Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.
Cardiometabolic Risk Factors
Chromosomes, Human, X
/ genetics
Eye Proteins
/ metabolism
Female
Gene Expression Regulation
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
Genotype
Humans
Lipids
/ blood
Male
Middle Aged
Nerve Tissue Proteins
/ metabolism
Phenomics
Polymorphism, Single Nucleotide
/ genetics
Subcutaneous Tissue
/ metabolism
Whole Genome Sequencing
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 04 2021
12 04 2021
Historique:
received:
28
08
2020
accepted:
02
03
2021
entrez:
13
4
2021
pubmed:
14
4
2021
medline:
22
4
2021
Statut:
epublish
Résumé
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
Identifiants
pubmed: 33846329
doi: 10.1038/s41467-021-22339-1
pii: 10.1038/s41467-021-22339-1
pmc: PMC8042019
doi:
Substances chimiques
CHRDL1 protein, human
0
Eye Proteins
0
Lipids
0
Nerve Tissue Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2182Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL094301
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL046380
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139731
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL113338
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135824
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148050
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK072488
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL154284
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL140203
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117626
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL135405
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL141439
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL109946
Pays : United States
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 : R01 HL120393
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL125751
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007208
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142711
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL135818
Pays : United States
Investigateurs
Namiko Abe
(N)
Christine Albert
(C)
Laura Almasy
(L)
Alvaro Alonso
(A)
Seth Ament
(S)
Peter Anderson
(P)
Pramod Anugu
(P)
Deborah Applebaum-Bowden
(D)
Dan Arking
(D)
Allison Ashley-Koch
(A)
Paul Auer
(P)
Dimitrios Avramopoulos
(D)
John Barnard
(J)
Kathleen Barnes
(K)
R Graham Barr
(RG)
Emily Barron-Casella
(E)
Terri Beaty
(T)
Diane Becker
(D)
Rebecca Beer
(R)
Ferdouse Begum
(F)
Amber Beitelshees
(A)
Emelia Benjamin
(E)
Marcos Bezerra
(M)
Larry Bielak
(L)
Thomas Blackwell
(T)
Russell Bowler
(R)
Ulrich Broeckel
(U)
Karen Bunting
(K)
Esteban Burchard
(E)
Erin Buth
(E)
Jonathan Cardwell
(J)
Cara Carty
(C)
Richard Casaburi
(R)
James Casella
(J)
Mark Chaffin
(M)
Christy Chang
(C)
Daniel Chasman
(D)
Sameer Chavan
(S)
Bo-Juen Chen
(BJ)
