An ImmunoChip study of multiple sclerosis risk in African Americans

Abstract

*These authors contributed equally to this work.The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, 470% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P 5 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P 5 10 À 4 ), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 Â 10 À 5 ). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk.

The Genetics of Multiple Sclerosis

“…This could be done by employing batteries of genetic markers saturating the region of interest as well as by analyzing populations with different LD patterns. In this regard, we recently reported the analysis resulting from genotyping an African American MS dataset with the ImmunoChip platform (47). African American genomes possess shorter LD, reflecting their unique ancestral history, a characteristic that facilitated narrowing down the association to tumor necrosis factor receptor superfamily member 14 (TNFRSF14) in a confirmed locus that included tetratricopeptide repeat domain 34 (TTC34), LOC115110, membrane metalloendopeptidase like 1 (MMEL1), TNFRSF14, and family with sequence similarity 213 member B (FAM213B) as candidate genes.…”

Association Study of Two Polymorphisms in Vitamin D Pathway with Multiple Sclerosis in the Moroccan Population

“…Regarding rs2248359 (CYP24A1), besides the IMSGC/WTCCC2 study [13], only one other found an association between this polymorphism and MS risk. It was conducted exclusively on African Americans subjects (803 MS cases and 1516 controls) in order to determine if MS-associated loci discovered in European populations also influence susceptibility in African Americans [33]. However, two other studies found no association between rs2248359 and MS status within German [34] and Chinese populations [35].…”

Multiple sclerosis, a treatable disease

“…21 In terms of genetic susceptibility, the results of large genome-wide association studies (GWAS) have demonstrated the strongest susceptibility signal maps to HLA-DRB1 in the class II region of the major histocompatibility complex (MHC, 6p21.3) and accounts for 10% of the genetic variance underlying risk. 22,23 As MS affects a young adult population, the disease has a huge socioeconomic impact. Studies have shown that the costs of lost employment and productivity far outweigh the costs for health and social care in the UK.…”