The Impact of Ethnicity and Genetic Ancestry on Disease Prevalence and Risk in Colombia.

Currently, the vast majority of genomic research cohorts are made up of participants with European ancestry. Genomic medicine will only reach its full potential when genomic studies become more broadly representative of global populations. We are working to support the establishment of genomic medicine in developing countries in Latin America via studies of ethnically and ancestrally diverse Colombian populations. The goal of this study was to analyze the effect of ethnicity and genetic ancestry on observed disease prevalence and predicted disease risk in Colombia. Population distributions of Colombia's three major ethnic groups - Mestizo, Afro-Colombian, and Indigenous - were compared to disease prevalence and socioeconomic indicators. Indigenous and Mestizo ethnicity show the highest correlations with disease prevalence, whereas the effect of Afro-Colombian ethnicity is substantially lower. Mestizo ethnicity is mostly negatively correlated with six high-impact health conditions and positively correlated with seven of eight common cancers; Indigenous ethnicity shows the opposite effect. Malaria prevalence in particular is strongly correlated with ethnicity. Disease prevalence co-varies across geographic regions, consistent with the regional distribution of ethnic groups. Ethnicity is also correlated with regional variation in human development, partially explaining the observed differences in disease prevalence. Patterns of genetic ancestry and admixture for a cohort of 624 individuals from Medellín were compared to disease risk inferred via polygenic risk scores (PRS). African genetic ancestry is most strongly correlated with predicted disease risk, whereas European and Native American ancestry show weaker effects. African ancestry is mostly positively correlated with disease risk, and European ancestry is mostly negatively correlated. The relationships between ethnicity and disease prevalence do not show an overall correspondence with the relationships between ancestry and disease risk. We discuss possible reasons for the divergent health effects of ethnicity and ancestry as well as the implication of our results for the development of precision medicine in Colombia.

The Phenotypic Consequences of Genetic Divergence between Admixed Latin American Populations: Antioquia and Chocó, Colombia.

Genome-wide association studies have uncovered thousands of genetic variants that are associated with a wide variety of human traits. Knowledge of how trait-associated variants are distributed within and between populations can provide insight into the genetic basis of group-specific phenotypic differences, particularly for health-related traits. We analyzed the genetic divergence levels for 1) individual trait-associated variants and 2) collections of variants that function together to encode polygenic traits, between two neighboring populations in Colombia that have distinct demographic profiles: Antioquia (Mestizo) and Chocó (Afro-Colombian). Genetic ancestry analysis showed 62% European, 32% Native American, and 6% African ancestry for Antioquia compared with 76% African, 10% European, and 14% Native American ancestry for Chocó, consistent with demography and previous results. Ancestry differences can confound cross-population comparison of polygenic risk scores (PRS); however, we did not find any systematic bias in PRS distributions for the two populations studied here, and population-specific differences in PRS were, for the most part, small and symmetrically distributed around zero. Both genetic differentiation at individual trait-associated single nucleotide polymorphisms and population-specific PRS differences between Antioquia and Chocó largely reflected anthropometric phenotypic differences that can be readily observed between the populations along with reported disease prevalence differences. Cases where population-specific differences in genetic risk did not align with observed trait (disease) prevalence point to the importance of environmental contributions to phenotypic variance, for both infectious and complex, common disease. The results reported here are distributed via a web-based platform for searching trait-associated variants and PRS divergence levels at http://map.chocogen.com (last accessed August 12, 2020).

Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations.

BACKGROUND: Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations. METHODS: Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here. RESULTS: T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences. CONCLUSIONS: T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.

Population Pharmacogenomics for Precision Public Health in Colombia.

While genomic approaches to precision medicine hold great promise, they remain prohibitively expensive for developing countries. The precision public health paradigm, whereby healthcare decisions are made at the level of populations as opposed to individuals, provides one way for the genomics revolution to directly impact health outcomes in the developing world. Genomic approaches to precision public health require a deep understanding of local population genomics, which is still missing for many developing countries. We are investigating the population genomics of genetic variants that mediate drug response in an effort to inform healthcare decisions in Colombia. Our work focuses on two neighboring populations with distinct ancestry profiles: Antioquia and Chocó. Antioquia has primarily European genetic ancestry followed by Native American and African components, whereas Chocó shows mainly African ancestry with lower levels of Native American and European admixture. We performed a survey of the global distribution of pharmacogenomic variants followed by a more focused study of pharmacogenomic allele frequency differences between the two Colombian populations. Worldwide, we found pharmacogenomic variants to have both unusually high minor allele frequencies and high levels of population differentiation. A number of these pharmacogenomic variants also show anomalous effect allele frequencies within and between the two Colombian populations, and these differences were found to be associated with their distinct genetic ancestry profiles. For example, the C allele of the single nucleotide polymorphism (SNP) rs4149056 [Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1)∗5], which is associated with an increased risk of toxicity to a commonly prescribed statin, is found at relatively high frequency in Antioquia and is associated with European ancestry. In addition to pharmacogenomic alleles related to increased toxicity risk, we also have evidence that alleles related to dosage and metabolism have large frequency differences between the two populations, which are associated with their specific ancestries. Using these findings, we have developed and validated an inexpensive allele-specific PCR assay to test for the presence of such population-enriched pharmacogenomic SNPs in Colombia. These results serve as an example of how population-centered approaches to pharmacogenomics can help to realize the promise of precision medicine in resource-limited settings.

