The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States

Abstract

Background: Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States. Objective: We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex ( n = 200) within these populations. Methods: Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses. Results: We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene–environment or gene–gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability. Conclusion: These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

Assessment of Racial/Ethnic Disparities in Volumetric MRI Correlates of Clinical Disability in Multiple Sclerosis: A Preliminary Study

“…Consistent with previous reports, 2,17 the Hispanic subjects in our cohort were more likely to present with optic neuritis and transverse myelitis at onset, to have a higher risk for development of ambulatory disability, and to lose employment as a result of disease compared to Caucasians with MS. Epidemiological data in MS suggest that socioeconomic disparities and barriers to healthcare access may account, at least in part, for the differences in clinical outcome across racial groups. 18,19 However, due to the lack of significant socioeconomic disparities between our matched study cohorts, the racial/ethnic differences we identified cannot be ascribed to socioeconomic factors alone, and may be better explained by a complex interaction between genetic predisposition and environmental factors.…”

Fine-Mapping Array Design for Multi-Ethnic Studies of Multiple Sclerosis

“…In our previous replication study in Hispanics and African Americans [8], we found that not all of the 200 currently identified variants were replicated among these minority populations. In fact, less replication was found than expected, particularly among African Americans.…”

“…This inconsistency could be due to limited participant engagement, making it difficult to attain the sample sizes necessary to achieve adequate power. This is true in Hispanic and African American MS study samples (with sizes currently approaching ~2000 cases and ~2000 controls in the Alliance for Research in Hispanic MS (ARHMS)) [8]; while European MS study samples currently approach 110,00 in the IMSGC (~50,000 MS cases and ~60,000 controls) [1]. Yet, the admixture and unique LD structure of Hispanics and African Americans make them distinctly valuable for localizing association signals and identifying causal variants, despite the limited sample size.…”

“…We additionally designed the custom content to allow for detection of causal variation in the absence of allelic and locus heterogeneity by leveraging information regarding the replication status of each of the 200 autosomal non-MHC variants in our Hispanic and African American samples [8]. We extracted 3,207,498 variants that were within 1-Mb of each of the 200 variants from 1000 Genomes Project populations (phase 3, version 5) of unrelated non-Finnish Europeans (NFE: 403 individuals of northern and western European ancestry in Utah (CEU), Toscani in Italy (TSI), British in England and Scotland (GBR), and Iberians in Spain (IBS)); African Americans (AA: 149 individuals of African ancestry in southwestern United States (ASW), and African Caribbeans in Barbados (ACB)); and Hispanics (AMR: 338 individuals of Mexican ancestry in Los Angeles (MXL), Puerto Ricans in Puerto Rico (PUR), Colombians in Colombia (CLM), and Peruvians in Peru (PEL)).…”

“…These variants were then filtered further using LD criteria, which were specific to replication statuses based on the previous replication study [8]. For the 16 variants that were replicated in both the Hispanic and African American samples (one-sided p ≤ 0.05), the square of the correlation coefficient (R 2 ) ≥ 0.1 with the associated variant was required from 1000 Genomes’ NFE, AMR, and AA samples.…”