Abstract
BackgroundRecent 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.ResultsWe 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.ConclusionOur 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.
Highlights
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
The quest for susceptibility genes of common complex disorders such as type 2 diabetes mellitus (T2DM) has led to recent successful discoveries of novel disease-related genes through the use of large scale genome-wide association studies including thousands of patients belonging to major ethnic groups [1]
A total of 1,179 T2DM patients comprised of three populations (762 Ashkenazi Jews [Ash], 191 non-Ashkenazi European Jews [Seph], and 226 North African Jews [NAF]), were genotyped and assigned to different mitochondrial DNA (mtDNA) haplogroups
Summary
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. These large-scale population screens often overlook the tremendous variation in the mitochondrial genome (mtDNA) and its involvement in complex disorders. The quest for susceptibility genes of common complex disorders such as type 2 diabetes mellitus (T2DM) has led to recent successful discoveries of novel disease-related genes through the use of large scale genome-wide association studies including thousands of patients belonging to major ethnic groups [1]. Jews represent an excellent model to study possible association of population-specific alleles with common disorders, including T2DM [5]
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