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Background <p>Mitochondria, the cell’s powerhouse, play a central role in energy homeostasis and may influence obesity risk. Variations in mitochondrial DNA (mtDNA) have been hypothesized to influence early-life metabolic programming; however, prospective evidence remains limited, and no study has jointly examined multiple mtDNA biomarkers. We aimed to investigate the individual and combined associations of cord blood mtDNA heteroplasmy and copy number with the risk of childhood overweight or obesity (OWO).</p> Methods <p>Data were obtained from 952 children enrolled at birth and followed longitudinally in the Boston Birth Cohort. Body mass index (BMI) z scores were calculated using U.S. reference data, and OWO was defined as BMI ≥85th percentile for age and sex. Cord blood mtDNA heteroplasmy and copy number were assessed by targeted sequencing, with functional region heteroplasmy defined as heteroplasmic variants in coding regions and classified as inherited or de novo. Mixed-effects models were used to evaluate associations between mtDNA measures and repeated measures of child BMI and OWO.</p> Results <p>In sex-specific analyses, de novo functional region heteroplasmy was associated with higher BMI z score (<i>β</i> = 0.29, 95% CI: 0.01, 0.57) and increased risk of OWO (RR = 1.46, 95% CI: 1.07, 2.00) among girls, whereas no associations were observed overall. BMI associations were more evident in adolescent girls (aged 10–18 years). MtDNA copy number <i>z</i> score was negatively associated with BMI in children with overall or de novo functional region heteroplasmy but showed modest positive associations in those without specific heteroplasmy (p for interaction &lt; 0.05).</p> Conclusions <p>Cord blood mtDNA heteroplasmy and copy number interactively influence the risk of childhood OWO, with associations varying by sex and age. This is the first prospective study to jointly evaluate these mtDNA biomarkers, offering new insight into mitochondrial contributions to the developmental origins of OWO and a potential framework for early-life risk assessment.</p> <p></p>

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Association of cord blood mitochondrial DNA heteroplasmy and copy number with childhood overweight or obesity

  • 期刊论文

  • 发表日期：

    2026年4月14日

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  • Xueqi Qu,
  • Guoying Wang,
  • Xiumei Hong,
  • Jessica An,
  • Hilary J. Vernon,
  • Xiaobin Wang

摘要

Background

Mitochondria, the cell’s powerhouse, play a central role in energy homeostasis and may influence obesity risk. Variations in mitochondrial DNA (mtDNA) have been hypothesized to influence early-life metabolic programming; however, prospective evidence remains limited, and no study has jointly examined multiple mtDNA biomarkers. We aimed to investigate the individual and combined associations of cord blood mtDNA heteroplasmy and copy number with the risk of childhood overweight or obesity (OWO).

Methods

Data were obtained from 952 children enrolled at birth and followed longitudinally in the Boston Birth Cohort. Body mass index (BMI) z scores were calculated using U.S. reference data, and OWO was defined as BMI ≥85th percentile for age and sex. Cord blood mtDNA heteroplasmy and copy number were assessed by targeted sequencing, with functional region heteroplasmy defined as heteroplasmic variants in coding regions and classified as inherited or de novo. Mixed-effects models were used to evaluate associations between mtDNA measures and repeated measures of child BMI and OWO.

Results

In sex-specific analyses, de novo functional region heteroplasmy was associated with higher BMI z score (β = 0.29, 95% CI: 0.01, 0.57) and increased risk of OWO (RR = 1.46, 95% CI: 1.07, 2.00) among girls, whereas no associations were observed overall. BMI associations were more evident in adolescent girls (aged 10–18 years). MtDNA copy number z score was negatively associated with BMI in children with overall or de novo functional region heteroplasmy but showed modest positive associations in those without specific heteroplasmy (p for interaction < 0.05).

Conclusions

Cord blood mtDNA heteroplasmy and copy number interactively influence the risk of childhood OWO, with associations varying by sex and age. This is the first prospective study to jointly evaluate these mtDNA biomarkers, offering new insight into mitochondrial contributions to the developmental origins of OWO and a potential framework for early-life risk assessment.