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

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

International Journal of Epidemiology ◽

10.1093/ije/dyab051 ◽

2021 ◽

Cited By ~ 1

Author(s):

Tom G Richardson ◽

Juha Mykkänen ◽

Katja Pahkala ◽

Mika Ala-Korpela ◽

Joshua A Bell ◽

...

Keyword(s):

Body Size ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Disease Risk ◽

Causal Effect ◽

Direct Effects ◽

Metabolic Markers ◽

Adult Body Size ◽

Childhood Adiposity ◽

Adult Body

Abstract Background Individuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways. Methods Two-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls. Results Univariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P < 4.07 × 10−4). However, the majority of these effects (35/42) substantially attenuated when accounting for adult body size using multivariable MR. We found little evidence that the biomarkers that were potentially influenced directly by childhood body size (leucine, isoleucine and tyrosine) mediate this effect onto adult disease risk. Very-low-density lipoprotein markers provided the strongest evidence of mediating the long-term effect of adiposity on CAD risk. Conclusions Our findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.

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Mendelian Randomization Analyses Suggest Childhood Body Size Indirectly Influences End Points From Across the Cardiovascular Disease Spectrum Through Adult Body Size

Journal of the American Heart Association ◽

10.1161/jaha.121.021503 ◽

2021 ◽

Author(s):

Grace M. Power ◽

Jessica Tyrrell ◽

Timothy M. Frayling ◽

George Davey Smith ◽

Tom G. Richardson

Keyword(s):

Cardiovascular Disease ◽

Body Size ◽

Mendelian Randomization ◽

Disease Risk ◽

Adult Body Size ◽

Disease Spectrum ◽

Disease Outcomes ◽

Increased Risk ◽

Adult Body ◽

Artery Disease

Background Obesity is associated with long‐term health consequences including cardiovascular disease. Separating the independent effects of childhood and adulthood obesity on cardiovascular disease risk is challenging as children with obesity typically remain overweight throughout the lifecourse. Methods and Results This study used 2‐sample univariable and multivariable Mendelian randomization to estimate the effect of childhood body size both independently and after accounting for adult body size on 12 endpoints across the cardiovascular disease disease spectrum. Univariable analyses identified strong evidence of a total effect between genetically predicted childhood body size and increased risk of atherosclerosis, atrial fibrillation, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral artery disease, and varicose veins. However, evidence of a direct effect was weak after accounting for adult body size using multivariable Mendelian randomization, suggesting that childhood body size indirectly increases risk of these 8 disease outcomes via the pathway involving adult body size. Conclusions These findings suggest that the effect of genetically predicted childhood body size on the cardiovascular disease outcomes analyzed in this study are a result of larger body size persisting into adulthood. Further research is necessary to ascertain the critical timepoints where, if ever, the detrimental impact of obesity initiated in early life begins to become immutable.

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A new module of AFRIMS’ spoon for larval food quantity affects development time, survival and adult body size ofAnopheles dirusunder laboratory conditions

10.1603/ice.2016.109374 ◽

2016 ◽

Author(s):

Kanchana Pantuwattana

Keyword(s):

Body Size ◽

Development Time ◽

Larval Food ◽

Adult Body Size ◽

Laboratory Conditions ◽

Food Quantity ◽

Adult Body

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Heritability and adaptive phenotypic plasticity of adult body size in the mosquito Aedes aegypti with implications for dengue vector competence

Infection Genetics and Evolution ◽

10.1016/j.meegid.2010.10.019 ◽

2011 ◽

Vol 11 (1) ◽

pp. 11-16 ◽

Cited By ~ 33

Author(s):

Jennifer R. Schneider ◽

Dave D. Chadee ◽

Akio Mori ◽

Jeanne Romero-Severson ◽

David W. Severson

Keyword(s):

Body Size ◽

Phenotypic Plasticity ◽

Aedes Aegypti ◽

Vector Competence ◽

Dengue Vector ◽

Adult Body Size ◽

Adult Body ◽

Adaptive Phenotypic Plasticity

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Grass-flower thrips of the genus Chirothrips (Thysanoptera: Thripidae), with a key to species from Iran

Zootaxa ◽

10.11646/zootaxa.2411.1.3 ◽

2010 ◽

Vol 2411 (1) ◽

pp. 33 ◽

Cited By ~ 4

Author(s):

KAMBIZ MINAEI ◽

LAURENCE MOUND

Keyword(s):

Body Size ◽

Species Group ◽

Identification Key ◽

Key To Species ◽

Adult Body Size ◽

Flower Thrips ◽

New Synonym ◽

Adult Body ◽

Structural Differences

Species of the genus Chirothrips Haliday breed and pupate only within grass florets. Each larva is restricted to a single floret, and adult body size is thus presumably related to floret size. Despite this, some Chirothrips species are distinguished only on states that are related to body size. The validity of some commonly recorded members of the C. manicatus species-group, including C. africanus and C. pallidicornis, is therefore considered questionable. Character states that have been used to define the genus Agrostothrips Hood are shown to be variable, and this genus is placed as a new synonym of Chirothrips. An identification key, based on illustrated structural differences, is provided to the Chirothrips known from Iran: C. aculeatus, C. atricorpus, C. kurdistanus, C. manicatus, C. meridionalis and C. molestus.

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Polygenic Hyperlipidemias and Coronary Artery Disease Risk

10.1101/735167 ◽

2019 ◽

Author(s):

Pietari Ripatti ◽

Joel T Rämö ◽

Nina J Mars ◽

Sanni Söderlund ◽

Christian Benner ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Genome Wide Association Study ◽

Disease Risk ◽

Cumulative Exposure ◽

Risk Scores ◽

Lipid Levels ◽

Artery Disease ◽

The Impact ◽

Cad Risk

AbstractBackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.Methods and ResultsWe derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95th percentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).ConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

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