Wei-Min Chen
(WM)
Michael Cho
(M)
Seung Hoan Choi
(SH)
Lee-Ming Chuang
(LM)
Mina Chung
(M)
Matthew P Conomos
(MP)
Elaine Cornell
(E)
Carolyn Crandall
(C)
James Crapo
(J)
Jeffrey Curtis
(J)
Brian Custer
(B)
Coleen Damcott
(C)
Dawood Darbar
(D)
Sayantan Das
(S)
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)
Qing Duan
(Q)
Ravi Duggirala
(R)
Jon Peter Durda
(JP)
Susan Dutcher
(S)
Charles Eaton
(C)
Lynette Ekunwe
(L)
Charles Farber
(C)
Leanna Farnam
(L)
Tasha Fingerlin
(T)
Matthew Flickinger
(M)
Nora Franceschini
(N)
Mao Fu
(M)
Stephanie M Fullerton
(SM)
Lucinda Fulton
(L)
Weiniu Gan
(W)
Yan Gao
(Y)
Margery Gass
(M)
Bruce Gelb
(B)
Xiaoqi Priscilla Geng
(XP)
Chris Gignoux
(C)
Mark Gladwin
(M)
David Glahn
(D)
Stephanie Gogarten
(S)
Da-Wei Gong
(DW)
Harald Goring
(H)
C Charles Gu
(CC)
Yue Guan
(Y)
Xiuqing Guo
(X)
Jeff Haessler
(J)
Michael Hall
(M)
Daniel Harris
(D)
Nicola Hawley
(N)
Ben Heavner
(B)
Susan Heckbert
(S)
Ryan Hernandez
(R)
David Herrington
(D)
Craig Hersh
(C)
Bertha Hidalgo
(B)
James Hixson
(J)
John Hokanson
(J)
Elliott Hong
(E)
Karin Hoth
(K)
Chao Agnes Hsiung
(CA)
Haley Huston
(H)
Chii Min Hwu
(CM)
Rebecca Jackson
(R)
Deepti Jain
(D)
Cashell Jaquish
(C)
Min A Jhun
(MA)
Jill Johnsen
(J)
Andrew Johnson
(A)
Craig Johnson
(C)
Rich Johnston
(R)
Kimberly Jones
(K)
Hyun Min Kang
(HM)
Laura Kaufman
(L)
Shannon Kelly
(S)
Michael Kessler
(M)
Greg Kinney
(G)
Barbara Konkle
(B)
Holly Kramer
(H)
Stephanie Krauter
(S)
Christoph Lange
(C)
Ethan Lange
(E)
Cecelia Laurie
(C)
Meryl LeBoff
(M)
Seunggeun Shawn Lee
(SS)
Wen-Jane Lee
(WJ)
Jonathon LeFaive
(J)
David Levine
(D)
Dan Levy
(D)
Joshua Lewis
(J)
Yun Li
(Y)
Honghuang Lin
(H)
Keng Han Lin
(KH)
Xihong Lin
(X)
Simin Liu
(S)
Yongmei Liu
(Y)
Kathryn Lunetta
(K)
James Luo
(J)
Michael Mahaney
(M)
Barry Make
(B)
Ani Manichaikul
(A)
JoAnn Manson
(J)
Lauren Margolin
(L)
Susan Mathai
(S)
Patrick McArdle
(P)
Merry-Lynn McDonald
(ML)
Sean McFarland
(S)
Caitlin McHugh
(C)
Hao Mei
(H)
Deborah A Meyers
(DA)
Julie Mikulla
(J)
Nancy Min
(N)
Mollie Minear
(M)
Ryan L Minster
(RL)
Solomon Musani
(S)
Stanford Mwasongwe
(S)
Josyf C Mychaleckyj
(JC)
Girish Nadkarni
(G)
Rakhi Naik
(R)
Take Naseri
(T)
Sergei Nekhai
(S)
Sarah C Nelson
(SC)
Deborah Nickerson
(D)
Jeff O'Connell
(J)
Tim O'Connor
(T)
Heather Ochs-Balcom
(H)
James Pankow
(J)
George Papanicolaou
(G)
Margaret Parker
(M)
Afshin Parsa
(A)
Sara Penchev
(S)
Marco Perez
(M)
Ulrike Peters
(U)
Lawrence S Phillips
(LS)
Sam Phillips
(S)
Toni Pollin
(T)
Wendy Post
(W)
Julia Powers Becker
(JP)
Meher Preethi Boorgula
(MP)
Michael Preuss
(M)
Dmitry Prokopenko
(D)
Pankaj Qasba
(P)
Dandi Qiao
(D)
Zhaohui Qin
(Z)
Nicholas Rafaels
(N)
Laura Raffield
(L)
Laura Rasmussen-Torvik
(L)
Aakrosh Ratan
(A)
Robert Reed
(R)
Elizabeth Regan
(E)
Muagututi'a Sefuiva Reupena
(MS)
Ken Rice
(K)
Dan Roden
(D)
Carolina Roselli
(C)
