Mitochondrial DNA variants in obesity.
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.
Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
Nadja
N
Knoll
Institute of Medical Biometry and Epidemiology, Philipps-University of Marburg, Marburg, Germany.
Ivonne
I
Jarick
Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
Anna-Lena
AL
Volckmar
Molecular Nutritional Medicine, Technical University of Munich, Else Kröner-Fresenius Center, Freising-Weihenstephan, Germany.
Martin
M
Klingenspor
Research Unit of Molecular Epidemiology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
Thomas
T
Illig
Research Unit of Molecular Epidemiology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
Harald
H
Grallert
Institute of Genetic Epidemiology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.
Christian
C
Gieger
Institute of Epidemiology I, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany, Neuherberg, Germany; Institute of Medical Informatics, Biometry, and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany; Munich University Hospital, Campus Grosshadern, Munich, Germany.
Heinz-Erich
HE
Wichmann
Institute of Epidemiology II, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.
Annette
A
Peters
Institute of Experimental Pediatric Endocrinology, Charité Berlin, Germany.
Susanna
S
Wiegand
Institute of Experimental Pediatric Endocrinology, Charité Berlin, Germany.
Heike
H
Biebermann
Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University of Ulm University Medical Center, Ulm, Germany.
Pamela
P
Fischer-Posovszky
Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University of Ulm University Medical Center, Ulm, Germany.
Martin
M
Wabitsch
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Henry
H
Völzke
Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Matthias
M
Nauck
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Alexander
A
Teumer
Institute for Pharmacology, University Medicine Greifswald, Greifswald, Greifswald, Germany.
Dieter
D
Rosskopf
Institute for Pharmacology, University Medicine Greifswald, Greifswald, Greifswald, Germany.
Christian
C
Rimmbach
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Stefan
S
Schreiber
Institute of Epidemiology and Biobank popgen, Christian-Albrechts-University of Kiel, Kiel, Germany.
Gunnar
G
Jacobs
Institute of Epidemiology and Biobank popgen, Christian-Albrechts-University of Kiel, Kiel, Germany.
Wolfgang
W
Lieb
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Andre
A
Franke
Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
Johannes
J
Hebebrand
Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.
Anke
A
Hinney
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
D004272:DNA, Mitochondrial