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

Stavroula Kanoni; Sarah E. Graham; Yuxuan Wang; Jouke Jan Hottenga; Brenda Penninx; Dorret I. Boomsma; Gonneke Willemsen; Cristen J. Willer; Themistocles L. Assimes; Gina M. Peloso; Global Lipids Genetics Consortium

doi:10.1186/s13059-022-02837-1

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

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Jouke Jan Hottenga, Brenda Penninx, Dorret I. Boomsma, Gonneke Willemsen, Cristen J. Willer^*, Themistocles L. Assimes, Gina M. Peloso, Global Lipids Genetics Consortium

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	268
Number of pages	42
Journal	Genome Biology
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s13059-022-02837-1
Publication status	Published - 27 Dec 2022

Bibliographical note

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).

Funding

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.

Funders	Funder number
Academy of Finland Center of Excellence in Complex Disease Genetics	312062
Finnish innovation fund Sitra
ISCIII Spanish Health Institute	CP17/00142
University of Bristol NIHR Biomedical Research Centre	BRC-1215–2001
Westlake Education Foundation
American Diabetes Association	19-ICTS-068
National Human Genome Research Institute	U01HG011723
American Heart Association	WT 217065/Z/19/Z, Z01HG200362, 202802/Z/16/Z, 15POST24470131, 17POST33650016
Helsingin Yliopisto
Finska Läkaresällskapet
Wellcome Trust	201543/B/16/Z
H2020 Marie Skłodowska-Curie Actions	786833
Seventh Framework Programme	608765
Virginia Marine Resources Commission	MC_UU_00011
National Institute for Health and Care Research	18CDA34110116
British Heart Foundation	FS/14/66/3129, R01HL105756
Cancer Research UK	C18281/A19169
University of Bristol	MC_UU_00011/1
European Social Fund
Seventh Framework Programme	HEALTH-F2-2013–601456
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Novo Nordisk Fonden	NNF15CC0018486

Keywords

Cholesterol
Genetics
Genome-wide association study
GWAS
Lipids

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13059-022-02837-1

Persistent URL (handle)

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Cite this

Kanoni, S., Graham, S. E., Wang, Y., Hottenga, J. J., Penninx, B., Boomsma, D. I., Willemsen, G., Willer, C. J., Assimes, T. L., Peloso, G. M., & Global Lipids Genetics Consortium (2022). Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. Genome Biology, 23(1), Article 268. https://doi.org/10.1186/s13059-022-02837-1