Ingo Ruczinski
(I)
Pamela Russell
(P)
Sarah Ruuska
(S)
Kathleen Ryan
(K)
Ester Cerdeira Sabino
(EC)
Phuwanat Sakornsakolpat
(P)
Shabnam Salimi
(S)
Steven Salzberg
(S)
Kevin Sandow
(K)
Vijay G Sankaran
(VG)
Christopher Scheller
(C)
Ellen Schmidt
(E)
Karen Schwander
(K)
David Schwartz
(D)
Frank Sciurba
(F)
Christine Seidman
(C)
Jonathan Seidman
(J)
Vivien Sheehan
(V)
Amol Shetty
(A)
Aniket Shetty
(A)
Wayne Hui-Heng Sheu
(WH)
M Benjamin Shoemaker
(MB)
Brian Silver
(B)
Edwin Silverman
(E)
Jennifer Smith
(J)
Josh Smith
(J)
Nicholas Smith
(N)
Tanja Smith
(T)
Sylvia Smoller
(S)
Beverly Snively
(B)
Tamar Sofer
(T)
Nona Sotoodehnia
(N)
Elizabeth Streeten
(E)
Jessica Lasky Su
(JL)
Yun Ju Sung
(YJ)
Jody Sylvia
(J)
Adam Szpiro
(A)
Carole Sztalryd
(C)
Daniel Taliun
(D)
Hua Tang
(H)
Margaret Taub
(M)
Kent D Taylor
(KD)
Simeon Taylor
(S)
Marilyn Telen
(M)
Timothy A Thornton
(TA)
Lesley Tinker
(L)
David Tirschwell
(D)
Hemant Tiwari
(H)
Dhananjay Vaidya
(D)
Peter VandeHaar
(P)
Scott Vrieze
(S)
Tarik Walker
(T)
Robert Wallace
(R)
Avram Walts
(A)
Emily Wan
(E)
Heming Wang
(H)
Karol Watson
(K)
Bruce Weir
(B)
Scott Weiss
(S)
Lu-Chen Weng
(LC)
Kayleen Williams
(K)
L Keoki Williams
(LK)
Carla Wilson
(C)
Quenna Wong
(Q)
Huichun Xu
(H)
Ivana Yang
(I)
Rongze Yang
(R)
Norann Zaghloul
(N)
Maryam Zekavat
(M)
Yingze Zhang
(Y)
Snow Xueyan Zhao
(SX)
Wei Zhao
(W)
Degui Zhi
(D)
Xiang Zhou
(X)
Xiaofeng Zhu
(X)
Michael Zody
(M)
Sebastian Zoellner
(S)
Aarno Palotie
(A)
Mark Daly
(M)
Howard Jacob
(H)
Athena Matakidou
(A)
Heiko Runz
(H)
Sally John
(S)
Robert Plenge
(R)
Mark McCarthy
(M)
Julie Hunkapiller
(J)
Meg Ehm
(M)
Dawn Waterworth
(D)
Caroline Fox
(C)
Anders Malarstig
(A)
Kathy Klinger
(K)
Kathy Call
(K)
Tomi Mkel
(T)
Jaakko Kaprio
(J)
Petri Virolainen
(P)
Kari Pulkki
(K)
Terhi Kilpi
(T)
Markus Perola
(M)
Jukka Partanen
(J)
Anne Pitkranta
(A)
Riitta Kaarteenaho
(R)
Seppo Vainio
(S)
Kimmo Savinainen
(K)
Veli-Matti Kosma
(VM)
Urho Kujala
(U)
Outi Tuovila
(O)
Minna Hendolin
(M)
Raimo Pakkanen
(R)
Jeff Waring
(J)
Bridget Riley-Gillis
(B)
Jimmy Liu
(J)
Shameek Biswas
(S)
Dorothee Diogo
(D)
Catherine Marshall
(C)
Xinli Hu
(X)
Matthias Gossel
(M)
Samuli Ripatti
(S)
Johanna Schleutker
(J)
Mikko Arvas
(M)
Olli Carpen
(O)
Reetta Hinttala
(R)
Johannes Kettunen
(J)
Reijo Laaksonen
(R)
Arto Mannermaa
(A)
Juha Paloneva
(J)
Hilkka Soininen
(H)
Valtteri Julkunen
(V)
Anne Remes
(A)
Reetta Klviinen
(R)
Mikko Hiltunen
(M)
Jukka Peltola
(J)
Pentti Tienari
(P)
Juha Rinne
(J)
Adam Ziemann
(A)
Jeffrey Waring
(J)
Sahar Esmaeeli
(S)
Nizar Smaoui
(N)
Anne Lehtonen
(A)
Susan Eaton
(S)
Sanni Lahdenper
(S)
John Michon
(J)
Geoff Kerchner
(G)
Natalie Bowers
(N)
Edmond Teng
(E)
John Eicher
(J)
Vinay Mehta
(V)
Padhraig Gormley
(P)
Kari Linden
(K)
Christopher Whelan
(C)
Fanli Xu
(F)
David Pulford
(D)
Martti Frkkil
(M)
Sampsa Pikkarainen
(S)
Airi Jussila
(A)
