Continental Ancestry Research Articles

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

BackgroundThe Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries.MethodsWe characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes.ResultsWe identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent.ConclusionsColombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

AFA: Ancestry-specific allele frequency estimation in admixed populations: The Hispanic Community Health Study/Study of Latinos.

SummaryAllele frequency estimates in admixed populations, such as Hispanics and Latinos, rely on the sample’s specific admixture composition and thus may differ between two seemingly similar populations. However, ancestry-specific allele frequencies, i.e., pertaining to the ancestral populations of an admixed group, may be particularly useful for prioritizing genetic variants for genetic discovery and personalized genomic health. We developed a method, ancestry-specific allele frequency estimation in admixed populations (AFA), to estimate the frequencies of biallelic variants in admixed populations with an unlimited number of ancestries. AFA uses maximum-likelihood estimation by modeling the conditional probability of having an allele given proportions of genetic ancestries. It can be applied using either local ancestry interval proportions encompassing the variant (local-ancestry-specific allele frequency estimations in admixed populations [LAFAs]) or global proportions of genetic ancestries (global-ancestry-specific allele frequency estimations in admixed populations [GAFAs]), which are easier to compute and are more widely available. Simulations and comparisons to existing software demonstrated the high accuracy of the method. We implemented AFA on high-quality imputed data of ∼9,000 Hispanics and Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), an understudied, admixed population with three predominant continental ancestries: Amerindian, European, and African. Comparison of the European and African estimated frequencies to the respective gnomAD frequencies demonstrated high correlations (Pearson R2 = 0.97–0.99). We provide a genome-wide dataset of the estimated ancestry-specific allele frequencies for available variants with allele frequency between 5% and 95% in at least one of the three ancestral populations. Association analysis of Amerindian-enriched variants with cardiometabolic traits identified five loci associated with lipid traits in Hispanics and Latinos, demonstrating the utility of ancestry-specific allele frequencies in admixed populations.

A framework for research into continental ancestry groups of the UK Biobank

BackgroundThe UK Biobank is a large prospective cohort, based in the UK, that has deep phenotypic and genomic data on roughly a half a million individuals. Included in this resource are data on approximately 78,000 individuals with “non-white British ancestry.” While most epidemiology studies have focused predominantly on populations of European ancestry, there is an opportunity to contribute to the study of health and disease for a broader segment of the population by making use of the UK Biobank’s “non-white British ancestry” samples. Here, we present an empirical description of the continental ancestry and population structure among the individuals in this UK Biobank subset.ResultsReference populations from the 1000 Genomes Project for Africa, Europe, East Asia, and South Asia were used to estimate ancestry for each individual. Those with at least 80% ancestry in one of these four continental ancestry groups were taken forward (N = 62,484). Principal component and K-means clustering analyses were used to identify and characterize population structure within each ancestry group. Of the approximately 78,000 individuals in the UK Biobank that are of “non-white British” ancestry, 50,685, 6653, 2782, and 2364 individuals were associated to the European, African, South Asian, and East Asian continental ancestry groups, respectively. Each continental ancestry group exhibits prominent population structure that is consistent with self-reported country of birth data and geography.ConclusionsMethods outlined here provide an avenue to leverage UK Biobank’s deeply phenotyped data allowing researchers to maximize its potential in the study of health and disease in individuals of non-white British ancestry.

Factores asociados a dolores musculares y articulares en mujeres afrodescendientes climatéricas

