Clustered Mendelian Randomization analyses identifies distinct and opposing pathways in the causal association between insulin-like growth factor-1 and type 2 diabetes mellitus Article Swipe
Wenyi Wang
,
Ephrem Baraki Tesfay
,
Ko Willems van Dijk
,
Andrzej Bartke
,
Diana van Heemst
,
Raymond Noordam
·
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1101/2021.05.12.21257093
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1101/2021.05.12.21257093
Aims/hypothesis There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of type 2 diabetes. Here, we investigated the association between IGF-1 and type 2 diabetes using a combination of multivariable-adjusted and (clustered) Mendelian Randomization (MR) analyses in the UK Biobank. Methods We conducted Cox proportional hazard analyses in 451,232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13,247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent SNPs associated with IGF-1. Given the heterogeneity between the causal estimates of individual instruments (P-value for Q statistic=4.03e-145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by overrepresentation analyses. Results In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes (HR: 1.31; CI: 1.23-1.39). In contrast, in the two-sample MR analyses, higher genetically-influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of causal effect estimates, six clusters associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth-hormone signaling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity. Conclusion The IGF-1 associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of causal effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.
Related Topics
Concepts
Mendelian randomization
Type 2 diabetes
Diabetes mellitus
Hazard ratio
Proportional hazards model
Internal medicine
Biobank
Risk factor
Medicine
Single-nucleotide polymorphism
Demography
Disease
Oncology
Endocrinology
Biology
Bioinformatics
Genetics
Genotype
Gene
Confidence interval
Genetic variants
Sociology
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2021.05.12.21257093
- https://www.medrxiv.org/content/medrxiv/early/2021/05/17/2021.05.12.21257093.full.pdf
- OA Status
- green
- Cited By
- 1
- References
- 43
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3160743681
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W3160743681Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1101/2021.05.12.21257093Digital Object Identifier
- Title
-
Clustered Mendelian Randomization analyses identifies distinct and opposing pathways in the causal association between insulin-like growth factor-1 and type 2 diabetes mellitusWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2021Year of publication
- Publication date
-
2021-05-17Full publication date if available
- Authors
-
Wenyi Wang, Ephrem Baraki Tesfay, Ko Willems van Dijk, Andrzej Bartke, Diana van Heemst, Raymond NoordamList of authors in order
- Landing page
-
https://doi.org/10.1101/2021.05.12.21257093Publisher landing page
- PDF URL
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https://www.medrxiv.org/content/medrxiv/early/2021/05/17/2021.05.12.21257093.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.medrxiv.org/content/medrxiv/early/2021/05/17/2021.05.12.21257093.full.pdfDirect OA link when available
- Concepts
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Mendelian randomization, Type 2 diabetes, Diabetes mellitus, Hazard ratio, Proportional hazards model, Internal medicine, Biobank, Risk factor, Medicine, Single-nucleotide polymorphism, Demography, Disease, Oncology, Endocrinology, Biology, Bioinformatics, Genetics, Genotype, Gene, Confidence interval, Genetic variants, SociologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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1Total citation count in OpenAlex
- Citations by year (recent)
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2022: 1Per-year citation counts (last 5 years)
- References (count)
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43Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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