Integrative proteogenomic analyses provide novel interpretations of type 1 diabetes risk loci through circulating proteins

Tianyuan Lu; Despoina Manousaki; Lei Sun; Andrew D Paterson

doi:10.2337/db24-0380

Integrative proteogenomic analyses provide novel interpretations of type 1 diabetes risk loci through circulating proteins

Diabetes. 2025 Jan 6:db240380. doi: 10.2337/db24-0380. Online ahead of print.

Authors

Tianyuan Lu^{1

2

3

4

5

6}, Despoina Manousaki^{7

8

9}, Lei Sun^{1

10}, Andrew D Paterson^{10

11

12}

Affiliations

¹ Department of Statistical Sciences, Faculty of Arts and Science, University of Toronto, Toronto, ON, Canada.
² Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
³ Department of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁴ Center for Demography of Health and Aging, University of Wisconsin-Madison, Madison, WI, USA.
⁵ Center for Genomic Science Innovation, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Center for Human Genomics and Precision Medicine, University of Wisconsin-Madison, Madison, WI, USA.
⁷ Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
⁸ Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
⁹ Research Center of the Sainte-Justine University Hospital, Université de Montréal, Montreal, QC, Canada.
¹⁰ Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
¹¹ Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
¹² Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

PMID: 39761376
DOI: 10.2337/db24-0380

Abstract

Circulating proteins may be promising biomarkers or drug targets. Leveraging genome-wide association studies of type 1 diabetes (18,942 cases and 501,638 controls of European ancestry) and circulating protein abundances (10,708 European ancestry individuals), Mendelian randomization analyses were conducted to assess the associations between circulating abundances of 1,560 candidate proteins and the risk of type 1 diabetes, followed by multiple sensitivity and colocalization analyses, horizontal pleiotropy examinations, and replications. Bulk tissue and single-cell gene expression enrichment analyses were performed to explore candidate tissues and cell types for prioritized proteins. After validating Mendelian randomization assumptions and colocalization evidence, we found that genetically predicted circulating abundances of CTSH (OR=1.17 per one standard deviation increase; 95% CI:1.10-1.24), IL27RA (OR=1.13; 95% CI:1.07-1.19), SIRPG (OR=1.37; 95% CI:1.26-1.49), and PGM1 (OR=1.66; 95% CI:1.40-1.96) were associated with the risk of type 1 diabetes. These findings were consistently replicated in other cohorts. CTSH, IL27RA, and SIRPG were strongly enriched in immune system-related tissues, while PGM1 was enriched in muscle and liver tissues. Amongst immune cells, CTSH was enriched in B cells and myeloid cells, while SIRPG was enriched in T cells and natural killer cells. These proteins may be explored as biomarkers or drug targets for type 1 diabetes.