Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the "omnigenic" sparse effector hypothesis of complex trait genetics

Andrii Iakovliev; Stuart J McGurnaghan; Caroline Hayward; Marco Colombo; Debby Lipschutz; Athina Spiliopoulou; Helen M Colhoun; Paul M McKeigue

doi:10.1016/j.ajhg.2023.04.003

Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the "omnigenic" sparse effector hypothesis of complex trait genetics

Andrii Iakovliev, Stuart J McGurnaghan, Caroline Hayward, Marco Colombo, Debby Lipschutz, Athina Spiliopoulou, Helen M Colhoun, Paul M McKeigue

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

The "omnigenic" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated through trans-effects on expression of a relatively sparse set of effector ("core") genes. We tested this hypothesis in a study of 4,964 cases of type 1 diabetes (T1D) and 7,497 controls by using summary statistics to calculate aggregated (excluding the HLA region) trans-scores for gene expression in blood. From associations of T1D with aggregated trans-scores, nine putative core genes were identified, of which three-STAT1, CTLA4 and FOXP3-are genes in which variants cause monogenic forms of autoimmune diabetes. Seven of these genes affect the activity of regulatory T cells, and two are involved in immune responses to microbial lipids. Four T1D-associated genomic regions could be identified as master regulators via trans-effects on gene expression. These results support the sparse effector hypothesis and reshape our understanding of the genetic architecture of T1D.

Original language	English
Pages (from-to)	913-926
Journal	American Journal of Human Genetics
Volume	110
Issue number	6
Early online date	4 May 2023
DOIs	https://doi.org/10.1016/j.ajhg.2023.04.003
Publication status	Published - 1 Jun 2023

Keywords / Materials (for Non-textual outputs)

Diabetes Mellitus, Type 1/genetics
Genetic Predisposition to Disease
Humans
Multifactorial Inheritance
Polymorphism, Single Nucleotide/genetics
Quantitative Trait Loci/genetics

Access to Document

10.1016/j.ajhg.2023.04.003Licence: Creative Commons: Attribution (CC-BY)

PIIS0002929723001271Final published version, 3.78 MBLicence: Creative Commons: Attribution (CC-BY)

Trans-eQTL effects on risk of type 1 diabetes: a test of the sparse effector (omnigenic) hypothesis of complex trait genetics (supplementary data)
Iakovliev, A. (Creator), McGurnaghan, S. (Researcher), Hayward, C. (Producer), Colombo, M. (Researcher), Lipschutz, D. (Researcher), Spiliopoulou, A. (Researcher), Colhoun, H. (Project Leader) & McKeigue, P. (Project Leader), Zenodo, 30 Mar 2023
DOI: 10.5281/zenodo.7786862, https://www.cell.com/ajhg/pdf/S0002-9297(23)00127-1.pdf
Dataset

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Iakovliev, A., McGurnaghan, S. J., Hayward, C., Colombo, M., Lipschutz, D., Spiliopoulou, A., Colhoun, H. M., & McKeigue, P. M. (2023). Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the "omnigenic" sparse effector hypothesis of complex trait genetics. American Journal of Human Genetics, 110(6), 913-926. https://doi.org/10.1016/j.ajhg.2023.04.003

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abstract = "The {"}omnigenic{"} hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated through trans-effects on expression of a relatively sparse set of effector ({"}core{"}) genes. We tested this hypothesis in a study of 4,964 cases of type 1 diabetes (T1D) and 7,497 controls by using summary statistics to calculate aggregated (excluding the HLA region) trans-scores for gene expression in blood. From associations of T1D with aggregated trans-scores, nine putative core genes were identified, of which three-STAT1, CTLA4 and FOXP3-are genes in which variants cause monogenic forms of autoimmune diabetes. Seven of these genes affect the activity of regulatory T cells, and two are involved in immune responses to microbial lipids. Four T1D-associated genomic regions could be identified as master regulators via trans-effects on gene expression. These results support the sparse effector hypothesis and reshape our understanding of the genetic architecture of T1D.",