Objective: To estimate the frequency of muscle and joint pain and to identify if other menopausal symptoms, age, nutritional status, metabolic risk, and menopausal status were associated factors. Methods: A Cross-sectional study which is part of the CAVIMEC project (Calidad de vida en la menopausia y Etnias Colombianas) was carried out in climacteric Afro-descendant women, between 40 and 59 years old, living in the Colombian Caribbean. They were surveyed in their own residences, prior informed consent. The Menopause Rating Scale was applied, this instrument assesses menopausal symptoms. Logistic regression was performed and the Spearman correlation coefficient was estimated. P value<0.05 was statistically significant. Results: 420 women were studied, median age 50.0 ± 6.1, 22.8% postmenopausal and 82.8% with abdominal obesity. 243 (57.9%) had muscle and joint pain. All menopausal symptoms were more frequent among women with muscle and joint pain. Depressed mood OR: 4.20 (95 % CI:1.55-11.74), age 50-54 years OR: 3.68 (95 % CI:1.53-8.82), heart palpitations OR:3.00 (95 % CI:1.51-5.98), age 55-50 years OR: 2.48 (95 % CI:1.08-5.64) and hot flashes OR: 1.92 (95 % CI:1.11-3.31) were associated with muscle and joint pain. The same was identified with the abdominal circumference OR: 0.322 (95 % CI:0.233-0.405) and hip circumference OR: 0.318 (95 % CI:0.229-0.401). Conclusions: High frequency of muscle and joint pain was identified. Aging, psychological and somato/vegetative symptoms, as well as abdominal and hip circumference, were significantly associated with muscle and joint pain. Keywords: Climacteric, Menopause, Arthralgia, Ethnic Groups, African Continental Ancestry Group.

Self- Reported Ancestry and Craniofacial SNPs: Assessing Correspondence with Implications for Forensic Case Analysis and Reporting

Genotype-phenotype studies increasingly link single nucleotide polymorphism (SNPs) to the dimensions of the face for presumed homogeneous populations. To appreciate the significance of these findings, it is essential to investigate how these results differ between the genetic and phenotypic profiles of individuals. In prior work, we investigated the connection between SNPs previously iden-tified as informative of soft tissue expression and measurements of the craniofacial skeleton. Using matched genetic and skeletal informa-tion on 17 individuals who self-identified as White with presumed common continental ancestry (European), we obtained significant Spearman correlations for 11 SNPs. In the present study, we looked at self-identified ancestry to understand the intersectional background of the individual’s phenotype and genotype. We integrated our samples within a diverse dataset of 2,242 modern Americans and applied an unsupervised model-based clustering routine to 13 craniometrics. We generated a mean estimate of 69.65% (±SD = 18%) European ances-try for the White sample under an unsupervised cluster model. We estimated higher quantities of European ancestry, 88.5%–93%, for our subset of 17 individuals. These elevated estimates were of interest with respect to the distribution of population-informative SNPs; we found, for example, that one of our sampled self-identified White individuals displayed SNPs commonly associated with Latin American populations. These results underscore the complex interrelationship between environment and genetics, and the need for continued research into connections between population affinity, social identity, and morphogenetic expression.

Self- Reported Ancestry and Craniofacial SNPs: Assessing Correspondence with Implications for Forensic Case Analysis and Reporting

Genotype-phenotype studies increasingly link single nucleotide polymorphism (SNPs) to the dimensions of the face for presumed homogeneous populations. To appreciate the significance of these findings, it is essential to investigate how these results differ between the genetic and phenotypic profiles of individuals. In prior work, we investigated the connection between SNPs previously iden-tified as informative of soft tissue expression and measurements of the craniofacial skeleton. Using matched genetic and skeletal informa-tion on 17 individuals who self-identified as White with presumed common continental ancestry (European), we obtained significant Spearman correlations for 11 SNPs. In the present study, we looked at self-identified ancestry to understand the intersectional background of the individual’s phenotype and genotype. We integrated our samples within a diverse dataset of 2,242 modern Americans and applied an unsupervised model-based clustering routine to 13 craniometrics. We generated a mean estimate of 69.65% (±SD = 18%) European ances-try for the White sample under an unsupervised cluster model. We estimated higher quantities of European ancestry, 88.5%–93%, for our subset of 17 individuals. These elevated estimates were of interest with respect to the distribution of population-informative SNPs; we found, for example, that one of our sampled self-identified White individuals displayed SNPs commonly associated with Latin American populations. These results underscore the complex interrelationship between environment and genetics, and the need for continued research into connections between population affinity, social identity, and morphogenetic expression.

Uniparental origins of the admixed Argentine Patagonia.