Timo Blomster
(T)
Mikko Kiviniemi
(M)
Markku Voutilainen
(M)
Bob Georgantas
(B)
Graham Heap
(G)
Fedik Rahimov
(F)
Keith Usiskin
(K)
Joseph Maranville
(J)
Tim Lu
(T)
Danny Oh
(D)
Kirsi Kalpala
(K)
Melissa Miller
(M)
Linda McCarthy
(L)
Kari Eklund
(K)
Antti Palomki
(A)
Pia Isomki
(P)
Laura Piril
(L)
Oili Kaipiainen-Seppnen
(O)
Johanna Huhtakangas
(J)
Apinya Lertratanakul
(A)
David Close
(D)
Marla Hochfeld
(M)
Nan Bing
(N)
Jorge Esparza Gordillo
(JE)
Nina Mars
(N)
Tarja Laitinen
(T)
Margit Pelkonen
(M)
Paula Kauppi
(P)
Hannu Kankaanranta
(H)
Terttu Harju
(T)
Steven Greenberg
(S)
Hubert Chen
(H)
Jo Betts
(J)
Soumitra Ghosh
(S)
Veikko Salomaa
(V)
Teemu Niiranen
(T)
Markus Juonala
(M)
Kaj Metsrinne
(K)
Mika Khnen
(M)
Juhani Junttila
(J)
Markku Laakso
(M)
Jussi Pihlajamki
(J)
Juha Sinisalo
(J)
Marja-Riitta Taskinen
(MR)
Tiinamaija Tuomi
(T)
Jari Laukkanen
(J)
Ben Challis
(B)
Andrew Peterson
(A)
Audrey Chu
(A)
Jaakko Parkkinen
(J)
Anthony Muslin
(A)
Heikki Joensuu
(H)
Tuomo Meretoja
(T)
Lauri Aaltonen
(L)
Annika Auranen
(A)
Peeter Karihtala
(P)
Saila Kauppila
(S)
Pivi Auvinen
(P)
Klaus Elenius
(K)
Relja Popovic
(R)
Jennifer Schutzman
(J)
Andrey Loboda
(A)
Aparna Chhibber
(A)
Heli Lehtonen
(H)
Stefan McDonough
(S)
Marika Crohns
(M)
Diptee Kulkarni
(D)
Kai Kaarniranta
(K)
Joni Turunen
(J)
Terhi Ollila
(T)
Sanna Seitsonen
(S)
Hannu Uusitalo
(H)
Vesa Aaltonen
(V)
Hannele Uusitalo-Jrvinen
(H)
Marja Luodonp
(M)
Nina Hautala
(N)
Erich Strauss
(E)
Hao Chen
(H)
Anna Podgornaia
(A)
Joshua Hoffman
(J)
Kaisa Tasanen
(K)
Laura Huilaja
(L)
Katariina Hannula-Jouppi
(K)
Teea Salmi
(T)
Sirkku Peltonen
(S)
Leena Koulu
(L)
Ilkka Harvima
(I)
Ying Wu
(Y)
David Choy
(D)
Anu Jalanko
(A)
Risto Kajanne
(R)
Ulrike Lyhs
(U)
Mari Kaunisto
(M)
Justin Wade Davis
(JW)
Danjuma Quarless
(D)
Slav Petrovski
(S)
Chia-Yen Chen
(CY)
Paola Bronson
(P)
Robert Yang
(R)
Diana Chang
(D)
Tushar Bhangale
(T)
Emily Holzinger
(E)
Xulong Wang
(X)
Xing Chen
(X)
Sa Hedman
(S)
Kirsi Auro
(K)
Clarence Wang
(C)
Ethan Xu
(E)
Franck Auge
(F)
Clement Chatelain
(C)
Mitja Kurki
(M)
Juha Karjalainen
(J)
Aki Havulinna
(A)
Kimmo Palin
(K)
Priit Palta
(P)
Pietro Della Briotta Parolo
(PDB)
Wei Zhou
(W)
Susanna Lemmel
(S)
Manuel Rivas
(M)
Jarmo Harju
(J)
Arto Lehisto
(A)
Andrea Ganna
(A)
Vincent Llorens
(V)
Antti Karlsson
(A)
Kati Kristiansson
(K)
Kati Hyvrinen
(K)
Jarmo Ritari
(J)
Tiina Wahlfors
(T)
Miika Koskinen
(M)
Katri Pylks
(K)
Marita Kalaoja
(M)
Minna Karjalainen
(M)
Tuomo Mantere
(T)
Eeva Kangasniemi
(E)
Sami Heikkinen
(S)
Eija Laakkonen
(E)
Juha Kononen
(J)
Anu Loukola
(A)
Pivi Laiho
(P)
Tuuli Sistonen
(T)
Essi Kaiharju
(E)
Markku Laukkanen
(M)
Elina Jrvensivu
(E)
Sini Lhteenmki
(S)
Lotta Mnnikk
(L)
Regis Wong
(R)
Hannele Mattsson
(H)
Tero Hiekkalinna
(T)
Manuel Gonzlez Jimnez
(MG)
Kati Donner
(K)
Kalle Prn
(K)
Javier Nunez-Fontarnau
(J)
