Phenome-Wide Investigation of the Causal Associations between Childhood BMI and Adult Outcomes Using Two-Sample Mendelian Randomization

Abstract

Background: The causal effects of childhood obesity have not been systematically characterized. We aimed to assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR). Methods: Over 5,000 datasets for adult outcomes were obtained from various resources. After data filtering, 269 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. The number of independent outcomes was 148, setting the significant threshold as P < 3.38 × 10-4. Inverse-variance weighted method, MR-Egger, weighted median method, and weighted mode method were used to estimate the causal effects. Findings: We identified potential causal effects of childhood obesity on 92 adult traits (48 disease-related traits, 35 lifestyle factors, and 9 other traits). Higher childhood BMI was associated with a reduced overall health rating (β = −0.10, 95% CI: −0.13 to −0.07, P = 6.26 × 10-11) and lower average total household income before tax (β = −0.0576, 95% CI: −0.0862 to −0.0291, P = 7.57 × 10 -5 ). Findings on diseases included some novel effects, such as the adverse effects of higher childhood BMI on venous thromboembolic disease (OR = 1.06, 95% CI: 1.03 to 1.09, P = 2.09 × 10 -4). For dietary habits, we found that higher childhood BMI was positively associated adult diet portion size (β = 0.26, 95% CI: 0.18 to 0.34, P= 7.34 × 10-11) and variation in diet (β = 0.06, 95% CI: 0.03 to 0.09, P = 3.15 × 10-5). The association between adulthood BMI and heel bone mineral density no longer existed after excluding the SNPs existing in or in linkage disequilibrium with childhood BMI. Network MR analyses suggested that past tobacco smoking, variation in diet and portion size mediated 6.39%, 3.29%, and 10.90% of the associations between childhood BMI and Type 2 Diabetes, respectively. Interpretation: In summary, childhood obesity is a risk factor for general health outcomes and socioeconomic status. The importance of control portion size and reduce dietary variation is noted. The positive association between adulthood BMI and heel BMD depend on childhood BMI. Our results highlight the need to intervene in childhood to reduce obesity from a young age and its later-life effects. Funding Statement: This study is supported by the National Natural Science Foundation of China: (31871264, 31701095); Natural Science Basic Research Program Shaanxi Province (2018JQ3058,); Innovative Talent Promotion Plan of Shaanxi Province for Young Sci-Tech New Star (2018KJXX-010), the Fundamental Research Funds for the Central Universities. This work was also supported by the high performance computing platform of Xi’an Jiaotong University. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: All data are publicly available through data resources indicated in the methods.