Exploring Mitochondrial Heteroplasmy in Neonates: Implications for Growth Patterns in the First Years of Life

Abstract Background: Mitochondrial heteroplasmy reflects genetic diversity within individuals due to the presence of varying mitochondrial DNA (mtDNA) sequences, possibly affecting mitochondrial function and energy production in cells. Rapid growth during early childhood is a critical development with long-term implications for health and well-being. In this study, we investigated if cord blood mtDNA heteroplasmy is associated with rapid growth at six and 12 months and overweight in childhood at four to six years. Methods: This study included 200 mother-child pairs of the ENVIR ON AGE birth cohort. Whole mitochondrial genome sequencing was performed to determine mtDNA heteroplasmy levels (in variant allele frequency; VAF) in cord blood. Rapid growth was defined for each child as the difference between WHO-SD scores of predicted weight at either six or 12 months and birth weight. Logistic regression models were used to determine the association of mitochondrial heteroplasmy with rapid growth and childhood overweight. Determinants of relevant cord blood mitochondrial heteroplasmies were identified using multiple linear regression models. Results: One % increase in VAF of cord blood MT-D-Loop 16362T>C heteroplasmy was associated with rapid growth at six (OR=1.03; 95% CI: 1.01 to 1.05; p =0.001) and 12 months (OR=1.02; 95% CI: 1.00 to 1.03; p =0.02). Furthermore, this variant was associated with childhood overweight at four to six years (OR=1.01; 95% CI 1.00 to 1.02; p =0.05). Additionally, rapid growth at six (OR=3.00; 95% CI: 1.49 to 6.14; p =0.002) and 12 months (OR=4.05; 95% CI: 2.06 to 8.49; p <0.001) was also associated with childhood overweight at four to six years. Furthermore, we identified maternal age, pre-pregnancy BMI, maternal education, parity, and gestational age as determinants of cord blood MT-D-Loop 16362T>C heteroplasmy. Conclusions: Our findings, based on mitochondrial DNA genotyping, offer insights into the molecular machinery leading to rapid growth in early life, potentially explaining a working mechanism of the development towards childhood overweight.