Elina Kilpelinen
(E)
Timo P Sipil
(TP)
Georg Brein
(G)
Alexander Dada
(A)
Ghazal Awaisa
(G)
Anastasia Shcherban
(A)
Tuomas Sipil
(T)
Hannele Laivuori
(H)
Tuomo Kiiskinen
(T)
Harri Siirtola
(H)
Javier Gracia Tabuenca
(JG)
Lila Kallio
(L)
Sirpa Soini
(S)
Kimmo Pitknen
(K)
Teijo Kuopio
(T)
Références
Peloso, G. M. & Natarajan, P. Insights from population-based analyses of plasma lipids across the allele frequency spectrum. Curr. Opin. Genet. Dev. 50, 1–6 (2018).
pubmed: 29448166
pmcid: 6087690
doi: 10.1016/j.gde.2018.01.003
Natarajan, P. et al. Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat. Commun. 9, 3391 (2018).
pubmed: 30140000
pmcid: 6107638
doi: 10.1038/s41467-018-05747-8
Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).
pubmed: 12730697
doi: 10.1038/ng1161
Brown, M. S. & Goldstein, J. L. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Proc. Natl Acad. Sci. USA 71, 788–792 (1974).
pubmed: 4362634
doi: 10.1073/pnas.71.3.788
pmcid: 388099
Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr. & Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).
pubmed: 16554528
doi: 10.1056/NEJMoa054013
Holmes, M. V. et al. Mendelian randomization of blood lipids for coronary heart disease. Euro. Heart J. 36, 539–550 (2015).
doi: 10.1093/eurheartj/eht571
Ference, B. A. et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N. Engl. J. Med. 375, 2144–2153 (2016).
pubmed: 27959767
doi: 10.1056/NEJMoa1604304
Myocardial Infarction Genetics Consortium, I. et al. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371, 2072–2082 (2014).
doi: 10.1056/NEJMoa1405386
Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1615664 (2017).
Wise, A. L., Gyi, L. & Manolio, T. A. eXclusion: toward integrating the X chromosome in genome-wide association analyses. Am. J. Hum. Genet. 92, 643–647 (2013).
pubmed: 23643377
pmcid: 3644627
doi: 10.1016/j.ajhg.2013.03.017
Coronary Artery Disease Genetics, C. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat. Genet. 43, 339–344 (2011).
doi: 10.1038/ng.782
Consortium, U. K. et al. The UK10K project identifies rare variants in health and disease. Nature 526, 82–90 (2015).
doi: 10.1038/nature14962
Hoffmann, T. J. et al. A large electronic-health-record-based genome-wide study of serum lipids. Nat. Genet. 50, 401–413 (2018).
pubmed: 29507422
pmcid: 5942247
doi: 10.1038/s41588-018-0064-5
Bonas-Guarch, S. et al. Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes. Nat. Commun. 9, 321 (2018).
pubmed: 29358691
pmcid: 5778074
doi: 10.1038/s41467-017-02380-9
McNamara, J. R. et al. Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. Results from the Framingham Offspring Study. Arteriosclerosis 7, 483–490 (1987).
pubmed: 3675308
doi: 10.1161/01.ATV.7.5.483
Schaefer, E. J. et al. Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J. Lipid Res. 35, 779–792 (1994).
