A comprehensive framework for trans-ancestry pathway analysis using GWAS summary data from diverse populations.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Genetic Predisposition to Disease* ; Polymorphism, Single Nucleotide* ; Schizophrenia*/genetics; Humans ; Black People/genetics ; Computer Simulation ; Genetics, Population/methods ; Genome-Wide Association Study/methods ; White People/genetics ; East Asian People/genetics

As more multi-ancestry GWAS summary data become available, we have developed a comprehensive trans-ancestry pathway analysis framework that effectively utilizes this diverse genetic information. Within this framework, we evaluated various strategies for integrating genetic data at different levels-SNP, gene, and pathway-from multiple ancestry groups. Through extensive simulation studies, we have identified robust strategies that demonstrate superior performance across diverse scenarios. Applying these methods, we analyzed 6,970 pathways for their association with schizophrenia, incorporating data from African, East Asian, and European populations. Our analysis identified over 200 pathways significantly associated with schizophrenia, even after excluding genes near genome-wide significant loci. This approach substantially enhances detection efficiency compared to traditional single-ancestry pathway analysis and the conventional approach that amalgamates single-ancestry pathway analysis results across different ancestry groups. Our framework provides a flexible and effective tool for leveraging the expanding pool of multi-ancestry GWAS summary data, thereby improving our ability to identify biologically relevant pathways that contribute to disease susceptibility.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Brief Bioinform. 2020 Jul 15;21(4):1302-1312. (PMID: 31297505)
PLoS Genet. 2013 Jun;9(6):e1003566. (PMID: 23785302)
Am J Hum Genet. 2011 May 13;88(5):586-98. (PMID: 21565292)
Bioinformatics. 2011 Jun 15;27(12):1739-40. (PMID: 21546393)
Nature. 2022 Apr;604(7906):502-508. (PMID: 35396580)
Nat Genet. 2019 Sep;51(9):1339-1348. (PMID: 31427789)
Stat Med. 2008 Feb 28;27(5):625-50. (PMID: 17590884)
Nat Rev Genet. 2019 Sep;20(9):520-535. (PMID: 31235872)
Nat Genet. 2024 Sep;56(9):1841-1850. (PMID: 39187616)
Nucleic Acids Res. 2017 Jan 4;45(D1):D896-D901. (PMID: 27899670)
Am J Hum Genet. 2015 Jul 2;97(1):86-98. (PMID: 26119817)
Nat Genet. 2016 Mar;48(3):245-52. (PMID: 26854917)
Am J Hum Genet. 2017 Jul 6;101(1):5-22. (PMID: 28686856)
Nat Genet. 2023 Oct;55(10):1757-1768. (PMID: 37749244)
PLoS Comput Biol. 2015 Apr 17;11(4):e1004219. (PMID: 25885710)
Nat Rev Genet. 2010 May;11(5):356-66. (PMID: 20395969)
Nat Genet. 2024 Jan;56(1):170-179. (PMID: 38168930)
Bioinformatics. 2017 Jul 15;33(14):i379-i388. (PMID: 28881976)
Am J Hum Genet. 2023 Feb 2;110(2):179-194. (PMID: 36634672)
Mol Neuropsychiatry. 2019 Mar;5(1):6-12. (PMID: 31019914)
Nucleic Acids Res. 2018 Jun 1;46(10):e60. (PMID: 29562348)
PLoS Genet. 2019 Mar 15;15(3):e1007530. (PMID: 30875371)
Sci Rep. 2023 Feb 6;13(1):2139. (PMID: 36747015)
Brief Bioinform. 2023 Jan 19;24(1):. (PMID: 36611240)
Am J Hum Genet. 2007 Dec;81(6):1278-83. (PMID: 17966091)
Int J Mol Sci. 2023 Oct 26;24(21):. (PMID: 37958606)
Nat Genet. 2021 Oct;53(10):1415-1424. (PMID: 34594039)
Nucleic Acids Res. 2020 Jan 8;48(D1):D498-D503. (PMID: 31691815)
Sci Rep. 2021 Mar 4;11(1):5240. (PMID: 33664403)
PLoS Genet. 2016 Jun 30;12(6):e1006122. (PMID: 27362418)
Am J Hum Genet. 2019 Mar 7;104(3):410-421. (PMID: 30849328)
Nat Neurosci. 2015 Feb;18(2):199-209. (PMID: 25599223)
Hum Mol Genet. 2017 Sep 15;26(18):3639-3650. (PMID: 28911207)
Nat Genet. 2004 Dec;36(12):1312-8. (PMID: 15543147)
Am J Hum Genet. 2013 Aug 8;93(2):236-48. (PMID: 23891470)
Sci Rep. 2020 Jul 28;10(1):12655. (PMID: 32724114)
Nat Rev Genet. 2010 Dec;11(12):843-54. (PMID: 21085203)
Nature. 2019 Jun;570(7762):514-518. (PMID: 31217584)
PLoS Genet. 2021 Sep 20;17(9):e1009733. (PMID: 34543273)
Nat Rev Genet. 2016 Apr 12;17(6):353-64. (PMID: 27070863)
Nature. 2015 Oct 1;526(7571):68-74. (PMID: 26432245)
Nature. 2016 Oct 12;538(7624):161-164. (PMID: 27734877)
Genet Epidemiol. 2011 Dec;35(8):809-22. (PMID: 22125221)
Neurosci Biobehav Rev. 2010 May;34(6):882-8. (PMID: 19879893)
Nat Genet. 2018 Feb;50(2):229-237. (PMID: 29292387)
Complex Psychiatry. 2023 Nov 9;9(1-4):154-171. (PMID: 38058955)
Mol Brain. 2021 Jan 22;14(1):21. (PMID: 33482876)
Biomolecules. 2020 Mar 02;10(3):. (PMID: 32121669)
Arch Gen Psychiatry. 2005 Aug;62(8):829-40. (PMID: 16061760)
Am J Hum Genet. 2022 Jul 7;109(7):1317-1337. (PMID: 35714612)
Cell. 2019 Mar 21;177(1):26-31. (PMID: 30901543)
Nat Commun. 2018 Oct 19;9(1):4361. (PMID: 30341297)
Am J Hum Genet. 2020 Jun 4;106(6):805-817. (PMID: 32442408)
Bioinformatics. 2017 May 1;33(9):1271-1277. (PMID: 28453686)
Nat Med. 2022 Feb;28(2):243-250. (PMID: 35145307)
Genet Epidemiol. 2009 Dec;33(8):700-9. (PMID: 19333968)
Mol Psychiatry. 2010 May;15(5):453-62. (PMID: 20424623)
Brief Bioinform. 2014 Jul;15(4):504-18. (PMID: 23413432)
Nature. 2024 Mar;627(8004):604-611. (PMID: 38448582)
Sci Rep. 2021 Mar 26;11(1):6980. (PMID: 33772054)
Am J Hum Genet. 2022 Aug 4;109(8):1388-1404. (PMID: 35931050)
Cell. 2019 Oct 17;179(3):589-603. (PMID: 31607513)
Nucleic Acids Res. 2012 Sep 1;40(17):e133. (PMID: 22638577)

R01 MH106575 United States MH NIMH NIH HHS; R01 MH116281 United States MH NIMH NIH HHS

Date Created: 20241023 Date Completed: 20241104 Latest Revision: 20241203

20250114

PMC11534268

10.1371/journal.pgen.1011322

39441834