Influence of genetic ancestry and socioeconomic status on type 2 diabetes in the diverse Colombian populations of Chocó and Antioquia.

Differences in genetic ancestry and socioeconomic status (SES) among Latin American populations have been linked to health disparities for a number of complex diseases, such as diabetes. We used a population genomic approach to investigate the role that genetic ancestry and socioeconomic status (SES) play in the epidemiology of type 2 diabetes (T2D) for two Colombian populations: Chocó (Afro-Latino) and Antioquia (Mestizo). Chocó has significantly higher predicted genetic risk for T2D compared to Antioquia, and the elevated predicted risk for T2D in Chocó is correlated with higher African ancestry. Despite its elevated predicted genetic risk, the population of Chocó has a three-times lower observed T2D prevalence than Antioquia, indicating that environmental factors better explain differences in T2D outcomes for Colombia. Chocó has substantially lower SES than Antioquia, suggesting that low SES in Chocó serves as a protective factor against T2D. The combination of lower prevalence of T2D and lower SES in Chocó may seem surprising given the protective nature of elevated SES in many populations in developed countries. However, low SES has also been documented to be a protective factor in rural populations in less developed countries, and this appears to be the case when comparing Chocó to Antioquia.

A Comparative Analysis of Genetic Ancestry and Admixture in the Colombian Populations of Chocó and Medellín.

At least 20% of Colombians identify as having African ancestry, yielding the second largest population of Afro-descendants in Latin America. To date, there have been relatively few studies focused on the genetic ancestry of Afro-Latino populations. We report a comparative analysis of the genetic ancestry of Chocó, a state located on Colombia's Pacific coast with a population that is >80% Afro-Colombian. We compared genome-wide patterns of genetic ancestry and admixture for Chocó to six other admixed American populations, with an emphasis on a Mestizo population from the nearby Colombian city of Medellín. One hundred sample donors from Chocó were genotyped across 610,545 genomic sites and compared with 94 publicly available whole genome sequences from Medellín. At the continental level, Chocó shows mostly African genetic ancestry (76%) with a nearly even split between European (13%) and Native American (11%) fractions, whereas Medellín has primarily European ancestry (75%), followed by Native American (18%) and African (7%). Sample donors from Chocó self-identify as having more African ancestry, and conversely less European and Native American ancestry, than can be genetically inferred, as opposed to what we previously found for Medellín, where individuals tend to overestimate levels of European ancestry. We developed a novel approach for subcontinental ancestry assignment, which allowed us to characterize subcontinental source populations for each of the three distinct continental ancestry fractions separately. Despite the clear differences between Chocó and Medellín at the level of continental ancestry, the two populations show overall patterns of subcontinental ancestry that are highly similar. Their African subcontinental ancestries are only slightly different, with Chocó showing more exclusive shared ancestry with the modern Yoruba (Nigerian) population, and Medellín having relatively more shared ancestry with West African populations in Sierra Leone and Gambia. Both populations show very similar Spanish ancestry within Europe and virtually identical patterns of Native American ancestry, with main contributions from the Embera and Waunana tribes. When the three subcontinental ancestry components are considered jointly, the populations of Chocó and Medellín are shown to be most closely related, to the exclusion of the other admixed American populations that we analyzed. We consider the implications of the existence of shared subcontinental ancestries for Colombian populations that appear, at first glance, to be clearly distinct with respect to competing notions of national identity that emphasize ethnic mixing (mestizaje) vs. group-specific identities (multiculturalism).

Chocó, Colombia: a hotspot of human biodiversity.

OBJECTIVE: Chocó is a state located on the Pacific coast of Colombia that has a majority Afro-Colombian population. The objective of this study was to characterize the genetic ancestry, admixture and diversity of the population of Chocó, Colombia. METHODOLOGY: Genetic variation was characterized for a sample of 101 donors (61 female and 40 male) from the state of Chocó. Genotypes were determined for each individual via the characterization of 610,545 single nucleotide polymorphisms genome-wide. Haplotypes for the uniparental mitochondrial DNA (female) and Y-DNA (male) chromosomes were also determined. These data were used for comparative analyses with a number of worldwide populations, including putative ancestral populations from Africa, the Americas and Europe, along with several admixed American populations. RESULTS: The population of Chocó has predominantly African genetic ancestry (75.8%) with approximately equal parts European (13.4%) and Native American (11.1%) ancestry. Chocó shows relatively high levels of three-way genetic admixture, and far higher levels of Native American ancestry, compared to other New World African populations from the Caribbean and the United States. There is a striking pattern of sex-specific ancestry in Chocó, with Native American admixture along the female lineage and European admixture along the male lineage. The population of Chocó is also characterized by relatively high levels of overall genetic diversity compared to both putative ancestral populations and other admixed American populations. CONCLUSION: These results suggest a unique genetic heritage for the population of Chocó and underscore the profound human genetic diversity that can be found in the region.