pubmed: 8071601
doi: 10.1016/S0022-2275(20)39173-2
Silberbach, M. et al. Cardiovascular Health in Turner Syndrome: a scientific statement from the American Heart Association. Circ. Genom. Precis. Med. 11, e000048 (2018).
pubmed: 30354301
doi: 10.1161/HCG.0000000000000048
Stochholm, K., Juul, S., Juel, K., Naeraa, R. W. & Gravholt, C. H. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J. Clin. Endocrinol. Metab. 91, 3897–3902 (2006).
pubmed: 16849410
doi: 10.1210/jc.2006-0558
Van, P. L., Bakalov, V. K. & Bondy, C. A. Monosomy for the X-chromosome is associated with an atherogenic lipid profile. J. Clin. Endocrinol. Metab. 91, 2867–2870 (2006).
pubmed: 16705071
doi: 10.1210/jc.2006-0503
Cooley, M., Bakalov, V. & Bondy, C. A. Lipid profiles in women with 45,X vs 46,XX primary ovarian failure. JAMA 290, 2127–2128 (2003).
pubmed: 14570947
doi: 10.1001/jama.290.16.2127
Belling, K. et al. Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity. Hum. Mol. Genet. 26, 1219–1229 (2017).
pubmed: 28369266
pmcid: 5390676
doi: 10.1093/hmg/ddx014
Zore, T., Palafox, M. & Reue, K. Sex differences in obesity, lipid metabolism, and inflammation-A role for the sex chromosomes? Mol. Metab. 15, 35–44 (2018).
pubmed: 29706320
pmcid: 6066740
doi: 10.1016/j.molmet.2018.04.003
Link, J. C. et al. Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes. Arterioscler. Thromb. Vasc. Biol. 35, 1778–1786 (2015).
pubmed: 26112012
pmcid: 4668127
doi: 10.1161/ATVBAHA.115.305460
Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590, 290–299 (2021).
pubmed: 33568819
pmcid: 7875770
doi: 10.1038/s41586-021-03205-y
Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).
pubmed: 30305743
pmcid: 6786975
doi: 10.1038/s41586-018-0579-z
Krokstad, S. et al. Cohort Profile: the HUNT Study, Norway. Int. J. Epidemiol. 42, 968–977 (2013).
pubmed: 22879362
doi: 10.1093/ije/dys095
Tabassum, R. et al. Genetic architecture of human plasma lipidome and its link to cardiovascular disease. Nat. Commun. 10, 4329 (2019).
pubmed: 31551469
pmcid: 6760179
doi: 10.1038/s41467-019-11954-8
Emdin, C. A. et al. Genetic association of waist-to-hip ratio with cardiometabolic traits, type 2 diabetes, and coronary heart disease. JAMA 317, 626–634 (2017).
pubmed: 28196256
pmcid: 5571980
doi: 10.1001/jama.2016.21042
Lotta, L. A. et al. Association of genetic variants related to gluteofemoral vs abdominal fat distribution with type 2 diabetes, coronary disease, and cardiovascular risk factors. JAMA 320, 2553–2563 (2018).
pubmed: 30575882
pmcid: 6583513
doi: 10.1001/jama.2018.19329
Dahlman, I. et al. Numerous genes in loci associated with body fat distribution are linked to adipose function. Diabetes 65, 433–437 (2016).
pubmed: 26798124
doi: 10.2337/db15-0828
Ambele, M. A., Dessels, C., Durandt, C. & Pepper, M. S. Genome-wide analysis of gene expression during adipogenesis in human adipose-derived stromal cells reveals novel patterns of gene expression during adipocyte differentiation. Stem Cell Res. 16, 725–734 (2016).
pubmed: 27108396
doi: 10.1016/j.scr.2016.04.011
Gustafson, B. et al. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes 64, 1670–1681 (2015).
pubmed: 25605802
doi: 10.2337/db14-1127
Dahlman, I. et al. Functional annotation of the human fat cell secretome. Arch Physiol. Biochem. 118, 84–91 (2012).
pubmed: 22616691
doi: 10.3109/13813455.2012.685745
Menni, C. et al. Circulating proteomic signatures of chronological age. J. Gerontol. A Biol. Sci. Med. Sci. 70, 809–816 (2015).
