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Evaluating the direct effects of childhood adiposity on adult systemic metabolism: A multivariable Mendelian randomization analysis

By Tom G Richardson, Juha Mykkanen, Katja Pahkala, Mika Ala-Korpela, Joshua A Bell, Kurt A Taylor, Jorma Viikari, Terho Lehtimaki, Olli Raitakari, George Davey Smith

Posted 31 Aug 2020
medRxiv DOI: 10.1101/2020.08.25.20181412

Background: Individuals who are obese in childhood have an elevated risk of cardiometabolic disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independent of adult adiposity, is unclear. Methods and Results: We conducted a multivariable Mendelian randomization (MR) study to simultaneously evaluate the effects of childhood and adulthood body size on over 100 systemic molecular biomarkers representing multiple metabolic pathways. We first validated UK Biobank-derived genetic risk scores using data on body mass index (BMI) measured during childhood (n=2,427, age: 3-18 years) and adulthood (n=1,762, age: 34-49 years) from the Young Finns Study (YFS). Results indicated that the childhood score is a stronger predictor of childhood BMI (0.74 vs 0.62 area under the curve (AUC) for the childhood and adult scores respectively), whereas the adult score was a stronger predictor of adulthood BMI (0.57 vs 0.62 AUC). Two-sample MR analyses in a univariable setting using summary genome-wide association study (GWAS) data in up to 24,925 adults provided evidence of an effect of childhood body size on 42 of the 123 metabolic markers assessed (based on P<4.07x10-04). Undertaking multivariable MR analyses suggested that the effects for the majority of these metabolic biomarkers (35/42) substantially attenuated when accounting for adult body size. In further analyses, the biomarkers with the strongest evidence of mediating a long-term effect of adiposity on coronary artery disease (CAD) risk were those related to triglyceride-rich very-low-density lipoprotein particles. In contrast, the biomarkers which showed the strongest evidence of being directly influenced by childhood body size (amino acids leucine, isoleucine and tyrosine) provided little evidence that they mediate this effect on adult disease risk. Conclusions: The effects of childhood adiposity on the majority of biomarkers investigated in this study were greatly attenuated when accounting for adult body size. This suggests that the detrimental impact of genetically predicted childhood adiposity on systemic metabolism, as well as subsequent later life risk of CAD, can likely be mitigated through lifestyle modifications during adolescence and early adulthood.

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