M)
Susan Mathai
(S)
Susanne May
(S)
Patrick McArdle
(P)
Merry-Lynn McDonald
(ML)
Sean McFarland
(S)
Daniel McGoldrick
(D)
Caitlin McHugh
(C)
Becky McNeil
(B)
Hao Mei
(H)
James Meigs
(J)
Vipin Menon
(V)
Luisa Mestroni
(L)
Ginger Metcalf
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Deborah A Meyers
(DA)
Emmanuel Mignot
(E)
Julie Mikulla
(J)
Nancy Min
(N)
Mollie Minear
(M)
Ryan L Minster
(RL)
Matt Moll
(M)
Zeineen Momin
(Z)
Courtney Montgomery
(C)
Donna Muzny
(D)
Josyf C Mychaleckyj
(JC)
Girish Nadkarni
(G)
Rakhi Naik
(R)
Sergei Nekhai
(S)
Sarah C Nelson
(SC)
Bonnie Neltner
(B)
Caitlin Nessner
(C)
Osuji Nkechinyere
(O)
Jeff O'Connell
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Tim O'Connor
(T)
Heather Ochs-Balcom
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Allan Pack
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David T Paik
(DT)
James Pankow
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George Papanicolaou
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Cora Parker
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Juan Manuel Peralta
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Marco Perez
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Ulrike Peters
(U)
Lawrence S Phillips
(LS)
Jacob Pleiness
(J)
Toni Pollin
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Wendy Post
(W)
Julia Powers Becker
(JP)
Meher Preethi Boorgula
(MP)
Michael Preuss
(M)
Pankaj Qasba
(P)
Dandi Qiao
(D)
Zhaohui Qin
(Z)
Nicholas Rafaels
(N)
Laura Raffield
(L)
Mahitha Rajendran
(M)
Ramachandran S Vasan
(RS)
D C Rao
(DC)
Laura Rasmussen-Torvik
(L)
Aakrosh Ratan
(A)
Robert Reed
(R)
Catherine Reeves
(C)
Elizabeth Regan
(E)
Alex Reiner
(A)
Ken Rice
(K)
Rebecca Robillard
(R)
Nicolas Robine
(N)
Dan Roden
(D)
Carolina Roselli
(C)
Ingo Ruczinski
(I)
Alexi Runnels
(A)
Pamela Russell
(P)
Sarah Ruuska
(S)
Kathleen Ryan
(K)
Ester Cerdeira Sabino
(EC)
Danish Saleheen
(D)
Shabnam Salimi
(S)
Sejal Salvi
(S)
Steven Salzberg
(S)
Kevin Sandow
(K)
Vijay G Sankaran
(VG)
Jireh Santibanez
(J)
Karen Schwander
(K)
David Schwartz
(D)
Frank Sciurba
(F)
Christine Seidman
(C)
Jonathan Seidman
(J)
Frédéric Sériès
(F)
Vivien Sheehan
(V)
Stephanie L Sherman
(SL)
Amol Shetty
(A)
Aniket Shetty
(A)
Wayne Hui-Heng Sheu
(WH)
M Benjamin Shoemaker
(MB)
Brian Silver
(B)
Edwin Silverman
(E)
Robert Skomro
(R)
Albert Vernon Smith
(AV)
Josh Smith
(J)
Nicholas Smith
(N)
Tanja Smith
(T)
Sylvia Smoller
(S)
Beverly Snively
(B)
Michael Snyder
(M)
Tamar Sofer
(T)
Nona Sotoodehnia
(N)
Adrienne M Stilp
(AM)
Garrett Storm
(G)
Elizabeth Streeten
(E)
Jessica Lasky Su
(JL)
Yun Ju Sung
(YJ)
Jody Sylvia
(J)
Adam Szpiro
(A)
Daniel Taliun
(D)
Hua Tang
(H)
Margaret Taub
(M)
Matthew Taylor
(M)
Simeon Taylor
(S)
Marilyn Telen
(M)
Timothy A Thornton
(TA)
Machiko Threlkeld
(M)
Lesley Tinker
(L)
David Tirschwell
(D)
Sarah Tishkoff
(S)
Hemant Tiwari
(H)
Catherine Tong
(C)
Dhananjay Vaidya
(D)
David Van Den Berg
(DVD)
Peter VandeHaar
(P)
Scott Vrieze
(S)
Tarik Walker
(T)
Robert Wallace
(R)
Avram Walts
(A)
Fei Fei Wang
(FF)
Heming Wang
(H)
Jiongming Wang
(J)
Karol Watson
(K)
Jennifer Watt
(J)
Daniel E Weeks
(DE)
Joshua Weinstock
(J)
Bruce Weir
(B)
Scott T Weiss
(ST)
Lu-Chen Weng
(LC)
Jennifer Wessel
(J)
Kayleen Williams
(K)
L Keoki Williams
(LK)
Carla Wilson
(C)
James Wilson
(J)
Lara Winterkorn
(L)
Quenna Wong
(Q)
Joseph Wu
(J)
Huichun Xu
(H)
Ivana Yang
(I)
Ketian Yu
(K)
Seyedeh Maryam Zekavat
(SM)
Yingze Zhang
(Y)
Snow Xueyan Zhao
(SX)
Wei Zhao
(W)
Xiaofeng Zhu
(X)
Michael Zody
(M)
Sebastian Zoellner
(S)
Informations de copyright
© 2022. The Author(s).
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