Exploring Genetic Variants Associated with Multiple Sclerosis in African-Americans
Multiple sclerosis (MS) is a complex, autoimmune disease of the central nervous system, which disproportionately affects individuals of European descent. Recent research has turned to understanding the genetic factors behind this, especially in African-American populations who carry both European and African genetic ancestry. A groundbreaking study conducted by Nathan Nakatsuka and colleagues in 2020, published in Scientific Reports, explores how two specific genetic variants explain much of the increased risk of MS observed in African-Americans with European ancestry.
Admixture Mapping: A Powerful Tool in Genetic Research
The researchers utilized admixture mapping, a method ideal for studying populations with mixed ancestries, like African-Americans. In these populations, genetic segments from different ancestral backgrounds can be traced, enabling scientists to pinpoint regions of the genome where disease risk may vary. This approach is particularly powerful when studying MS because individuals of European ancestry have a higher prevalence of the disease than those of African ancestry. The average African-American genome is about 20% European, making it a suitable population to study how genetic contributions from these two ancestries influence disease risk.
Chromosome 1: A Key Region Linked to MS Risk
In this study, the team analyzed the genomes of 1305 African-American MS patients and 1155 controls. The initial findings replicated a signal first detected in 2005, identifying a significant association between European ancestry and MS risk on chromosome 1. The key to this risk, as revealed by further genetic analysis, lies in two specific variants located near the CD58 and FCRL3 genes.
The CD58 gene, a known immune regulatory gene, had previously been linked to MS susceptibility in European populations. The variant near CD58 associated with decreased gene expression increases MS risk. The second variant, located near the FCRL3 gene, is involved in immune function and similarly contributes to the increased risk in individuals with European ancestry. The researchers found that these two variants together are sufficient to explain the increased MS risk seen in African-Americans with higher European genetic ancestry at this locus.
The Impact of European Ancestry on MS Risk in African-Americans
Through their analyses, the authors estimated that the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans. However, the risk for African-Americans carrying two copies of European ancestry at this specific locus could be even higher, approaching a nearly two-fold increased risk. These findings emphasize that European ancestry is a significant contributor to MS susceptibility in African-Americans, and the CD58 variant plays a particularly central role.
Fine-Mapping Genetic Risk: Lessons from African-American Genomes
One of the study's key revelations is the utility of fine-mapping in populations of African ancestry. Due to differences in linkage disequilibrium (LD) patterns—how variants are inherited together—African genomes provide a clearer view of the true causal variants behind disease risk. In this case, the shorter LD blocks in African genomes allowed the researchers to more precisely identify the variants associated with MS. This precision is less attainable in European populations, where LD patterns make it harder to distinguish between closely linked genetic variants.
Implications for Genetic and Environmental Interactions in MS
While the study focused on genetic factors, it also acknowledged that environmental factors play a crucial role in MS risk. The complex interplay between genes and environment may contribute to the variability in MS prevalence between different populations. For instance, African-Americans with European ancestry might have different environmental exposures than European-Americans, potentially influencing the effect of these genetic variants.
Future Directions in MS Research
This research highlights the importance of studying diverse populations to uncover the genetic underpinnings of complex diseases like MS. The findings demonstrate that even in smaller sample sizes, African-American genetic data can provide valuable insights into disease risk and help refine our understanding of genetic susceptibility in multi-ethnic populations. Going forward, further studies are needed to explore how these genetic variants interact with environmental factors and how they contribute to the overall risk of MS across different populations.
In conclusion, Nakatsuka et al.’s 2020 study provides compelling evidence that two genetic variants, located near the CD58 and FCRL3 genes, explain much of the increased MS risk associated with European ancestry in African-Americans. By utilizing admixture mapping and fine-mapping techniques, the researchers have shed light on the complex genetic architecture of MS and set the stage for future studies aimed at unraveling the intricate web of genetic and environmental interactions that drive MS susceptibility.
References:
Nakatsuka, N., Patterson, N., Patsopoulos, N. A., Altemose, N., Tandon, A., Beecham, A. H., ... & Reich, D. (2020). Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans. Scientific reports, 10(1), 16902.
