Mitochondrial DNA variants in obesity

PLoS One. 2014 May 2;9(5):e94882. doi: 10.1371/journal.pone.0094882. eCollection 2014.

Abstract

Heritability estimates for body mass index (BMI) variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers. Variation(s) in the exclusively maternally inherited mitochondrial DNA (mtDNA) might contribute to this parental effect. Thirty-two to 40 mtDNA single nucleotide polymorphisms (SNPs) were available from genome-wide association study SNP arrays (Affymetrix 6.0). For discovery, we analyzed association in a case-control (CC) sample of 1,158 extremely obese children and adolescents and 435 lean adult controls. For independent confirmation, 7,014 population-based adults were analyzed as CC sample of n = 1,697 obese cases (BMI ≥ 30 kg/m2) and n = 2,373 normal weight and lean controls (BMI<25 kg/m2). SNPs were analyzed as single SNPs and haplogroups determined by HaploGrep. Fisher's two-sided exact test was used for association testing. Moreover, the D-loop was re-sequenced (Sanger) in 192 extremely obese children and adolescents and 192 lean adult controls. Association testing of detected variants was performed using Fisher's two-sided exact test. For discovery, nominal association with obesity was found for the frequent allele G of m.8994G/A (rs28358887, p = 0.002) located in ATP6. Haplogroup W was nominally overrepresented in the controls (p = 0.039). These findings could not be confirmed independently. For two of the 252 identified D-loop variants nominal association was detected (m.16292C/T, p = 0.007, m.16189T/C, p = 0.048). Only eight controls carried the m.16292T allele, five of whom belonged to haplogroup W that was initially enriched among these controls. m.16189T/C might create an uninterrupted poly-C tract located near a regulatory element involved in replication of mtDNA. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and their offspring could not be substantiated by the findings of the present study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Case-Control Studies
  • DNA, Mitochondrial / genetics*
  • Female
  • Genome-Wide Association Study*
  • Haplotypes / genetics
  • Humans
  • Male
  • Middle Aged
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide*
  • Sequence Analysis, DNA
  • Young Adult

Substances

  • DNA, Mitochondrial

Grants and funding

This work was supported by grants of the German Research Foundation (HI865/2-1), the German Federal Ministry of Education and Research (01KU0903, 01GS0830, 01GS0820), the European Community's Seventh Framework Program (FP7/2007–2013, grant number 245009) and the IFORES program of the University of Duisburg-Essen. The KORA research platform (KORA), Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Data of the Study of Health of Pomerania (SHIP) were provided by the research alliance “Community Medicine” of the medical faculty of the Ernst-Moritz-Arndt University of Greifswald and supported by grants of the German Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, 01ZZ0701, D352300006 and 03ZIK012). Genotyping in SHIP was partly funded by Siemens Healthcare. The popgen 2.0 network is supported by a grant from the German Federal Ministry of Education and Research (01EY1103). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.