Admixture and Clinical Phenotypic Variation

Abstract

All human populations exhibit some level of genetic differentiation. This differentiation, or population stratification, has many interacting sources, including historical migrations, population isolation over time, genetic drift, and selection and adaptation. If differentiated populations remained isolated from each other over a long period of time such that there is no mating of individuals between those populations, then some level of global consanguinity within those populations will lead to the formation of gene pools that will become more and more distinct over time. Global genetic differentiation of this sort can lead to overt phenotypic differences between populations if phenotypically relevant variants either arise uniquely within those populations or begin to exhibit frequency differences across the populations. This can occur at the single variant level for monogenic phenotypes or at the level of aggregate variant frequency differences across the many loci that contribute to a phenotype with a multifactorial or polygenic basis. However, if individuals begin to interbreed (or ‘admix') from populations with different frequencies of phenotypically relevant genetic variants, then these admixed individuals will exhibit the phenotype to varying degrees. The level of phenotypic expression will depend on the degree to which the admixed individuals have inherited causative variants that have descended from the ancestral population in which those variants were present (or, more likely, simply more frequent). We review studies that consider the association between the degree of admixture (or ancestry) and phenotypes of clinical relevance. We find a great deal of literature-based evidence for associations between the degree of admixture and phenotypic variation for a number of admixed populations and phenotypes, although not all this evidence is confirmatory. We also consider the implications of such associations for gene-mapping initiatives as well as general clinical epidemiology studies and medical practice. We end with some thoughts on the future of studies exploring phenotypic differences among admixed individuals as well as individuals with different ancestral backgrounds.

Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities

“…Several studies have associated genetic ancestry with numerous clinical endpoints. African ancestry was inversely related to FEV1 ( p = 0.007), FVC ( p = 0.0003), and FEV1/FVC ( p = 0.035) (Table 2 , Figure 3 ) [ 38 , 62 ]. Higher vs. lower proportion of African ancestry, categorized based on median value, has also been shown to be associated with greater decline in the lung function per pack-year of smoking (−5.7 vs. –4.6 ml FEV1 per pack-year) in contrast to the −3.9 ml FEV1 per pack-year smoked observed among European Americans [ 63 ].…”

“… Modified from Goetz et al [ 62 ]. The structure is model-based clustering method; IBGA is a maximum likelihood-based clustering method, and LAMP is a local ancestry in admixed population inference method.…”

Different Association of Human Papillomavirus 16 Variants with Early and Late Presentation of Cervical Cancer

“…The examination of HPV16 variants in more countries may reveal the origin of these variants. To determine how the frequency of lineage D variants is related to the Amerindian genetics, it will be necessary to conduct a detailed study involving admixture mapping [45]. …”

The Pediatric Imaging, Neurocognition, and Genetics (PING) Data Repository

“…Although some individuals could be easily associated with a particular continental population, other individuals were clearly admixed. Such admixture could easily be associated with important phenotypic variation and hence needs to be quantified 41–44 . We therefore determined the degree of ancestry of each participant, effectively quantifying the amount of their genome that is likely to be derived from each of the six populations.…”