Influence of genetic ancestry and socioeconomic status on type 2 diabetes in the diverse Colombian populations of Choco and Antioquia.
ABSTRACT: 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.
Project description: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.
Project description: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).
Project description:The "thrifty genotype" hypothesis proposes that the high prevalence of type 2 diabetes (T2D) in Native Americans and admixed Latin Americans has a genetic basis and reflects an evolutionary adaptation to a past low calorie/high exercise lifestyle. However, identification of the gene variants underpinning this hypothesis remains elusive. Here we assessed the role of Native American ancestry, socioeconomic status (SES) and 21 candidate gene loci in susceptibility to T2D in a sample of 876 T2D cases and 399 controls from Antioquia (Colombia). Although mean Native American ancestry is significantly higher in T2D cases than in controls (32% v 29%), this difference is confounded by the correlation of ancestry with SES, which is a stronger predictor of disease status. Nominally significant association (P<0.05) was observed for markers in: TCF7L2, RBMS1, CDKAL1, ZNF239, KCNQ1 and TCF1 and a significant bias (P<0.05) towards OR>1 was observed for markers selected from previous T2D genome-wide association studies, consistent with a role for Old World variants in susceptibility to T2D in Latin Americans. No association was found to the only known Native American-specific gene variant previously associated with T2D in a Mexican sample (rs9282541 in ABCA1). An admixture mapping scan with 1,536 ancestry informative markers (AIMs) did not identify genome regions with significant deviation of ancestry in Antioquia. Exclusion analysis indicates that this scan rules out ~95% of the genome as harboring loci with ancestry risk ratios >1.22 (at P < 0.05).
Project description: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.
Project description: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 (<i>mestizaje</i>) <i>vs.</i> group-specific identities (multiculturalism).
Project description:Although it is well established that Hispanics generally have a mixed Native American, African, and European ancestry, the dynamics of admixture at the foundation of Hispanic populations is heterogeneous and poorly documented. Genetic analyses are potentially very informative for probing the early demographic history of these populations. Here we evaluate the genetic structure and admixture dynamics of a province in northwest Colombia (Antioquia), which prior analyses indicate was founded mostly by Spanish men and native women. We examined surname, Y chromosome, and mtDNA diversity in a geographically structured sample of the region and obtained admixture estimates with highly informative autosomal and X chromosome markers. We found evidence of reduced surname diversity and support for the introduction of several common surnames by single founders, consistent with the isolation of Antioquia after the colonial period. Y chromosome and mtDNA data indicate little population substructure among founder Antioquian municipalities. Interestingly, despite a nearly complete Native American mtDNA background, Antioquia has a markedly predominant European ancestry at the autosomal and X chromosome level, which suggests that, after foundation, continuing admixture with Spanish men (but not with native women) increased the European nuclear ancestry of Antioquia. This scenario is consistent with historical information and with results from population genetics theory.
Project description:Puerto Ricans, an admixed population of African, European, and Native American ancestries, have the highest asthma prevalence, morbidity, and mortality rates of any United States' population. Although socioeconomic status (SES) is negatively correlated with asthma incidence in most populations, no such relationship has been identified among Puerto Ricans. We hypothesized that, in this admixed population, the association between SES and asthma may interact with genetic ancestry.We analyzed 135 Puerto Rican subjects with asthma and 156 control subjects recruited from six different recruitment centers in Puerto Rico. Individual ancestry for each subject was estimated using 44 ancestry informative markers. SES was assigned using the census tracts' median family income. Analyses of SES were based on the SES of the clinic site from which the subjects were recruited and on a subset of individuals on whom home address-based SES was available.In the two (independent) analyses, we found a significant interaction between SES, ancestry, and asthma disease status. At lower SES, European ancestry was associated with increased risk of asthma, whereas African ancestry was associated with decreased risk. The opposite was true for their higher SES counterparts.The observed interaction may help to explain the unique pattern of risk for asthma in Puerto Ricans and the lack of association with SES observed in previous studies when not accounting for varying proportions of ancestry.
