Abstract
Background/ObjectivesWhole-exome sequencing is a valuable tool to determine genetic variations that are associated with rare and common health conditions. A limited number of studies demonstrated that mitochondrial DNA can be captured using whole-exome sequencing. Previous studies have suggested that mitochondrial DNA variants and haplogroup lineages are associated with obesity. Therefore, we investigated the role of mitochondrial variants and haplogroups contributing to the risk of obesity in Arabs in Kuwait using exome sequencing data.Subjects/MethodsIndirect mitochondrial genomes were extracted from exome sequencing data from 288 unrelated native Arab individuals from Kuwait. The cohort was divided into obese [body mass index (BMI) ≥ 30 kg/m2] and non-obese (BMI < 30 kg/m2) groups. Mitochondrial variants were identified, and haplogroups were classified and compared with other sequencing technologies. Statistical analysis was performed to determine associations and identify mitochondrial variants and haplogroups affecting obesity.ResultsHaplogroup R showed a protective effect on obesity [odds ratio (OR) = 0.311; P = 0.006], whereas haplogroup L individuals were at high risk of obesity (OR = 2.285; P = 0.046). Significant differences in mitochondrial variants between the obese and non-obese groups were mainly haplogroup-defining mutations and were involved in processes in energy generation. The majority of mitochondrial variants and haplogroups extracted from exome were in agreement with technical replica from Sanger and whole-genome sequencing.ConclusionsThis is the first to utilize whole-exome data to extract entire mitochondrial haplogroups to study its association with obesity in an Arab population.
Highlights
Mitochondria play a role in generating cellular energy via oxidative phosphorylation (OXPHOS), reactive oxygen species production, and apoptosis
Haplogroup R showed a protective effect on obesity [odds ratio (OR) = 0.311; P = 0.006], whereas haplogroup L individuals were at high risk of obesity (OR = 2.285; P = 0.046)
The majority of mitochondrial variants and haplogroups extracted from exome were in agreement with technical replica from Sanger and whole-genome sequencing
Summary
Mitochondria play a role in generating cellular energy via oxidative phosphorylation (OXPHOS), reactive oxygen species production, and apoptosis. Human mitochondrial DNA (mtDNA) is circular, double-stranded, and 16,569 base pairs (bp) in size and contains 37 genes that code for 22 transfer RNAs, two ribosomal RNAs that are necessary for protein synthesis, and 13 messenger RNAs that are required for OXPHOS (Anderson et al, 1981; Andrews et al, 1999). MtDNA contains a major non-coding region called the control/D-loop region, which regulates mitochondrial transcription and replication. The mitochondrial control region is located at mitochondrial nucleotide positions 16,024–576 and is susceptible to a high rate of mtDNA alterations, at the hypervariable regions (Greenberg et al, 1983) as well as under conditions of increased oxidative stress (Clayton, 2000). MtDNA variants are maternally inherited without recombination and may accumulate over time. A mitochondrial haplogroup is a group of individuals who share the same accumulated mtDNA variants and can be geographically restricted, making traceable via maternal linage. The sub-Saharan Africans are characterized by L0–L6; the South Asians by haplogroups R5–R8, M2–M6, and M4–67; the Europeans, Southwest Asians, and North Africans by haplogroups U, HV, JT, N1, N2, and X; and the East Asians by haplogroups A–G, Z, and M7–M9 (Loogvali et al, 2004; Chaubey et al, 2007; Soares et al, 2010; Kivisild, 2015)
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