Sex-specific regulation of mitochondrial DNA levels : Genome-wide linkage analysis to identify quantitative trait loci
López, Sonia (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Buil, Alfonso (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Souto, Juan Carlos (Institut d'Investigació Biomèdica Sant Pau)
Casademont i Pou, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Blangero, John (Texas Biomedical Research Institute)
Martinez-Perez, Angel (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Fontcuberta, Jordi (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Lathrop, Mark (Centre National de Génotypage (Evry, França))
Almasy, Laura (Texas Biomedical Research Institute)
Soria Fernández, José Manuel (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona

Data:	2012
Resum:	Altered mitochondrial DNA (mtDNA) levels have been associated with common diseases in humans. We investigated the genetic mechanism that controls mtDNA levels using genome-wide linkage analyses in families from the Genetic Analysis of Idiopathic Thrombophilia Project (GAIT). We measure mtDNA levels by quantitative real-time PCR in 386 subjects from 21 extended Spanish families. A variance component linkage method using 485 microsatellites was conducted to evaluate linkage and to detect quantitative trait loci (QTLs) involved in the control of mtDNA levels. The heritalibility of mtDNA levels was 0. 33 (p = 1. 82e-05). We identified a QTL on Chromosome 2 (LOD = 2. 21) using all of the subjects, independently on their sex. When females and males were analysed separately, three QTLs were identified. Females showed the same QTL on Chromosome 2 (LOD = 3. 09), indicating that the QTL identified in the analysis using all of the subjects was a strong female QTL, and another one on Chromosome 3 (LOD = 2. 67), whereas in males a QTL was identified on Chromosome 1 (LOD = 2. 81). These QTLs were fine-mapped to find associations with mtDNA levels. The most significant SNP association was for the rs10888838 on Chromosome 1 in males. This SNP mapped to the gene MRPL37, involved in mitochondrial protein translation. The rs2140855 on Chromosome 2 showed association in the analysis using all of the subjects. It was near the gene CMPK2, which encodes a mitochondrial enzyme of the salvage pathway of deoxyribonucleotide synthesis. Our results provide evidence of a sex-specific genetic mechanism for the control of mtDNA levels and provide a framework to identify new genes that influence mtDNA levels. © 2012 López et al.
Ajuts:	Ministerio de Ciencia e Innovación PI-11/00184 Ministerio de Ciencia e Innovación SAF2008/01859 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-1240
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PloS one, Vol. 7 Núm. 8 (20 2012) , p. e42711, ISSN 1932-6203

DOI: 10.1371/journal.pone.0042711
PMID: 22916149

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