Project description:Type 2 diabetes (T2D) is a global health problem showing substantial ethnic disparity in disease prevalence. African Americans have one of the highest prevalence of T2D in the USA but little is known about their genetic risks. This review summarizes the findings of genetic regions and loci associated with T2D and related glycemic traits using linkage, admixture, and association approaches in populations of African ancestry. In particular, findings from genome-wide association and exome chip studies suggest the presence of both ancestry-specific and shared loci for T2D and glycemic traits. Among the European-identified loci that are transferable to individuals of African ancestry, allelic heterogeneity as well as differential linkage disequilibrium and risk allele frequencies pose challenges and opportunities for fine mapping and identification of causal variant(s) by trans-ancestry meta-analysis. More genetic research is needed in African ancestry populations including the next-generation sequencing to improve the understanding of genetic architecture of T2D.
Project description:Background:Relationships between genetic risks for chronic diseases and long-run wellbeing are largely unexplored. We examined the associations between genetic predispositions to several chronic conditions and long-term functional health and socioeconomic status (SES). Methods:We used data on a nationally representative sample of 9,317 adults aged 65 years or older from the 1992 to 2012 Health and Retirement Survey (HRS) in the US. Survey data were linked to genetic data on nearly 2 million single-nucleotide polymorphisms (SNPs). We measured individual-level genetic predispositions for coronary-artery disease, type 2 diabetes (T2D), obesity, rheumatoid arthritis (RA), Alzheimer's disease, and major depressive disorder (MDD) by polygenic risk scores (PRS) derived from genome-wide association studies (GWAS). The outcomes were self-rated health, depressive symptoms, cognitive ability, activities of everyday life, educational attainment, and wealth. We employed regression analyses for the outcomes including all polygenic scores and adjusting for gender, birth period, and genetic ancestry. Results:The polygenic scores had important associations with functional health and SES. An increase in genetic risk for all conditions except T2D was significantly (p < .01) associated with reduced functional health and socioeconomic outcomes. The magnitudes of functional health declines were meaningful and in many cases equivalent in magnitude to several years of aging. These associations were robust to several sensitivity checks for ancestry and adjustment for parental educational attainment and age at death or the last interview if alive. Conclusion:Stronger genetic predispositions for leading chronic conditions are related to worse long-run health and SES outcomes, likely reflecting the adverse effects of the onset of these conditions on one's wellbeing.
Project description:Type 2 diabetes (T2D) affects 415 million people worldwide, and has a much higher prevalence in Hispanics (16.9%), compared to non-Hispanic whites (10.2%). Genome-wide association studies and whole-genome and whole-exome sequencing studies have discovered more than 100 genetic regions associated with modified risk for T2D. However, the identified genetic factors explain a very small fraction of the estimated heritability. Until recently, little attention has been put in studying other non European populations that suffer from a higher burden of T2D, such as Hispanics/Latinos. In the past few years, genetic studies in Hispanic populations have started to provide new insights into the genetic architecture of T2D in this ancestry group. Of note, several genetic variants that are absent or very rare in non-Hispanic populations but more common in Hispanics have shown from moderate to strong association with T2D and have provided new insights into the biology of T2D, which may be ultimately useful for developing novel therapeutic strategies applicable to all populations. Studying diverse populations can also improve the ability to find the causal variants in known T2D loci by a multi-ancestry fine-mapping approach, which leverages the different patterns of linkage disequilibrium between the causal and the ascertained genetic variants. In this mini-review, we summarize the main genetic findings discovered in Hispanics and discuss the limitations and challenges of performing genetic studies in these populations. Finally, we present possible next steps to make studies in Latino populations more valuable in providing a deeper understanding of T2D and anticipate their future application to the development of predictive and preventive medicine and personalized therapies.