title: Differences in mtDNA haplogroup distribution among 3 Jewish populations alter susceptibility to T2DM complications.
abstract: BACKGROUND
  Recent genome-wide association studies searching for candidate susceptibility loci for common complex diseases such as type 2 diabetes mellitus (T2DM) and its common complications have uncovered novel disease-associated genes. Nevertheless these large-scale population screens often overlook the tremendous variation in the mitochondrial genome (mtDNA) and its involvement in complex disorders.
  
  
  RESULTS
  We have analyzed the mitochondrial DNA (mtDNA) genetic variability in Ashkenazi (Ash), Sephardic (Seph) and North African (NAF) Jewish populations (total n = 1179). Our analysis showed significant differences (p < 0.001) in the distribution of mtDNA genetic backgrounds (haplogroups) among the studied populations. To test whether these differences alter the pattern of disease susceptibility, we have screened our three Jewish populations for an association of mtDNA genetic haplogroups with T2DM complications. Our results identified population-specific susceptibility factors of which the best example is the Ashkenazi Jewish specific haplogroup N1b1, having an apparent protective effect against T2DM complications in Ash (p = 0.006), being absent in the NAF population and under-represented in the Seph population. We have generated and analyzed whole mtDNA sequences from the disease associated haplogroups revealing mutations in highly conserved positions that are good candidates to explain the phenotypic effect of these genetic backgrounds.
  
  
  CONCLUSIONS
  Our findings support the possibility that recent bottleneck events leading to over-representation of minor mtDNA alleles in specific genetic isolates, could result in population-specific susceptibility loci to complex disorders.
authors.affiliation: Department of Life Sciences and National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel. federj@bgu.ac.il
authors.forename: Jeanette
authors.initials: J
authors.lastname: Feder
authors.forename: Ilana
authors.initials: I
authors.lastname: Blech
authors.forename: Ofer
authors.initials: O
authors.lastname: Ovadia
authors.forename: Shirly
authors.initials: S
authors.lastname: Amar
authors.forename: Julio
authors.initials: J
authors.lastname: Wainstein
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.forename: Sarah
authors.initials: S
authors.lastname: Dadon
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.forename: Dan
authors.initials: D
authors.lastname: Mishmar
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D007585:Jews / Q000235:genetics*; D009154:Mutation; D010802:Phylogeny
chemical_list: D004272:DNA, Mitochondrial