Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
International Journal of Epidemiology, vol. 51, pp. 1874–1885
Abstract
BACKGROUND: There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of human age-related diseases such as type 2 diabetes (T2D). Here, we investigated the association between IGF-1 and T2D using (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 single nucleotide polymorphisms (SNPs) associated with IGF-1. Given the heterogeneity between the MR effect 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 over-representation 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 [hazard ratio (HR): 1.31; 95% 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 MR effect estimates of individual instruments, six clusters of genetically determined IGF-1 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 signalling 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. CONCLUSIONS: The IGF-1-associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of MR 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.
Authors 7
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , Leiden, The Netherlands
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Ephrem Baraki Tesfay Aachen
Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics; Leiden University Medical Center , Leiden, The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands
Department of Human Genetics, Leiden University Medical Center , Leiden, The Netherlands
Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands
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Ko Willems van Dijk Aachen Department of Human Genetics Department of Internal Medicine Division Endocrinology Leiden Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , Leiden, The Netherlands
Department of Internal Medicine, Division Endocrinology, Leiden University Medical Center , Leiden, The Netherlands
Leiden Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Leiden, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Southern Illinois University School of Medicine , Springfield, IL, USA
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Diana van Heemst Aachen
Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics; Leiden University Medical Center , Leiden, The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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Raymond Noordam Aachen
Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Section of Gerontology and Geriatrics; Leiden University Medical Center , Leiden, The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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