Publication Date

2019-12-09

Availability

Open access

Embargo Period

2019-12-09

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Human Genetics and Genomics (Medicine)

Date of Defense

2019-10-23

First Committee Member

Jacob L. McCauley

Second Committee Member

Eden R. Martin

Third Committee Member

Margaret A. Pericak-Vance

Fourth Committee Member

Alberto Pugliese

Fifth Committee Member

Nikolaos A. Patsopoulos

Abstract

Notable progress has been made towards unraveling the genetic architecture of multiple sclerosis (MS) within ancestral European populations; with 200 confirmed variants outside of the Major Histocompatibility Complex (MHC) explaining ~19% of the genetic predisposition to MS, and the MHC alone explaining ~20%. However, the genetics of MS in Hispanics and African Americans remains largely understudied. I proposed to examine the role of the previously confirmed non-MHC MS risk loci in United States patient populations of Hispanics and African Americans and to identify novel loci. In Hispanics, I proposed to extend these analyses; both to characterize the MHC and to assess the relationship between genetic ancestry and MS clinical presentation. The role of the 200 previously confirmed non-MHC risk variants was examined in 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). Fewer marginal associations were observed than would be expected based on power in African Americans (observe 41, expect 69 with 95% CI: 57-82), but were within expectation for Hispanics (observe 70, expect 80 with 95% CI: 67-93). These findings among African Americans could be due to limited correlation between tested and causal variants or could alternatively indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. 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. These findings have provided a framework for fine-mapping of MS risk loci in multi-ethnic populations of MS and have subsequently been used to design a custom genotyping array for this purpose. To identify novel MS risk loci, I completed an admixture mapping scan in Hispanics (187 MS cases, 46 controls) and African Americans (973 MS cases, 1354 controls), utilizing the ImmunoChip. Evidence for local ancestry association with MS; with more African ancestry in MS cases than controls, was seen at the NOD2 locus in African Americans (suggestive at p < 0.001) and Hispanics (nominal at p < 0.1). This region has not been previously associated with MS in much larger European populations and may be indicative of an African-specific risk haplotype. In the Hispanic study sample, conditional modeling identified 13 independent signals across the MHC (p < 0.001) including classical alleles: DQB1*6:02, A*2:01, DQB1*3:02, DQB1*2:01. Admixture mapping highlighted an increase in European ancestry in MS cases across class II alleles; whereas an increase in Native American ancestry was observed in MS controls across class I alleles. Protective Native American haplotypes may be present across the MHC. In a separate analysis to investigate the genetic component of clinical sub-phenotypes, genetic ancestry was found to be associated with Optic Neuritis presentation and age at onset among Hispanics. This collection of findings demonstrate the value of Hispanic and African American inclusion for fine-mapping of known MS risk loci, discovery of novel loci, and interpretation of clinical variation across racial and ethnic groups.

Keywords

multiple sclerosis; admixture; genetics; Hispanics; African Americans

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