Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets

Oleksandr Frei; Guy Hindley; Alexey A. Shadrin; Dennis van der Meer; Bayram C. Akdeniz; Espen Hagen; Weiqiu Cheng; Kevin S. O’Connell; Shahram Bahrami; Nadine Parker; Olav B. Smeland; Dominic Holland; Christiaan de Leeuw; Danielle Posthuma; Ole A. Andreassen; Anders M. Dale

doi:10.1038/s41588-024-01771-1

Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets

Oleksandr Frei^*, Guy Hindley, Alexey A. Shadrin, Dennis van der Meer, Bayram C. Akdeniz, Espen Hagen, Weiqiu Cheng, Kevin S. O’Connell, Shahram Bahrami, Nadine Parker, Olav B. Smeland, Dominic Holland, Christiaan de Leeuw, Danielle Posthuma, Ole A. Andreassen, Anders M. Dale

^*Corresponding author for this work

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Abstract

While genome-wide association studies are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. Here we developed the GSA-MiXeR analytical tool for gene set analysis (GSA), which fits a model for the heritability of individual genes, accounting for linkage disequilibrium across variants and allowing the quantification of partitioned heritability and fold enrichment for small gene sets. We validated the method using extensive simulations and sensitivity analyses. When applied to a diverse selection of complex traits and disorders, including schizophrenia, GSA-MiXeR prioritizes gene sets with greater biological specificity compared to standard GSA approaches, implicating voltage-gated calcium channel function and dopaminergic signaling for schizophrenia. Such biologically relevant gene sets, often with fewer than ten genes, are more likely to provide insights into the pathobiology of complex diseases and highlight potential drug targets.

Original language	English
Pages (from-to)	1310-1318
Number of pages	9
Journal	Nature genetics
Volume	56
Issue number	6
Early online date	3 Jun 2024
DOIs	https://doi.org/10.1038/s41588-024-01771-1
Publication status	Published - Jun 2024

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

Funding

Funders	Funder number
American National Institutes of Health
F. Hoffmann-La Roche
Helse Sør-Øst RHF
Horizon 2020
European Environment Agency
Horizon 2020 Framework Programme	847776
H2020 Marie Skłodowska-Curie Actions	223273, 801133, 326813, 324252, 300309, 273291, 324499
Norges Idrettshøgskole	5R01MH124839-02, U24DA041123, OT2 HL161847, R01AG076838, U24DA055330
HSØ	2022073, 964874, MED-021
Norges forskningsråd	334920
Norway	#EEA-RO-NO-2018-0573
Nasjonalforeningen for Folkehelsen	22731

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Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene setsFinal published version, 1.84 MBLicence: Article 25fa Dutch Copyright Act

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Frei, O., Hindley, G., Shadrin, A. A., van der Meer, D., Akdeniz, B. C., Hagen, E., Cheng, W., O’Connell, K. S., Bahrami, S., Parker, N., Smeland, O. B., Holland, D., de Leeuw, C., Posthuma, D., Andreassen, O. A., & Dale, A. M. (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nature genetics, 56(6), 1310-1318. https://doi.org/10.1038/s41588-024-01771-1

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abstract = "While genome-wide association studies are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. Here we developed the GSA-MiXeR analytical tool for gene set analysis (GSA), which fits a model for the heritability of individual genes, accounting for linkage disequilibrium across variants and allowing the quantification of partitioned heritability and fold enrichment for small gene sets. We validated the method using extensive simulations and sensitivity analyses. When applied to a diverse selection of complex traits and disorders, including schizophrenia, GSA-MiXeR prioritizes gene sets with greater biological specificity compared to standard GSA approaches, implicating voltage-gated calcium channel function and dopaminergic signaling for schizophrenia. Such biologically relevant gene sets, often with fewer than ten genes, are more likely to provide insights into the pathobiology of complex diseases and highlight potential drug targets.",

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Frei, O, Hindley, G, Shadrin, AA, van der Meer, D, Akdeniz, BC, Hagen, E, Cheng, W, O’Connell, KS, Bahrami, S, Parker, N, Smeland, OB, Holland, D, de Leeuw, C , Posthuma, D, Andreassen, OA & Dale, AM 2024, 'Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets', Nature genetics, vol. 56, no. 6, pp. 1310-1318. https://doi.org/10.1038/s41588-024-01771-1

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AU - Cheng, Weiqiu

AU - O’Connell, Kevin S.

AU - Bahrami, Shahram

AU - Parker, Nadine

AU - Smeland, Olav B.

AU - Holland, Dominic

AU - de Leeuw, Christiaan

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AU - Andreassen, Ole A.

AU - Dale, Anders M.

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Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets

Abstract

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