A Genome-Wide Homozygosity Association Study Identifies Runs of Homozygosity Associated with Rheumatoid Arthritis in the Human Major Histocompatibility Complex

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (−log10(p)>22.6591). RA-susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (−log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ∼40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases

Benign recurrent intrahepatic cholestasis (BRIC):evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. Ln the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region, Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 legion, or that represents incomplete penetrance of the BRIC genotype

Benign recurrent intrahepatic cholestasis (BRIC):evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. Ln the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region, Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 legion, or that represents incomplete penetrance of the BRIC genotype