Genetic and Phenotypic Analysis of Multiple Sclerosis in Hispanics

We sought to identify MS susceptibility variants specific to the Major Histocompatibility Complex and to assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals, as well as 2435 Black and African American individuals ascertained in collaboration with the Alliance for Research in Hispanic MS (ARHMS). All DNA samples were obtained through whole blood extraction and were genotyped on the MS Chip, an Illumina Infinium custom genotyping array that contains targeted and dense coverage of the extended MHC, specifically designed for imputation. Classical HLA alleles, SNPs, and amino acid residues were imputed simultaneously from genotyped SNPs using HLA-TAPAS and a multi-ethnic reference panel of 2504 samples from the 1000 Genomes Project. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have identified an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus; and we have identified several susceptibility variants for which MS risk is modified by global or local ancestry. We are making data on all genotyped and imputed SNPs, classical HLA alleles, and amino acid residues available through dbGaP for the Hispanic and African American samples utilized in these analyses.]]>
MS cases were excluded due to failure to satisfy McDonald criteria. Cases with pediatric onset were not specifically excluded but comprise < 5% of each of the study samples. Controls were excluded due to self-reported diagnosis or known family history of MS or other autoimmune disease. Additional exclusions based on available genotypic data include samples exhibiting low genotyping call rate (≤ 98%), discrepancy between reported and genotyped sex, excess autosomal heterozygosity ≥ 3 SD from the mean), and excess identity by descent signifying a sample duplication or relatedness (proportion IBD > 0.2). Additionally, principal components analysis was used to remove population specific outliers beyond 6 standard deviations from the mean of any of the first 10 principal components, separately within the Hispanic and African American sample.]]>