@article{9ce639f64d7e4365a087bce0a6721e09,

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

abstract = "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.",

keywords = "Cholesterol, Genetics, Genome-wide association study, GWAS, Lipids",

author = "Stavroula Kanoni and Graham, {Sarah E.} and Yuxuan Wang and Ida Surakka and Shweta Ramdas and Xiang Zhu and Clarke, {Shoa L.} and Bhatti, {Konain Fatima} and Sailaja Vedantam and Winkler, {Thomas W.} and Locke, {Adam E.} and Eirini Marouli and Zajac, {Greg J.M.} and Wu, {Kuan Han H.} and Ioanna Ntalla and Qin Hui and Derek Klarin and Hilliard, {Austin T.} and Zeyuan Wang and Chao Xue and Gudmar Thorleifsson and Anna Helgadottir and Gudbjartsson, {Daniel F.} and Hilma Holm and Isleifur Olafsson and Hwang, {Mi Yeong} and Sohee Han and Masato Akiyama and Saori Sakaue and Chikashi Terao and Masahiro Kanai and Wei Zhou and Brumpton, {Ben M.} and Humaira Rasheed and Havulinna, {Aki S.} and Yogasudha Veturi and Pacheco, {Jennifer Allen} and Rosenthal, {Elisabeth A.} and Todd Lingren and Feng, {Qi Ping} and Kullo, {Iftikhar J.} and Akira Narita and Jun Takayama and Martin, {Hilary C.} and Hunt, {Karen A.} and Bhavi Trivedi and Jeffrey Haessler and Franco Giulianini and Yuki Bradford and Miller, {Jason E.} and Archie Campbell and Kuang Lin and Millwood, {Iona Y.} and Asif Rasheed and George Hindy and Faul, {Jessica D.} and Wei Zhao and Weir, {David R.} and Constance Turman and Hongyan Huang and Mariaelisa Graff and Ananyo Choudhury and Dhriti Sengupta and Anubha Mahajan and Brown, {Michael R.} and Weihua Zhang and Ketian Yu and Schmidt, {Ellen M.} and Anita Pandit and Stefan Gustafsson and Xianyong Yin and Jian{\textquoteright}an Luan and Zhao, {Jing Hua} and Fumihiko Matsuda and Jang, {Hye Mi} and Kyungheon Yoon and Carolina Medina-Gomez and Achilleas Pitsillides and Hottenga, {Jouke Jan} and Wood, {Andrew R.} and Yingji Ji and Zishan Gao and Simon Haworth and Yousri, {Noha A.} and Mitchell, {Ruth E.} and Chai, {Jin Fang} and Mette Aadahl and Bjerregaard, {Anne A.} and Jie Yao and Ani Manichaikul and Hwu, {Chii Min} and Hung, {Yi Jen} and Warren, {Helen R.} and Julia Ramirez and Jette Bork-Jensen and K{\aa}rhus, {Line L.} and Anuj Goel and Maria Sabater-Lleal and 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Setten}, Jessica and Xiaoyin Li and Jingjing Liang and Hua Tang and Natalie Terzikhan and Shin, {Jae Hun} and Jackson, {Rebecca D.} and Reiner, {Alexander P.} and Martin, {Lisa Warsinger} and Zhengming Chen and Liming Li and Takahisa Kawaguchi and Joachim Thiery and Bis, {Joshua C.} and Launer, {Lenore J.} and Huaixing Li and Nalls, {Mike A.} and Raitakari, {Olli T.} and Sahoko Ichihara and Wild, {Sarah H.} and Nelson, {Christopher P.} and Harry Campbell and Susanne J{\"a}ger and Toru Nabika and Fahd Al-Mulla and Harri Niinikoski and Braund, {Peter S.} and Ivana Kolcic and Peter Kovacs and Tota Giardoglou and Tomohiro Katsuya and {de Kleijn}, Dominique and {de Borst}, {Gert J.} and Kim, {Eung Kweon} and Adams, {Hieab H.H.} and Ikram, {M. 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Janaka} and Wickremasinghe, {Ananda R.} and Krauss, {Ronald M.} and Wu, {Jer Yuarn} and Wei Zheng and Hollander, {Anneke Iden} and Dwaipayan Bharadwaj and Adolfo Correa and Wilson, {James G.} and Lars Lind and Heng, {Chew Kiat} and Nelson, {Amanda E.} and Golightly, {Yvonne M.} and Wilson, {James F.} and Brenda Penninx and Kim, {Hyung Lae} and John Attia and Scott, {Rodney J.} and Rao, {D. C.} and Arnett, {Donna K.} and Hunt, {Steven C.} and Mark Walker and Koistinen, {Heikki A.} and Chandak, {Giriraj R.} and Mercader, {Josep M.} and Costanzo, {Maria C.} and Dongkeun Jang and Burtt, {No{\"e}l P.} and Villalpando, {Clicerio Gonzalez} and Lorena Orozco and Myriam Fornage and Tai, {EShyong S.} and {van Dam}, {Rob M.} and Terho Lehtim{\"a}ki and Nish Chaturvedi and Mitsuhiro Yokota and Jianjun Liu and Reilly, {Dermot F.} and McKnight, {Amy Jayne} and Frank Kee and J{\"o}ckel, {Karl Heinz} and McCarthy, {Mark I.} and Palmer, {Colin N.A.} and Veronique Vitart and Caroline Hayward and Eleanor Simonsick and {van Duijn}, {Cornelia M.} and Jin, {Zi Bing} and Jia Qu and Haretsugu Hishigaki and Xu Lin and Winfried M{\"a}rz and Vilmundur Gudnason and Tardif, {Jean Claude} and Guillaume Lettre and Hart, {Leen M.{\textquoteleft}t} and Elders, {Petra J.M.} and Damrauer, {Scott M.} and Meena Kumari and Mika Kivimaki and {van der Harst}, Pim and Spector, {Tim D.} and Loos, {Ruth J.F.} and Province, {Michael A.} and Parra, {Esteban J.} and Miguel Cruz and Psaty, {Bruce M.} and Ivan Brandslund and Pramstaller, {Peter P.} and Rotimi, {Charles N.} and Kaare Christensen and Samuli Ripatti and Elisabeth Wid{\'e}n and Hakon Hakonarson and Grant, {Struan F.A.} and Kiemeney, {Lambertus A.L.M.} and {de Graaf}, Jacqueline and Markus Loeffler and Florian Kronenberg and Dongfeng Gu and Jeanette Erdmann and Heribert Schunkert and Franks, {Paul W.} and Allan Linneberg and Jukema, {J. Wouter} and Khera, {Amit V.} and Minna M{\"a}nnikk{\"o} and Jarvelin, {Marjo Riitta} and Zoltan Kutalik and Cucca Francesco and Mook-Kanamori, {Dennis O.} and {van Dijk}, {Ko Willems} and Hugh Watkins and Strachan, {David P.} and Niels Grarup and Peter Sever and Neil Poulter and Chuang, {Lee Ming} and Rotter, {Jerome I.} and Dantoft, {Thomas M.} and Fredrik Karpe and Neville, {Matt J.} and Timpson, {Nicholas J.} and Cheng, {Ching Yu} and Wong, {Tien Yin} and Khor, {Chiea Chuen} and Hengtong Li and Charumathi Sabanayagam and Annette Peters and Christian Gieger and Hattersley, {Andrew T.} and Pedersen, {Nancy L.} and Magnusson, {Patrik K.E.} and Boomsma, {Dorret I.} and Gonneke Willemsen and Cupples, {LAdrienne A.} and {van Meurs}, {Joyce B.J.} and Mohsen Ghanbari and Penny Gordon-Larsen and Wei Huang and Kim, {Young Jin} and Yasuharu Tabara and Wareham, {Nicholas J.} and Claudia Langenberg and Eleftheria Zeggini and Johanna Kuusisto and Markku Laakso and Erik Ingelsson and Goncalo Abecasis and Chambers, {John C.} and Kooner, {Jaspal S.} and {de Vries}, {Paul S.} and Morrison, {Alanna C.} and Scott Hazelhurst and Mich{\`e}le Ramsay and North, {Kari E.} and Martha Daviglus and Peter Kraft and Martin, {Nicholas G.} and Whitfield, {John B.} and Shahid Abbas and Danish Saleheen and Walters, {Robin G.} and Holmes, {Michael V.} and Corri Black and Smith, {Blair H.} and Aris Baras and Justice, {Anne E.} and Buring, {Julie E.} and Ridker, {Paul M.} and Chasman, {Daniel I.} and Charles Kooperberg and Gen Tamiya and Masayuki Yamamoto and {van Heel}, {David A.} and Trembath, {Richard C.} and Wei, {Wei Qi} and Jarvik, {Gail P.} and Bahram Namjou and Hayes, {M. Geoffrey} and Ritchie, {Marylyn D.} and Pekka Jousilahti and Veikko Salomaa and Kristian Hveem and {\AA}svold, {Bj{\o}rn Olav} and Michiaki Kubo and Yoichiro Kamatani and Yukinori Okada and Yoshinori Murakami and Kim, {Bong Jo} and Unnur Thorsteinsdottir and Kari Stefansson and Jifeng Zhang and Chen, {YEugene E.} and Ho, {Yuk Lam} and Lynch, {Julie A.} and Rader, {Daniel J.} and Tsao, {Philip S.} and Chang, {Kyong Mi} and Kelly Cho and O{\textquoteright}Donnell, {Christopher J.} and Gaziano, {John M.} and Wilson, {Peter W.F.} and Frayling, {Timothy M.} and Hirschhorn, {Joel N.} and Sekar Kathiresan and Mohlke, {Karen L.} and Sun, {Yan V.} and Morris, {Andrew P.} and Michael Boehnke and Brown, {Christopher D.} and Pradeep Natarajan and Panos Deloukas and Willer, {Cristen J.} and Assimes, {Themistocles L.} and Peloso, {Gina M.} and {Global Lipids Genetics Consortium}",

