An ImmunoChip study of multiple sclerosis risk in African Americans

Abstract

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, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 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 < 10(-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 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk.

Keywords: African Americans; ImmunoChip; linkage disequilibrium; multiple sclerosis.

Isobe et al. genotype 803 African American multiple sclerosis cases and 1,516 controls using the ImmunoChip custom array (130,135 SNPs). The results show shared genetic contributions to risk across ancestral groups and highlight the power of trans-ancestral studies to discover novel candidate susceptibility loci and fine-map established regions of interest.

Figure 1

Principal component analysis of the African American Immunochip data set with reference to samples from the 1000 Genome Project. African American (AfAm) case/control samples are shown as ‘+’ and reference samples from the 1000 Genome Project are shown as closed circles. YRI and LWK = Africans; ASW = African Americans; CEU, TSI, FIN, GBR and IBS = Europeans; MXL, PUR, CLM = Central-South Americans; CHB, CHS and JPN = Asians.

Figure 2

Circos plot of ImmunoChip in African Americans. The outermost track shows the autosomal chromosomes. The second track indicates the genes closest to the non-MHC multiple sclerosis-associated variants. Gene names of replicated loci in African Americans with identical SNPs as Europeans are shown in bold black, replicated loci with alternate variants are shown in bold blue, and unreplicated loci are shown in grey. The replicated novel multiple sclerosis locus in African Americans is indicated in bold red. The innermost track indicates –log₁₀(P) (two-tailed test) of association tests for each ImmunoChip SNP from African Americans (dark blue) and Europeans (light blue). The range of y-axis is 0–8, excluding the peaks of Europeans with higher significance. The dark red line in the middle of the plot represents –log₁₀(P) = 4.

Figure 3

Narrowing in the causative region using African American data set.. Comparative association plots for the loci of (A) PVT1/MIR1208 and (B) MMEL1 of (i) African Americans after fine mapping with imputation; and (ii) the discovery data set of European ImmunoChip. SNPs with the top association P-values are shown in purple with SNP IDs. For the plots of African Americans, genotyped SNPs are shown in closed circles and imputed ones in closed triangles. Colours of the marks represent linkage disequilibrium (r²) with the top SNP in each population. Chromosomal positions are based on human genome 19. Note differences in the scales of y-axis.