We aimed to contribute to the understanding of the ancient geographic origins of the uniparentally inherited markers in modern admixed Argentinian populations from central Patagonia with new information provided for the city of Trelew. We attempted to highlight the importance of combining different genetic markers when studying population history. The mtDNA control region sequence was typified in 89 individuals and 12 Y-STR and 15 Y-SNP loci were analyzed in 66 males. With these data, analysis of molecular variance and Network analyses were carried out. We exhaustively compared the modern data with ancient mtDNA information. Finally, we tested the differences in continental origins estimated by uniparental and previously published biparental markers. Native American mtDNAs (53.9%) increased when maternal ancestors were born in the northern (81.8%) and southern (58.5%) regions of Argentina or in Chile (77.8%). Population substructure was only observed for Y-chromosome haplotypes. Some mtDNA haplogroups have been present in the area for at least ca. 2762-2430 and ca. 500 (D1g and D1g4 haplogroups) and ca. 6736 and ca. 6620 (C1b and C1c haplogroups) years, respectively. In contrast, haplogroups B2i2 and C1b13, frequent in modern Patagonia populations, had not been found in previous ancient DNA studies of the region. The results suggest that Native American ancestry is well preserved in the region. Trelew samples had characteristic native mtDNA haplogroups previously described in Chilean and Argentine Patagonian populations, but not observed in ancient samples until now. These findings support the idea that these lineages have a recent regional origin. Finally, the estimated proportions of continental ancestry depend on the genetic marker analyzed.

Genetic ancestry and ethnic identity in Ecuador.

SummaryWe investigated the ancestral origins of four Ecuadorian ethnic groups—Afro-Ecuadorian, Mestizo, Montubio, and the Indigenous Tsáchila—in an effort to gain insight on the relationship between ancestry, culture, and the formation of ethnic identities in Latin America. The observed patterns of genetic ancestry are largely concordant with ethnic identities and historical records of conquest and colonization in Ecuador. Nevertheless, a number of exceptional findings highlight the complex relationship between genetic ancestry and ethnicity in Ecuador. Afro-Ecuadorians show far less African ancestry, and the highest levels of Native American ancestry, seen for any Afro-descendant population in the Americas. Mestizos in Ecuador show high levels of Native American ancestry, with substantially less European ancestry, despite the relatively low Indigenous population in the country. The recently recognized Montubio ethnic group is highly admixed, with substantial contributions from all three continental ancestries. The Tsáchila show two distinct ancestry subgroups, with most individuals showing almost exclusively Native American ancestry and a smaller group showing a Mestizo characteristic pattern. Considered together with historical data and sociological studies, our results indicate the extent to which ancestry and culture interact, often in unexpected ways, to shape ethnic identity in Ecuador.

A 3D basicranial shape-based assessment of local and continental northwest European ancestry among 5th to 9th century CE Anglo-Saxons.

The settlement of Great Britain by Germanic-speaking people from continental northwest Europe in the Early Medieval period (early 5th to mid 11th centuries CE) has long been recognised as an important event, but uncertainty remains about the number of settlers and the nature of their relationship with the preexisting inhabitants of the island. In the study reported here, we sought to shed light on these issues by using 3D shape analysis techniques to compare the cranial bases of Anglo-Saxon skeletons to those of skeletons from Great Britain that pre-date the Early Medieval period and skeletons from Denmark that date to the Iron Age. Analyses that focused on Early Anglo-Saxon skeletons indicated that between two-thirds and three-quarters of Anglo-Saxon individuals were of continental northwest Europe ancestry, while between a quarter and one-third were of local ancestry. In contrast, analyses that focused on Middle Anglo-Saxon skeletons suggested that 50-70% were of local ancestry, while 30-50% were of continental northwest Europe ancestry. Our study suggests, therefore, that ancestry in Early Medieval Britain was similar to what it is today-mixed and mutable.

Summix: A method for detecting and adjusting for population structure in genetic summary data

Publicly available genetic summary data have high utility in research and the clinic, including prioritizing putative causal variants, polygenic scoring, and leveraging common controls. However, summarizing individual-level data can mask population structure, resulting in confounding, reduced power, and incorrect prioritization of putative causal variants. This limits the utility of publicly available data, especially for understudied or admixed populations where additional research and resources are most needed. Although several methods exist to estimate ancestry in individual-level data, methods to estimate ancestry proportions in summary data are lacking. Here, we present Summix, a method to efficiently deconvolute ancestry and provide ancestry-adjusted allele frequencies (AFs) from summary data. Using continental reference ancestry, African (AFR), non-Finnish European (EUR), East Asian (EAS), Indigenous American (IAM), South Asian (SAS), we obtain accurate and precise estimates (within 0.1%) for all simulation scenarios. We apply Summix to gnomAD v.2.1 exome and genome groups and subgroups, finding heterogeneous continental ancestry for several groups, including African/African American (∼84% AFR, ∼14% EUR) and American/Latinx (∼4% AFR, ∼5% EAS, ∼43% EUR, ∼46% IAM). Compared to the unadjusted gnomAD AFs, Summix's ancestry-adjusted AFs more closely match respective African and Latinx reference samples. Even on modern, dense panels of summary statistics, Summix yields results in seconds, allowing for estimation of confidence intervals via block bootstrap. Given an accompanying R package, Summix increases the utility and equity of public genetic resources, empowering novel research opportunities.