pubmed: 25123647
doi: 10.1093/gerona/glu121
Ference, B. A. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Euro. Heart J. 38, 2459–2472 (2017).
doi: 10.1093/eurheartj/ehx144
Liu, D. J. et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 49, 1758–1766 (2017).
pubmed: 29083408
pmcid: 5709146
doi: 10.1038/ng.3977
Lotta, L. A. et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis. JAMA 316, 1383–1391 (2016).
pubmed: 27701660
pmcid: 5386134
doi: 10.1001/jama.2016.14568
Sattar, N. et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375, 735–742 (2010).
pubmed: 20167359
doi: 10.1016/S0140-6736(09)61965-6
Swerdlow, D. I. et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 385, 351–361 (2015).
pubmed: 25262344
pmcid: 4322187
doi: 10.1016/S0140-6736(14)61183-1
Lotta, L. A. et al. Association of genetically enhanced lipoprotein lipase-mediated lipolysis and low-density lipoprotein cholesterol-lowering alleles with risk of coronary disease and type 2 diabetes. JAMA Cardiol. 3, 957–966 (2018).
pubmed: 30326043
pmcid: 6217943
doi: 10.1001/jamacardio.2018.2866
White, J. et al. Association of lipid fractions with risks for coronary artery disease and diabetes. JAMA Cardiol. 1, 692–699 (2016).
pubmed: 27487401
pmcid: 5642865
doi: 10.1001/jamacardio.2016.1884
Klimentidis, Y. C., Chougule, A., Arora, A., Frazier-Wood, A. C. & Hsu, C. H. Triglyceride-increasing alleles associated with protection against type-2 diabetes. PLoS Genet. 11, e1005204 (2015).
pubmed: 26020539
pmcid: 4447354
doi: 10.1371/journal.pgen.1005204
Dewey, F. E. et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N. Engl. J. Med. 374, 1123–1133 (2016).
pubmed: 26933753
pmcid: 4900689
doi: 10.1056/NEJMoa1510926
Stitziel, N. O. et al. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N. Engl. J. Med. 374, 1134–1144 (2016).
pubmed: 26934567
doi: 10.1056/NEJMoa1507652
Dewey, F. E. et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377, 211–221 (2017).
pubmed: 28538136
pmcid: 5800308
doi: 10.1056/NEJMoa1612790
Stitziel, N. O. et al. ANGPTL3 deficiency and protection against coronary artery disease. J. Am. College Cardiol. 69, 2054–2063 (2017).
doi: 10.1016/j.jacc.2017.02.030
Sniderman, A. D. et al. Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk. Am. J. Cardiol. 91, 1173–1177 (2003).
pubmed: 12745098
doi: 10.1016/S0002-9149(03)00262-5
Wilkins, J. T., Li, R. C., Sniderman, A., Chan, C. & Lloyd-Jones, D. M. Discordance between apolipoprotein B and LDL-cholesterol in young adults predicts coronary artery calcification: The CARDIA Study. J. Am. College Cardiol. 67, 193–201 (2016).
doi: 10.1016/j.jacc.2015.10.055
Wagner, A. M. et al. LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in type 2 diabetes. Acta Diabetol. 39, 215–220 (2002).
pubmed: 12486496
doi: 10.1007/s005920200037
Tani, S. et al. Relation between low-density lipoprotein cholesterol/apolipoprotein B ratio and triglyceride-rich lipoproteins in patients with coronary artery disease and type 2 diabetes mellitus: a cross-sectional study. Cardiovasc. Diabetol. 16, 123 (2017).
pubmed: 28969633
pmcid: 5625702
doi: 10.1186/s12933-017-0606-7
Sakuta, H. et al. Ventroptin: a BMP-4 antagonist expressed in a double-gradient pattern in the retina. Science 293, 111–115 (2001).
pubmed: 11441185
doi: 10.1126/science.1058379
Webb, T. R. et al. X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am. J. Hum. Genet. 90, 247–259 (2012).
pubmed: 22284829
pmcid: 3276677
doi: 10.1016/j.ajhg.2011.12.019
Gao, F. et al. XWAS: A software toolset for genetic data analysis and association studies of the X chromosome. J. Hered. 106, 666–671 (2015).