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note = "Funding Information: This study was supported by Diabetes UK ( 15/0005301 ). The establishment of the SDRN Type 1 Bioresource was supported by the Chief Scientist Office of the Scottish Government Health Directorates ( ETM/47 ), by Diabetes UK ( 10/0004010 ), and by in-kind contributions from the Scottish Diabetes Research Network . Genotyping was supported by the Juvenile Diabetes Research Fund ( 17-2013-7 ). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates ( CZD/16/6 ) and the Scottish Funding Council ( HR03006 ). The development of the GENOSCORES platform was supported by a Springboard Award ( SBF006/1109 ) from the Academy of Medical Sciences , supported in turn by the Wellcome Trust , the UK Government Department of Business, Energy and Industrial Strategy , the British Heart Foundation , and Diabetes UK . Publisher Copyright: {\textcopyright} 2023 The Author(s)",

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Iakovliev, A , McGurnaghan, SJ , Hayward, C, Colombo, M, Lipschutz, D , Spiliopoulou, A , Colhoun, HM & McKeigue, PM 2023, 'Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the "omnigenic" sparse effector hypothesis of complex trait genetics', American Journal of Human Genetics, vol. 110, no. 6, pp. 913-926. https://doi.org/10.1016/j.ajhg.2023.04.003

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AU - Iakovliev, Andrii

AU - McGurnaghan, Stuart J

AU - Hayward, Caroline

AU - Colombo, Marco

AU - Lipschutz, Debby

AU - Spiliopoulou, Athina

AU - Colhoun, Helen M

AU - McKeigue, Paul M

N1 - Funding Information: This study was supported by Diabetes UK ( 15/0005301 ). The establishment of the SDRN Type 1 Bioresource was supported by the Chief Scientist Office of the Scottish Government Health Directorates ( ETM/47 ), by Diabetes UK ( 10/0004010 ), and by in-kind contributions from the Scottish Diabetes Research Network . Genotyping was supported by the Juvenile Diabetes Research Fund ( 17-2013-7 ). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates ( CZD/16/6 ) and the Scottish Funding Council ( HR03006 ). The development of the GENOSCORES platform was supported by a Springboard Award ( SBF006/1109 ) from the Academy of Medical Sciences , supported in turn by the Wellcome Trust , the UK Government Department of Business, Energy and Industrial Strategy , the British Heart Foundation , and Diabetes UK . Publisher Copyright: © 2023 The Author(s)

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N2 - The "omnigenic" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated through trans-effects on expression of a relatively sparse set of effector ("core") genes. We tested this hypothesis in a study of 4,964 cases of type 1 diabetes (T1D) and 7,497 controls by using summary statistics to calculate aggregated (excluding the HLA region) trans-scores for gene expression in blood. From associations of T1D with aggregated trans-scores, nine putative core genes were identified, of which three-STAT1, CTLA4 and FOXP3-are genes in which variants cause monogenic forms of autoimmune diabetes. Seven of these genes affect the activity of regulatory T cells, and two are involved in immune responses to microbial lipids. Four T1D-associated genomic regions could be identified as master regulators via trans-effects on gene expression. These results support the sparse effector hypothesis and reshape our understanding of the genetic architecture of T1D.

AB - The "omnigenic" hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated through trans-effects on expression of a relatively sparse set of effector ("core") genes. We tested this hypothesis in a study of 4,964 cases of type 1 diabetes (T1D) and 7,497 controls by using summary statistics to calculate aggregated (excluding the HLA region) trans-scores for gene expression in blood. From associations of T1D with aggregated trans-scores, nine putative core genes were identified, of which three-STAT1, CTLA4 and FOXP3-are genes in which variants cause monogenic forms of autoimmune diabetes. Seven of these genes affect the activity of regulatory T cells, and two are involved in immune responses to microbial lipids. Four T1D-associated genomic regions could be identified as master regulators via trans-effects on gene expression. These results support the sparse effector hypothesis and reshape our understanding of the genetic architecture of T1D.

KW - Diabetes Mellitus, Type 1/genetics

KW - Genetic Predisposition to Disease

KW - Humans

KW - Multifactorial Inheritance

KW - Polymorphism, Single Nucleotide/genetics

KW - Quantitative Trait Loci/genetics

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DO - 10.1016/j.ajhg.2023.04.003

M3 - Article

C2 - 37164005

SN - 0002-9297

VL - 110

SP - 913

EP - 926

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

Genome-wide aggregated trans-effects on risk of type 1 diabetes: A test of the "omnigenic" sparse effector hypothesis of complex trait genetics

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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Datasets

Trans-eQTL effects on risk of type 1 diabetes: a test of the sparse effector (omnigenic) hypothesis of complex trait genetics (supplementary data)

Cite this