Likely causal effects of insulin resistance and IGF-1 bioaction on childhood and adult adiposity: a Mendelian randomization study.
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BACKGROUND: Circulating insulin and insulin-like growth factor-1 (IGF-1) concentrations are positively correlated with adiposity. However, the causal effects of insulin and IGF-1 on adiposity are unclear. METHODS: We performed two-sample Mendelian randomization analyses to estimate the likely causal effects of fasting insulin and IGF-1 on relative childhood adiposity and adult body mass index (BMI). To improve accuracy and biological interpretation, we applied Steiger filtering (to avoid reverse causality) and 'biological effect' filtering of fasting insulin and IGF-1 associated variants. RESULTS: Fasting insulin-increasing alleles (35 variants also associated with higher fasting glucose, indicative of insulin resistance) were associated with lower relative childhood adiposity (P = 3.8 × 10-3) and lower adult BMI (P = 1.4 × 10-5). IGF-1-increasing alleles also associated with taller childhood height (351 variants indicative of greater IGF-1 bioaction) showed no association with relative childhood adiposity (P = 0.077) or adult BMI (P = 0.562). Conversely, IGF-1-increasing alleles also associated with shorter childhood height (306 variants indicative of IGF-1 resistance) were associated with lower relative childhood adiposity (P = 6.7 × 10-3), but effects on adult BMI were inconclusive. CONCLUSIONS: Genetic causal modelling indicates negative effects of insulin resistance on childhood and adult adiposity, and negative effects of IGF-1 resistance on childhood adiposity. Our findings demonstrate the need to distinguish between bioaction and resistance when modelling variants associated with biomarker concentrations.
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Acknowledgements: For the purpose of Open Access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. This work has been conducted using UK Biobank data, application number 9905. Data on glycaemic traits have been contributed by MAGIC investigators and have been downloaded from www.magicinvestigators.org. The authors were supported by the Medical Research Council (Unit programme MC_UU_00006/2). DO was also supported by a PhD studentship from King Abdullah International Medical Research Centre (KAIMRC), the Ministry of National Guard Health Affairs. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this ongoing cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Centre for Diabetes Research, the University of Bergen for providing genotype data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. Supported by grants from the European Research Council (AdG #293574), the Bergen Research Foundation (“Utilizing the Mother and Child Cohort and the Medical Birth Registry for Better Health”), Stiftelsen Kristian Gerhard Jebsen (Translational Medical Centre), the University of Bergen, the Research Council of Norway (FRIPRO grant #240413), the Western Norway Regional Health Authority (Strategic Fund “Personalized Medicine for Children and Adults”), the Novo Nordisk Foundation (grant #54741), and the Norwegian Diabetes Association; and (to S.J.) Helse Vest’s Open Research Grant (grant #912250), the Research Council of Norway (FRIPRO grant #315599), and Novo Nordisk Foundation (grant #NNF21OC0070349). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme (#262700), Better Health by Harvesting Biobanks (#229624) and The Swedish Research Council, Stockholm, Sweden (2015-02559), The Research Council of Norway, Oslo, Norway (FRIMEDBIO #547711), March of Dimes (#21-FY16-121). The Norwegian Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537-01 and grant no.2 UO1 NS 047537-06A1). MV acknowledges the support of the Research Council of Norway (project #301178) and SJ the Novo Nordisk Foundation (project NNF20OC0063872). Analyses were performed using digital laboratories in HUNT Cloud at the Norwegian University of Science and Technology, Trondheim, Norway. We are grateful for outstanding support from the HUNT Cloud community.
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1476-5497
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