Genomic profiling of interpopulation diversity guides prioritization of candidate-genes for autoimmunity.
Autoimmune diseases seem to have strong genetic attributes, and are affected to some extent by shared susceptibility loci. The latter potentially amount to hundreds of candidate genes (CG), creating the need for a prioritization strategy in genetic association studies. To form such a strategy, 26 autoimmune-related CG were genotyped for a total of 72 single nucleotide polymorphisms (SNPs) in three distinct Israeli ethnic populations: Ashkenazi Jews, Sephardic Jews and Arabs. Four quantitative criteria reflecting population stratification were analyzed: allele frequencies, haplotype frequencies, the Fst statistic for homozygotes distribution and linkage disequilibrium extents. According to the consequent interpopulation genomic diversity profiles, the genes were classified into conserved, intermediate and diversified gene groups. Our results demonstrate a correlation between the biological role of autoimmune-related CG and their interpopulation diversity profiles as classified by the different analyses. Annotation analysis suggests that genes more readily influenced by environmental conditions, such as immunological mediators, are 'population specific'. Conversely, genes showing genetic conservation across all populations are characterized by apoptotic and cleaving functions. We suggest a research strategy by which CG association studies should focus first on likely conserved gene categories, to increase the likelihood of attaining significant results and promote the development of gene-based therapies.
Grossman
I
I
Division of Neuroimmunology and Multiple Sclerosis Center, Rappaport Faculty of Medicine and Research Institute, Technion and Carmel Medical Center, Haifa, Israel.
Avidan
N
N
Singer
C
C
Paperna
T
T
Lancet
D
D
Beckmann
J S
JS
Miller
A
A
D000328:Adult; D018912:Arabs / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics*; D017124:Conserved Sequence; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007585:Jews / Q000235:genetics*; D015810:Linkage Disequilibrium; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*