pubmed: 26268243
pmcid: 4567842
doi: 10.1093/jhered/esv059
Ma, L., Hoffman, G. & Keinan, A. X-inactivation informs variance-based testing for X-linked association of a quantitative trait. BMC Genomics 16, 241 (2015).
pubmed: 25880738
pmcid: 4381508
doi: 10.1186/s12864-015-1463-y
Sudlow, C. et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med. 12, e1001779 (2015).
pubmed: 25826379
pmcid: 4380465
doi: 10.1371/journal.pmed.1001779
Regier, A. A. et al. Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects. Nat. Commun. 9, 4038 (2018).
pubmed: 30279509
pmcid: 6168605
doi: 10.1038/s41467-018-06159-4
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
pubmed: 19451168
pmcid: 2705234
doi: 10.1093/bioinformatics/btp324
Jun, G., Wing, M. K., Abecasis, G. R. & Kang, H. M. An efficient and scalable analysis framework for variant extraction and refinement from population-scale DNA sequence data. Genome Res. 25, 918–925 (2015).
pubmed: 25883319
pmcid: 4448687
doi: 10.1101/gr.176552.114
Emdin, C. A. et al. Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. Nat. Commun. 9, 1613 (2018).
pubmed: 29691411
pmcid: 5915445
doi: 10.1038/s41467-018-03911-8
Klarin, D. et al. Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease. Nat. Genet. https://doi.org/10.1038/ng.3914 (2017).
Denny, J. C. et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat. Biotechnol. 31, 1102–1110 (2013).
pubmed: 24270849
pmcid: 3969265
doi: 10.1038/nbt.2749
West, J. et al. Feasibility of MR-based body composition analysis in large scale population studies. PloS ONE 11, e0163332 (2016).
pubmed: 27662190
pmcid: 5035023
doi: 10.1371/journal.pone.0163332
Chua, S. Y. L. et al. Cohort profile: design and methods in the eye and vision consortium of UK Biobank. BMJ Open 9, e025077 (2019).
pubmed: 30796124
pmcid: 6398663
doi: 10.1136/bmjopen-2018-025077
Zhou, W. et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat. Genet. 50, 1335–1341 (2018).
pubmed: 30104761
pmcid: 6119127
doi: 10.1038/s41588-018-0184-y
Loh, P. R. et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat. Genet. 47, 284–290 (2015).
pubmed: 25642633
pmcid: 4342297
doi: 10.1038/ng.3190
Mackey, R. H. et al. Lipoprotein particles and incident type 2 diabetes in the multi-ethnic study of atherosclerosis. Diabetes Care 38, 628–636 (2015).
pubmed: 25592196
pmcid: 4370328
doi: 10.2337/dc14-0645
Otvos, J. D., Jeyarajah, E. J. & Cromwell, W. C. Measurement issues related to lipoprotein heterogeneity. Am. J. Cardiol. 90, 22i–29i (2002).
pubmed: 12419478
doi: 10.1016/S0002-9149(02)02632-2
Hoogeveen, R. C. et al. Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study. Arterioscler. Thromb. Vasc. Biol. 34, 1069–1077 (2014).
pubmed: 24558110
pmcid: 3999643
doi: 10.1161/ATVBAHA.114.303284
Conomos, M. P., Miller, M. B. & Thornton, T. A. Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness. Genet. Epidemiol. 39, 276–293 (2015).
pubmed: 25810074
pmcid: 4836868
doi: 10.1002/gepi.21896
Brody, J. A. et al. Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology. Nat. Genet. 49, 1560–1563 (2017).
pubmed: 29074945
pmcid: 5720686
doi: 10.1038/ng.3968
Karczewski, K. J. LOFTEE (Loss-Of-Function Transcript Effect Estimator). https://github.com/konradjk/loftee (2015).
Liu, X., Wu, C., Li, C. & Boerwinkle, E. dbNSFP v3.0: A one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum. Mutat. 37, 235–241 (2016).
pubmed: 26555599
pmcid: 4752381
doi: 10.1002/humu.22932
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6, 80–92 (2012).
pubmed: 22728672
pmcid: 3679285
doi: 10.4161/fly.19695