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

Abstract

While approximately 200 autosomal genetic associations outside of the major histocompatibility complex (MHC) have been identified for multiple sclerosis (MS) risk in European populations, causal variants identified at the majority of these associated loci have been much more elusive. We propose that knowledge gained from replication efforts in Hispanic and African American populations can be utilized to more efficiently fine-map these risk loci. To this end, we have customized a genotyping array by adding ~20,000 bead types (~17,000 variants) to the base content of the Ilumina Infinium expanded multi-ethnic genotyping array and the Infinium ImmunoArray-24 v2 BeadChip. These custom bead types were chosen to allow for the detection of causal variation (1) in the presence of allelic and locus heterogeneity, by incorporating regulatory and coding variation within 1-Mb of previously identified risk variants and (2) in the absence of allelic and locus heterogeneity by incorporation of variants using linkage disequilibrium criteria, which are based on knowledge of replication status in Hispanic and African American study samples. This array has been designed to maximize fine-mapping potential for currently identified MS susceptibility loci, particularly in multi-ethnic populations. The strategies described here could be additionally informative for fine-mapping of other disease phenotypes.

Ancestral risk modification for multiple sclerosis susceptibility detected across the Major Histocompatibility Complex in a multi-ethnic population

“…The current study focused on imputed genomic array data within the MHC containing rich information in genetic ancestry, population genomics, and MS susceptibility. Future research can integrate additional -omics data; including but not limited to transcriptomics, epigenomics, proteomics, and pharmacogenomics to further decipher the relationship between genetic ancestry and MS susceptibility within the MHC and within other known MS loci [ 45 ]; facilitating a comprehensive understanding of precision population health.…”

Genetic Basis of Inflammatory Demyelinating Diseases of the Central Nervous System: Multiple Sclerosis and Neuromyelitis Optica Spectrum

“…The first genetic analyses performed in multiple sclerosis were anonymous genome analyses based on the linkage analysis of the microsatellite markers in multiplexed families. Although they allow the identification of regions of interest outside the MHC, their participation in replication studies cannot be confirmed [41,54,55]. These studies have focused on designing genome-wide arrays aimed at identifying causal variants.…”

Towards a global view of multiple sclerosis genetics

“…Replication studies that focus on the lead SNP at a locus identified in a European population are, by design, primarily concerned with replication of known signals rather than discovery of heterogeneity in associated loci or alleles across populations. These efforts will be advanced by the development of new genotyping arrays designed specifically for cross-ancestry association testing and fine mapping 76 , and by decreasing sequencing costs, which could make sequencing feasible on a consortium scale.…”

“…Identifying sufficiently large numbers of patients with disease can be difficult and is complicated by differential access to healthcare facilities, phenotypic heterogeneity and a low incidence in some populations. We anticipate that the increasing number of international efforts to do this work will eventually lead to GWAS in populations of non-European ancestry with comparable sample sizes and statistical power to studies in populations of Europeanancestry 76 .…”