Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
Cholesterol
GWAS
Genetics
Genome-wide association study
Lipids
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
27 12 2022
27 12 2022
Historique:
received:
05
04
2022
accepted:
06
12
2022
entrez:
27
12
2022
pubmed:
28
12
2022
medline:
30
12
2022
Statut:
epublish
Résumé
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. 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. Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Sections du résumé
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.
Identifiants
pubmed: 36575460
doi: 10.1186/s13059-022-02837-1
pii: 10.1186/s13059-022-02837-1
pmc: PMC9793579
doi:
Substances chimiques
Lipids
0
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
268Subventions
Organisme : BLRD VA
ID : I01 BX004821
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG011172
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD030880
Pays : United States
Organisme : Medical Research Council
ID : G0601463
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL142302
Pays : United States
Organisme : British Heart Foundation
ID : FS/14/66/3129
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK075787
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG011723
Pays : United States
Organisme : Wellcome Trust
ID : 201543/B/16/Z
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK093757
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072975
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142711
Pays : United States
Organisme : Wellcome Trust
ID : 217065/Z/19/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00006/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00011
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL153805
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK072193
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_20026
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG065357
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127564
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00019/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R024227/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18281/A19169
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : Z01 HG200362
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062370
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
Organisme : CSRD VA
ID : IK2 CX001780
Pays : United States
Organisme : BLRD VA
ID : I01 BX003340
Pays : United States
Organisme : Department of Health
ID : BRC-1215-2001
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/14/5/30893
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00007/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S011676/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U54 HG006938
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NHLBI NIH HHS
ID : R03 HL154284
Pays : United States
Organisme : Wellcome Trust
ID : 202802/Z/16/Z
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Pharmacogenet Genomics. 2012 Mar;22(3):219-28
pubmed: 22237549
Nat Med. 2020 Feb;26(2):252-258
pubmed: 32042192
Hum Mol Genet. 2018 Mar 15;27(6):1122
pubmed: 29351605
N Engl J Med. 2010 Dec 2;363(23):2220-7
pubmed: 20942659
Front Med (Lausanne). 2022 Jan 11;8:798334
pubmed: 35087849
Eur J Hum Genet. 2021 Jan;29(1):154-163
pubmed: 32873964
Ann Epidemiol. 1992 Jan-Mar;2(1-2):23-8
pubmed: 1342260
N Engl J Med. 2020 Apr 16;382(16):1507-1519
pubmed: 32187462
Curr Opin Lipidol. 2021 Apr 1;32(2):141-146
pubmed: 33651746
Nat Protoc. 2014 May;9(5):1192-212
pubmed: 24762786
Atherosclerosis. 2012 May;222(1):257-62
pubmed: 22420889
Nat Genet. 2014 Feb;46(2):200-4
pubmed: 24336170
Am J Hum Genet. 2022 Jan 6;109(1):81-96
pubmed: 34932938
Ther Adv Endocrinol Metab. 2017 Apr;8(4):51-57
pubmed: 28507727
J Am Coll Cardiol. 2013 Jul 23;62(4):291-9
pubmed: 23707316
JAMA. 2009 Nov 11;302(18):1993-2000
pubmed: 19903920
Circulation. 2019 Jun 18;139(25):e1082-e1143
pubmed: 30586774
Diabetes Care. 2019 Jul;42(7):1202-1208
pubmed: 30659074
Vasc Health Risk Manag. 2019 Jun 05;15:149-157
pubmed: 31239693
Nat Genet. 2017 Dec;49(12):1758-1766
pubmed: 29083408
Nat Commun. 2018 May 8;9(1):1825
pubmed: 29739930
Nat Genet. 2014 Apr;46(4):345-51
pubmed: 24633158
Pharmacogenet Genomics. 2015 May;25(5):263-9
pubmed: 25794161
Hepatology. 2022 Apr;75(4):785-796
pubmed: 34624136
Mol Metab. 2018 Sep;15:35-44
