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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Titill: Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Höfundur: Kanoni, Stavroula
Graham, Sarah E.
Wang, Yuxuan
Surakka, Ida
Ramdas, Shweta
Zhu, Xiang
Clarke, Shoa L.
Bhatti, Konain Fatima
Vedantam, Sailaja
Winkler, Thomas W.
... 529 fleiri höfundar Sýna alla höfunda
Útgáfa: 2022-12
Tungumál: Enska
Umfang: 2235978
Svið: Engineering and Natural Sciences
Health Sciences
Deild: Other departments
Faculty of Medicine
Birtist í: Genome Biology; 23(1)
ISSN: 1474-7596
DOI: 10.1186/s13059-022-02837-1
Efnisorð: Lífefna- og sameindalíffræði; Cholesterol; Genetics; Genome-wide association study; GWAS; Lipids; Ecology, Evolution, Behavior and Systematics; Genetics; Cell Biology
URI: https://hdl.handle.net/20.500.11815/4020

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Kanoni , S , Graham , S E , Wang , Y , Surakka , I , Ramdas , S , Zhu , X , Clarke , S L , Bhatti , K F , Vedantam , S , Winkler , T W , Locke , A E , Marouli , E , Zajac , G J M , Wu , K H H , Ntalla , I , Hui , Q , Klarin , D , Hilliard , A T , Wang , Z , Xue , C , Thorleifsson , G , Helgadottir , A , Gudbjartsson , D F , Holm , H , Ólafsson , Í , Hwang , M Y , Han , S , Akiyama , M , Sakaue , S , Terao , C , Kanai , M , Zhou , W , Brumpton , B M , Rasheed , H , Havulinna , A S , Veturi , Y , Pacheco , J A , Rosenthal , E A , Lingren , T , Feng , Q P , Kullo , I J , Narita , A , Takayama , J , Martin , H C , Hunt , K A , Trivedi , B , Haessler , J , Giulianini , F , Bradford , Y , Miller , J E , Campbell , A , Lin , K , Millwood , I Y , Rasheed , A , Hindy , G , Faul , J D , Zhao , W , Weir , D R , Turman , C , Huang , H , Graff , M , Choudhury , A , Sengupta , D , Mahajan , A , Brown , M R , Zhang , W , Yu , K , Schmidt , E M , Pandit , A , Gustafsson , S , Yin , X , Luan , J , Zhao , J H , Matsuda , F , Jang , H M , Yoon , K , Medina-Gomez , C , Pitsillides , A , Hottenga , J J , Wood , A R , Ji , Y , Gao , Z , Haworth , S , Yousri , N A , Mitchell , R E , Chai , J F , Aadahl , M , Bjerregaard , A A , Yao , J , Manichaikul , A , Hwu , C M , Hung , Y J , Warren , H R , Ramirez , J , Bork-Jensen , J , Kårhus , L L , Goel , A , Sabater-Lleal , M , Noordam , R , Mauro , P , Matteo , F , McDaid , A F , Marques-Vidal , P , Wielscher , M , Trompet , S , Sattar , N , Møllehave , L T , Munz , M , Zeng , L , Huang , J , Yang , B , Poveda , A , Kurbasic , A , Lamina , C , Forer , L , Scholz , M , Galesloot , T E , Bradfield , J P , Ruotsalainen , S E , Daw , EW W , Zmuda , J M , Mitchell , J S , Fuchsberger , C , Christensen , H , Brody , J A , Vazquez-Moreno , M , Feitosa , M F , Wojczynski , M K , Wang , Z , Preuss , M H , Mangino , M , Christofidou , P , Verweij , N , Benjamins , J W , Engmann , J , Tsao , N L , Verma , A , Slieker , R C , Lo , K S , Zilhao , N R , Le , P , Kleber , M E , Delgado , G E , Huo , S , Ikeda , D D , Iha , H , Yang , J , Liu , J , Demirkan , A , Leonard , H L , Marten , J , Frank , M , Schmidt , B , Smyth , L J , Cañadas-Garre , M , Wang , C , Nakatochi , M , Wong , A , Hutri-Kähönen , N , Sim , X , Xia , R , Huerta-Chagoya , A , Fernandez-Lopez , J C , Lyssenko , V , Nongmaithem , S S , Bayyana , S , Stringham , H M , Irvin , M R , Oldmeadow , C , Kim , H N , Ryu , S , Timmers , P R H J , Arbeeva , L , Dorajoo , R , Lange , L A , Prasad , G , Lorés-Motta , L , Pauper , M , Long , J , Li , X , Theusch , E , Takeuchi , F , Spracklen , C N , Loukola , A , Bollepalli , S , Warner , S C , Wang , Y X , Wei , W B , Nutile , T , Ruggiero , D , Sung , Y J , Chen , S , Liu , F , Yang , J , Kentistou , K A , Banas , B , Nardone , G G , Meidtner , K , Bielak , L F , Smith , J A , Hebbar , P , Farmaki , A E , Hofer , E , Lin , M , Concas , M P , Vaccargiu , S , van der Most , P J , Pitkänen , N , Cade , B E , van der Laan , S W , Chitrala , K N , Weiss , S , Bentley , A R , Doumatey , A P , Adeyemo , A A , Lee , J Y , Petersen , E R B , Nielsen , A A , Choi , H S , Nethander , M , Freitag-Wolf , S , Southam , L , Rayner , N W , Wang , C A , Lin , S Y , Wang , J S , Couture , C , Lyytikäinen , L P , Nikus , K , Cuellar-Partida , G , Vestergaard , H , Hidalgo , B , Giannakopoulou , O , Cai , Q , Obura , M O , van Setten , J , Li , X , Liang , J , Tang , H , Terzikhan , N , Shin , J H , Jackson , R D , Reiner , A P , Martin , L W , Chen , Z , Li , L , Kawaguchi , T , Thiery , J , Bis , J C , Launer , L J , Li , H , Nalls , M A , Raitakari , O T , Ichihara , S , Wild , S H , Nelson , C P , Campbell , H , Jäger , S , Nabika , T , Al-Mulla , F , Niinikoski , H , Braund , P S , Kolcic , I , Kovacs , P , Giardoglou , T , Katsuya , T , de Kleijn , D , de Borst , G J , Kim , E K , Adams , H H H , Ikram , M A , Zhu , X , Asselbergs , F W , Kraaijeveld , A O , Beulens , J W J , Shu , X O , Rallidis , L S , Pedersen , O , Hansen , T , Mitchell , P , Hewitt , A W , Kähönen , M , Pérusse , L , Bouchard , C , Tönjes , A , Chen , Y D I , Pennell , C E , Mori , T A , Lieb , W , Franke , A , Ohlsson , C , Mellström , D , Cho , Y S , Lee , H , Yuan , J M , Koh , W P , Rhee , S Y , Woo , J T , Heid , I M , Stark , K J , Zimmermann , M E , Völzke , H , Homuth , G , Evans , M K , Zonderman , A B , Polasek , O , Pasterkamp , G , Hoefer , I E , Redline , S , Pahkala , K , Oldehinkel , A J , Snieder , H , Biino , G , Schmidt , R , Schmidt , H , Bandinelli , S , Dedoussis , G , Thanaraj , T A , Kardia , S L R , Peyser , P A , Kato , N , Schulze , M B , Girotto , G , Böger , C A , Jung , B , Joshi , P K , Bennett , D A , De Jager , P L , Lu , X , Mamakou , V , Brown , M , Caulfield , M J , Munroe , P B , Guo , X , Ciullo , M , Jonas , J B , Samani , N J , Kaprio , J , Pajukanta , P , Tusié-Luna , T , Aguilar-Salinas , C A , Adair , L S , Bechayda , S A , de Silva , H J , Wickremasinghe , A R , Krauss , R M , Wu , J Y , Zheng , W , Hollander , A I , Bharadwaj , D , Correa , A , Wilson , J G , Lind , L , Heng , C K , Nelson , A E , Golightly , Y M , Wilson , J F , Penninx , B , Kim , H L , Attia , J , Scott , R J , Rao , D C , Arnett , D K , Hunt , S C , Walker , M , Koistinen , H A , Chandak , G R , Mercader , J M , Costanzo , M C , Jang , D , Burtt , N P , Villalpando , C G , Orozco , L , Fornage , M , Tai , ES S , van Dam , R M , Lehtimäki , T , Chaturvedi , N , Yokota , M , Liu , J , Reilly , D F , McKnight , A J , Kee , F , Jöckel , K H , McCarthy , M I , Palmer , C N A , Vitart , V , Hayward , C , Simonsick , E , van Duijn , C M , Jin , Z B , Qu , J , Hishigaki , H , Lin , X , März , W , Gudnason , V , Tardif , J C , Lettre , G , Hart , L M , Elders , P J M , Damrauer , S M , Kumari , M , Kivimaki , M , van der Harst , P , Spector , T D , Loos , R J F , Province , M A , Parra , E J , Cruz , M , Psaty , B M , Brandslund , I , Pramstaller , P P , Rotimi , C N , Christensen , K , Ripatti , S , Widén , E , Hakonarson , H , Grant , S F A , Kiemeney , L A L M , de Graaf , J , Loeffler , M , Kronenberg , F , Gu , D , Erdmann , J , Schunkert , H , Franks , P W , Linneberg , A , Jukema , J W , Khera , A V , Männikkö , M , Jarvelin , M R , Kutalik , Z , Francesco , C , Mook-Kanamori , D O , van Dijk , K W , Watkins , H , Strachan , D P , Grarup , N , Sever , P , Poulter , N , Chuang , L M , Rotter , J I , Dantoft , T M , Karpe , F , Neville , M J , Timpson , N J , Cheng , C Y , Wong , T Y , Khor , C C , Li , H , Sabanayagam , C , Peters , A , Gieger , C , Hattersley , A T , Pedersen , N L , Magnusson , P K E , Boomsma , D I , Willemsen , A H M , Cupples , LA A , van Meurs , J B J , Ghanbari , M , Gordon-Larsen , P , Huang , W , Kim , Y J , Tabara , Y , Wareham , N J , Langenberg , C , Zeggini , E , Kuusisto , J , Laakso , M , Ingelsson , E , Abecasis , G , Chambers , J C , Kooner , J S , de Vries , P S , Morrison , A C , Hazelhurst , S , Ramsay , M , North , K E , Daviglus , M , Kraft , P , Martin , N G , Whitfield , J B , Abbas , S , Saleheen , D , Walters , R G , Holmes , M V , Black , C , Smith , B H , Baras , A , Justice , A E , Buring , J E , Ridker , P M , Chasman , D I , Kooperberg , C , Tamiya , G , Yamamoto , M , van Heel , D A , Trembath , R C , Wei , W Q , Jarvik , G P , Namjou , B , Hayes , M G , Ritchie , M D , Jousilahti , P , Salomaa , V , Hveem , K , Åsvold , B O , Kubo , M , Kamatani , Y , Okada , Y , Murakami , Y , Kim , B J , Thorsteinsdottir , U , Stefansson , K , Zhang , J , Chen , YE E , Ho , Y L , Lynch , J A , Rader , D J , Tsao , P S , Chang , K M , Cho , K , O’Donnell , C J , Gaziano , J M , Wilson , P W F , Frayling , T M , Hirschhorn , J N , Kathiresan , S , Mohlke , K L , Sun , Y V , Morris , A P , Boehnke , M , Brown , C D , Natarajan , P , Deloukas , P , Willer , C J , Assimes , T L & Peloso , G M 2022 , ' Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis ' , Genome Biology , vol. 23 , no. 1 , 268 . https://doi.org/10.1186/s13059-022-02837-1

Útdráttur:

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Athugasemdir:

Funding Information: GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file : Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Publisher Copyright: © 2022, The Author(s).

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