Ancestrally unbiased polygenic breast cancer (BC) risk assessment.

10502 Background: BC risk is influenced by single-nucleotide polymorphisms (SNPs) with small effects that can be aggregated into polygenic risk scores (PRSs). PRSs have primarily been developed and validated for populations of European descent. To make a PRS available for all women, we developed and validated a novel global PRS (gPRS) that utilizes individual ancestral genetic composition. Methods: Ancestry-specific PRSs corresponding to 3 continental ancestries were developed from 149 SNPs (93 BC and 56 ancestry-informative): an African PRS was developed using a cohort of 31,126 self-reported African American patients referred for hereditary cancer testing; an East Asian PRS was developed based on published data from the Asia Breast Cancer Consortium; and a European PRS was developed using data from the Breast Cancer Association Consortium and 24,259 European hereditary cancer testing patients. For each patient, ancestry-informative SNPs were used to calculate the fractional ancestry attributable to each of the 3 continents. The gPRS was the sum of ancestry specific PRSs weighted according to genetic ancestral composition. In an independent validation cohort (N = 62,707), we evaluated discrimination and calibration of gPRS, and compared performance against a previously described 86-SNP PRS for women of European ancestry. Associations of SNPs and PRSs with BC were analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Odds ratios (ORs) are reported per standard deviation within the corresponding patient population. P-values are reported as two-sided. Results: The gPRS was strongly associated with BC in the full validation cohort and in sub-cohorts defined by self-reported ancestry (Table). 95% (88/93) of BC SNPs had ≥1% frequency of risk alleles within each of the self-reported populations. Compared to the aforementioned 86-SNP PRS, the gPRS showed improved discrimination overall, and within each sub-cohort, with the exception of the Asian population where the sample size was too small to show superiority of either score. The 86-SNP PRS was calibrated for white non-Hispanic women but mis-calibrated for non-European ancestries. The gPRS was properly calibrated for all women. Conclusions: The 149-SNP gPRS is validated and calibrated for women of all ancestries. Combined with clinical and biological risk factors, this approach may offer improved risk stratification for all women, regardless of ancestry.[Table: see text]

Brain-Derived Neurotrophic Factor Val66Met and Behavioral Adjustment after Early Childhood Traumatic Brain Injury.

The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on behavioral adjustment in children with traumatic brain injury (TBI) relative to children with orthopedic injury (OI). Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Parents completed the Child Behavior Checklist (CBCL) at the immediate post-acute period, 6, 12, and 18 months after injury, and an average of 3.5 and 7 years after injury. Longitudinal mixed models examined the BDNF Val66Met allele status (Met carriers vs. Val/Val homozygotes) × injury group (TBI vs. OI) interaction in association with behavioral adjustment. After adjusting for continental ancestry, socioeconomic status, time post-injury, and pre-injury functioning, the allele status × injury group interaction was statistically significant for Internalizing, Externalizing, and Total Behavior problems. Post hoc within-group analysis suggested a consistent trend of poorer behavioral adjustment in Met carriers relative to Val/Val homozygotes in the TBI group; in contrast, the opposite trend was observed in the OI group. These within-group differences, however, did not reach statistical significance. The results support a differential effect of the BDNF Val66Met polymorphism on behavioral adjustment in children with early TBI relative to OI, and suggest that the Met allele associated with reduced activity-dependent secretion of BDNF may impart risk for poorer long-term behavioral adjustment in children with TBI.