pubmed: 29706320
Hum Mol Genet. 2018 Oct 15;27(20):3641-3649
pubmed: 30124842
BMC Med Genet. 2007 Sep 19;8 Suppl 1:S17
pubmed: 17903299
Ann Epidemiol. 2016 Mar;26(3):171-5
pubmed: 26907540
Circ Cardiovasc Genet. 2010 Aug;3(4):331-9
pubmed: 20529992
Int J Hepatol. 2018 Jun 03;2018:1286170
pubmed: 29973996
Gastroenterology. 2016 Aug;151(2):351-363.e28
pubmed: 27094239
Am J Hum Genet. 2014 Feb 6;94(2):223-32
pubmed: 24507774
Cardiovasc Drugs Ther. 2022 Aug;36(4):777-792
pubmed: 33860901
Nat Genet. 2018 Mar;50(3):390-400
pubmed: 29403010
Nat Genet. 2015 Jun;47(6):589-97
pubmed: 25961943
Diabetologia. 2013 Feb;56(2):298-310
pubmed: 23160641
Bioinformatics. 2010 May 1;26(9):1205-10
pubmed: 20335276
Circ Genom Precis Med. 2019 Dec;12(12):e002711
pubmed: 31756303
Nat Genet. 2021 May;53(5):663-671
pubmed: 33888908
PLoS Genet. 2014 May 15;10(5):e1004383
pubmed: 24830394
Nat Genet. 2007 Feb;39(2):226-31
pubmed: 17206142
Arteriosclerosis. 1983 May-Jun;3(3):260-72
pubmed: 6573877
Nat Genet. 2013 Nov;45(11):1274-1283
pubmed: 24097068
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Nat Genet. 2018 Sep;50(9):1335-1341
pubmed: 30104761
Nucleic Acids Res. 2022 Jan 7;50(D1):D1398-D1407
pubmed: 34718717
Nat Genet. 2018 Mar;50(3):401-413
pubmed: 29507422
Nat Rev Genet. 2016 Mar;17(3):129-45
pubmed: 26875678
Am J Hum Genet. 2012 Nov 2;91(5):823-38
pubmed: 23063622
PLoS One. 2017 Jul 27;12(7):e0181038
pubmed: 28749953
Eur J Clin Invest. 2000 Dec;30(12):1099-106
pubmed: 11122325
Ann Med Surg (Lond). 2019 Apr 24;42:11-13
pubmed: 31065353
Oxid Med Cell Longev. 2021 Apr 29;2021:5529256
pubmed: 34007401
Int J Cardiol. 2018 Sep 15;267:171-176
pubmed: 29804699
N Engl J Med. 2018 Nov 29;379(22):2097-2107
pubmed: 30403574
Drug Metab Dispos. 2018 Jun;46(6):888-896
pubmed: 29602798
Nat Genet. 2017 Sep;49(9):1385-1391
pubmed: 28714975
BMC Bioinformatics. 2018 Apr 4;19(1):120
pubmed: 29618318
Nature. 2021 Dec;600(7890):675-679
pubmed: 34887591
Lipids Health Dis. 2020 Mar 19;19(1):50
pubmed: 32192520
N Engl J Med. 2017 May 4;376(18):1713-1722
pubmed: 28304224
Science. 2007 Jun 1;316(5829):1331-6
pubmed: 17463246
PLoS Med. 2020 Mar 23;17(3):e1003062
pubmed: 32203549
Nat Commun. 2021 Apr 12;12(1):2182
pubmed: 33846329
J Clin Lipidol. 2020 Jul - Aug;14(4):398-413
pubmed: 32507592
Nat Commun. 2015 Jan 19;6:5890
pubmed: 25597830
Hum Mol Genet. 2017 Sep 15;26(18):3639-3650
pubmed: 28911207
Nature. 2010 Aug 5;466(7307):707-13
pubmed: 20686565
Nat Med. 2022 Aug;28(8):1679-1692
pubmed: 35915156
Eur Heart J. 2018 Feb 1;39(5):354-359
pubmed: 29020353
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Nat Genet. 2022 Dec;54(12):1803-1815
pubmed: 36474045
Am J Hum Genet. 2008 Dec;83(6):663-74
pubmed: 18992858
Nat Genet. 2016 Nov;48(11):1303-1312
pubmed: 27668658
Nat Genet. 2018 Nov;50(11):1505-1513
pubmed: 30297969
N Engl J Med. 2017 Apr 20;376(16):1527-1539
pubmed: 28304242
Rev Endocr Metab Disord. 2021 Jun;22(2):257-274
pubmed: 33616800
J Hepatol. 2020 Aug;73(2):263-276
pubmed: 32165250
Nat Commun. 2019 Apr 16;10(1):1776
pubmed: 30992449
Nat Commun. 2019 Jun 14;10(1):2631
pubmed: 31201301
Brain Sci. 2020 Jun 18;10(6):
pubmed: 32570800
Nat Genet. 2021 Jun;53(6):840-860
pubmed: 34059833
Nat Genet. 2021 Sep;53(9):1283-1289
pubmed: 34493869
Transl Psychiatry. 2020 May 12;10(1):145
pubmed: 32398686
Nat Genet. 2021 Jul;53(7):972-981
pubmed: 34140684
Nat Commun. 2013;4:2872
pubmed: 24343240
Clin Chim Acta. 2014 Jan 20;428:82-8
pubmed: 24252657
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Nat Commun. 2015 Mar 09;6:6065
pubmed: 25751400
BMC Res Notes. 2014 Aug 19;7:548
pubmed: 25135323
Genome Biol. 2019 Nov 6;20(1):233
pubmed: 31694669
Nat Commun. 2015 Dec 22;6:10206
pubmed: 26690388
Nat Commun. 2020 Dec 18;11(1):6417
pubmed: 33339817
Nature. 2010 Aug 5;466(7307):714-9
pubmed: 20686566
Lancet Diabetes Endocrinol. 2020 Jan;8(1):50-67
pubmed: 31582260
BMC Bioinformatics. 2022 May 8;23(1):169
pubmed: 35527238
N Engl J Med. 2008 Mar 20;358(12):1240-9
pubmed: 18354102
Nat Genet. 2017 Dec;49(12):1722-1730
pubmed: 29083407
Nat Genet. 2018 Nov;50(11):1514-1523
pubmed: 30275531
Am J Hum Genet. 2019 Jul 3;105(1):89-107
pubmed: 31204013
Circ Genom Precis Med. 2019 Jan;12(1):e002196
pubmed: 30645167
Lancet. 2020 Oct 17;396(10258):1204-1222
pubmed: 33069326
Nat Commun. 2021 Jul 16;12(1):4350
pubmed: 34272381
Am J Hum Genet. 2016 Jul 7;99(1):8-21
pubmed: 27346685