"Worldwide Survey of Haplotype Variation and Linkage Disequilibrium at the Sort 1 and Sorl 1 Genes: Implications for Human Demographic History, Modern Human Origins and Complex Disease" by Michael Colin Campbell

Michael Colin Campbell

Deposited 2007

Abstract
This dissertation examines SNP haplotype variation in the SORT1 and SORL1 genes, two newly identified risk factors for late-onset Alzheimer Disease (LOAD) (a) to characterize patterns of linkage disequilibrium (LD) and genetic structure within continental regions, especially in Africa, (b) to infer demographic model(s) that explain observed patterns of diversity, and (c) to determine if genetic structure at SORT1 contributes to differential risk for LOAD in African-Americans, Caribbean-Latinos and European-Americans.

To determine levels of LD, the population recombination rate (ρ) was calculated using approximate likelihood coalescent methods for each population. Also, divergence in haplotype frequency within continental regions was measured using standard statistical methods, including Wright's FST. Genealogical relationships among SORT1 haplotypes from African and non-African populations were also estimated to infer population level processes that have shaped patterns of diversity. To explore questions pertaining to genetic risk for disease, we also examined the association between the SORT1 variability and AD status and verbal memory in a cohort of unrelated cases and ethnically-matched controls from three distinct populations (African-Americans, Caribbean-Latinos and European-Americans).

Our results showed that in both SORT1 and SORL1 mean ρ was higher in sub-Saharan Africa than in other geographic regions. Also, the variance in ρ was greater in Africa than in other continents. In addition, the among-population divergence was significantly higher in sub-Saharan Africa compared to most other geographic regions. Our haplotype genealogy also suggested that East African populations diverged from the rest of Africa early in modern human evolution, and that haplotypes from East Africa were ancestral to haplotypes in non-African populations. These results together imply that ancestral Africans may have had a long complex history involving population subdivision, resulting in divergent patterns of LD and significant differentiation.

We also report that genotypic variation in SORT1 was associated with an increased risk for LOAD, as well as differences in memory performance in African-Americans. In contrast, the risk for LOAD was not significant in Caribbean-Latinos and European-Americans; as well, differences in memory performance conditional on genotype were weak to non-existent in these populations. We hypothesize that African-Americans possess genetic variants, including disease-susceptibility alleles, at this locus, which are not present in other populations due to their distinct demographic history.