Mitochondrial DNA variants in obesity

Area of Science:

• Genetics
• Obesity Research
• Human Physiology

Background:

• High heritability estimates for body mass index (BMI) variation are established.
• Maternal inheritance patterns show higher BMI correlations between mothers and offspring compared to fathers.
• Mitochondrial DNA (mtDNA), exclusively maternally inherited, is hypothesized to influence this parental effect.

Purpose of the Study:

• To investigate the potential contribution of mitochondrial DNA (mtDNA) variations to body mass index (BMI) heritability.
• To explore the association between mtDNA single nucleotide polymorphisms (SNPs) and obesity in a case-control study.
• To determine if mtDNA variation explains the stronger BMI correlation between mothers and offspring.

Main Methods:

• Analysis of 32-40 mtDNA SNPs using genome-wide association study (GWAS) SNP arrays.
• Case-control (CC) discovery sample: 1,158 extremely obese children/adolescents vs. 435 lean adult controls.
• Independent confirmation sample: 7,014 population-based adults (1,697 obese vs. 2,373 normal weight/lean).
• SNP and haplogroup analysis (HaploGrep), Fisher's exact test.
• D-loop region re-sequencing (Sanger) in 192 obese children and 192 lean adults.

Main Results:

• Nominal association of allele G (m.8994G/A, rs28358887) in ATP6 with obesity in the discovery phase (p=0.002).
• Nominal overrepresentation of Haplogroup W in lean controls (p=0.039).
• These initial findings were not independently confirmed.
• Two D-loop variants (m.16292C/T, m.16189T/C) showed nominal association with obesity in the discovery phase.
• Limited presence of the m.16292T allele, primarily in controls belonging to Haplogroup W.

Conclusions:

• The study did not substantiate the hypothesis that exclusively maternally inherited mtDNA variation contributes to higher BMI correlations between mothers and offspring.
• While some D-loop variants warrant further investigation, the primary hypothesis was not supported by the findings.
• The observed associations were nominal and lacked independent confirmation, suggesting no significant role for mtDNA in this specific maternal effect on BMI.