note = "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{\textquoteright}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 L{\"a}kares{\"a}llskapet. 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{\textquoteright}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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

day = "27",

doi = "10.1186/s13059-022-02837-1",

language = "English",

volume = "23",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "Springer Verlag",

number = "1",

}

TY - JOUR

T1 - Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

AU - Kanoni, Stavroula

AU - Graham, Sarah E.

AU - Wang, Yuxuan

AU - Surakka, Ida

AU - Ramdas, Shweta

AU - Zhu, Xiang

AU - Clarke, Shoa L.

AU - Bhatti, Konain Fatima

AU - Vedantam, Sailaja

AU - Winkler, Thomas W.

AU - Locke, Adam E.

AU - Marouli, Eirini

AU - Zajac, Greg J.M.

AU - Wu, Kuan Han H.

AU - Ntalla, Ioanna

AU - Hui, Qin

AU - Klarin, Derek

AU - Hilliard, Austin T.

AU - Wang, Zeyuan

AU - Xue, Chao

AU - Thorleifsson, Gudmar

AU - Helgadottir, Anna

AU - Gudbjartsson, Daniel F.

AU - Holm, Hilma

AU - Olafsson, Isleifur

AU - Hwang, Mi Yeong

AU - Han, Sohee

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AU - Peloso, Gina M.

AU - Global Lipids Genetics Consortium

N1 - 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).

PY - 2022/12/27

Y1 - 2022/12/27

N2 - 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.

AB - 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.

KW - Cholesterol

KW - Genetics

KW - Genome-wide association study

KW - GWAS

KW - Lipids

UR - http://www.scopus.com/inward/record.url?scp=85144774123&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85144774123&partnerID=8YFLogxK

U2 - 10.1186/s13059-022-02837-1

DO - 10.1186/s13059-022-02837-1

M3 - Article

C2 - 36575460

AN - SCOPUS:85144774123

SN - 1474-7596

VL - 23

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 268

ER -

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

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