Genome-wide association study of asthma, total IgE, and lung function in a cohort of Peruvian children

Genetic ancestry plays a role in asthma health disparities. Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function. A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study. The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P< .001) and IBS was associated with lower total serum IgE levels (P< .001). NAT was associated with higher FEV1 percent predicted values (P< .001), whereas IBS was associated with lower FEV1 values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P= 3.438×10-10) and was independent of an association with the haplotype HLA-DQA1∼HLA-DQB1:04.01∼04.02 (P= 1.55×10-05). For lung function, we identified a locus (rs4410198; P= 5.536×10-11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P= .005). This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.

Psychic suffering and depression in black children and adolescents: systematic review and meta-analysis.

Depression is a common disorder in the population, but some people are more vulnerable to this condition. Groups at higher risk of developing psychic suffering include black children and adolescents living in vulnerable socioeconomic conditions. This study aimed to analyze race and life conditions as determinants of depression in children and adolescents. This was a systematic review with meta-analysis. The study sources were MEDLINE Ovid, Web of Science, Latin American and Caribbean Health Science Information database, Science Citation Index-Expanded, PubMed, EMBASE, and Scopus. The following keywords were used: Child, Adolescent, Stress, Psychological, Depression, and African Continental Ancestry Group, using the logical operators AND and OR. The general criteria were observational studies published in the last 20 years. Language was not restricted to avoid possible bias in the selection of articles. Studies with a high risk of bias were excluded. General analysis was conducted with RStudio 3.0 software using odds ratio analysis with a 95% confidence interval and 0.05 significance level. We firstly found 654 studies, of which 18 met the criteria and were included in this review. Race and life conditions were determinants of depression in children and adolescents, with a negative impact for the black population.

EPCO-13. GENOME-WIDE ASSOCIATION STUDY IN INDIVIDUALS OF ASHKENAZI JEWISH ANCESTRY IDENTIFIES NOVEL RISK LOCI FOR GLIOMA

Abstract Population stratification, or systematic differences in allele frequencies between subpopulations, can distort the results from genome-wide association studies (GWAS). While GWAS are usually conducted within continental (e.g. European) ancestry groups, sub-groups may have specific population histories that result in enrichment for risk or protective alleles for complex disease. In this analysis, we examined genetic risk for glioma in a US population with predominantly Ashkenazi Jewish (AJ) ancestry. Genotyping data were obtained from three prior glioma case-control studies. Best-guess assignment to one of seven subcontinental European ancestry groups was performed using AIPS (https://github.com/biomedicaldatascience/AIPS). Out of a total of 6,416 cases and 7,441 controls across all three studies, 202 cases (3% of all cases, 63% GBM) and 403 controls (5% of all controls) were assigned to the AJ ancestry group. Unconditional logistic regression was performed for by study (adjusted for age and first two principal components) and then studies were combined using fixed effects meta-analysis. No associations reached genome-wide significance (p&amp;lt; 5x10-8), including those detected in prior pan-European GWAS. A nominally significant association was detected on chromosome 17 in ASPA (rs9904040, MAF=20%, p=2.61x10-6, Odds ratio=2.22 [95% confidence interval=1.59–3.09]) which is in linkage equilibrium (r2=0.0013) with the previously detected glioma risk SNP in TP53 (MAF=0.3% in this analysis, p=0.8801) in the European population. In our prior pan-European meta-analysis (Melin et al., 2017, this SNP was non-significant (p=0.0620). This study failed to replicate many previously identified glioma risk alleles, likely due to diminished power due to small sample size. We did identify a novel risk allele on chromosome 17 in ASPA, which encodes for aspartoacylase (which catalyzes deacylation of N-acetyl_L-aspartic acid). Larger sample sizes identified via targeted recruitment are necessary in order to fully characterize genetic risk for glioma in this population, including assessment of rare (MAF&amp;lt; 5%) risk allele associations.

APOE alleles' association with cognitive function differs across Hispanic/Latino groups and genetic ancestry in the study of Latinos-investigation of neurocognitive aging (HCHS/SOL).

IntroductionApolipoprotein E (APOE) alleles are associated with cognitive decline, mild cognitive impairment (MCI), and Alzheimer's disease in Whites, but have weaker and inconsistent effects reported in Latinos. We hypothesized that this heterogeneity is due to ancestry‐specific genetic effects.MethodsWe investigated the associations of the APOE alleles with significant cognitive decline and MCI in 4183 Latinos, stratified by six Latino backgrounds, and explored whether the proportion of continental genetic ancestry (European, African, and Amerindian) modifies these associations.Results APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P‐value = 0.03), with the strongest association in Cubans (OR = 1.46, P‐value = 0.007). APOE‐ε2 was associated with decreased risk of MCI (OR = 0.37, P‐value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline.DiscussionResults suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.

Population structure and pharmacogenomic risk stratification in the United States

BackgroundPharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity. We hypothesized that genetic ancestry (GA) would provide higher resolution for stratifying PGx risk, since it serves as a more reliable surrogate for genetic diversity than self-identified race/ethnicity (SIRE), which includes a substantial social component. We analyzed a cohort of 8628 individuals from the United States (US), for whom we had both SIRE information and whole genome genotypes, with a focus on the three largest SIRE groups in the US: White, Black (African-American), and Hispanic (Latino). Our approach to the question of PGx risk stratification entailed the integration of two distinct methodologies: population genetics and evidence-based medicine. This integrated approach allowed us to consider the clinical implications for the observed patterns of PGx variation found within and between population groups.ResultsWhole genome genotypes were used to characterize individuals’ continental ancestry fractions—European, African, and Native American—and individuals were grouped according to their GA profiles. SIRE and GA groups were found to be highly concordant. Continental ancestry predicts individuals’ SIRE with > 96% accuracy, and accordingly, GA provides only a marginal increase in resolution for PGx risk stratification. In light of the concordance between SIRE and GA, taken together with the fact that information on SIRE is readily available to clinicians, we evaluated PGx variation between SIRE groups to explore the potential clinical utility of race and ethnicity. PGx variants are highly diverged compared to the genomic background; 82 variants show significant frequency differences among SIRE groups, and genome-wide patterns of PGx variation are almost entirely concordant with SIRE. The vast majority of PGx variation is found within rather than between groups, a well-established fact for almost all genetic variants, which is often taken to argue against the clinical utility of population stratification. Nevertheless, analysis of highly differentiated PGx variants illustrates how SIRE partitions PGx variation based on groups’ characteristic ancestry patterns. These cases underscore the extent to which SIRE carries clinically valuable information for stratifying PGx risk among populations, albeit with less utility for predicting individual-level PGx alleles (genotypes), supporting the concept of population pharmacogenomics.ConclusionsPerhaps most interestingly, we show that individuals who identify as Black or Hispanic stand to gain far more from the consideration of race/ethnicity in treatment decisions than individuals from the majority White population.

Assessment of the potential role of natural selection in type 2 diabetes and related traits across human continental ancestry groups: comparison of phenotypic with genotypic divergence.

Prevalence of type 2 diabetes differs among human ancestry groups, and many hypotheses invoke differential natural selection to account for these differences. We sought to assess the potential role of differential natural selection across major continental ancestry groups for diabetes and related traits, by comparison of genetic and phenotypic differences. This was a cross-sectional comparison among 734 individuals from an urban sample (none of whom was more closely related to another than third-degree relatives), including 83 African Americans, 523 American Indians and 128 European Americans. Participants were not recruited based on diabetes status or other traits. BMI was calculated, and diabetes was diagnosed by a 75g oral glucose tolerance test. In those with normal glucose tolerance (n = 434), fasting insulin and 30min post-load insulin, adjusted for 30min glucose, were taken as measures of insulin resistance and secretion, respectively. Whole exome sequencing was performed, resulting in 97,388 common (minor allele frequency ≥ 5%) variants; the coancestry coefficient (FST) was calculated across all markers as a measure of genetic divergence among ancestry groups. The phenotypic divergence index (PST) was also calculated from the phenotypic differences and heritability (which was estimated from genetic relatedness calculated empirically across all markers in 761 American Indian participants prior to the exclusion of close relatives). Under evolutionary neutrality, the expectation is PST = FST, while for traits under differential selection PST is expected to be significantly greater than FST. A bootstrap procedure was used to test the hypothesis PST = FST. RESULTS: With adjustment for age and sex, prevalence of type 2 diabetes was 34.0% in American Indians, 12.4% in African Americans and 10.4% in European Americans (p = 2.9 × 10-10 for difference among groups). Mean BMI was 36.3, 33.4 and 33.0kg/m2, respectively (p =1.9 × 10-7). Mean fasting insulin was 63.8, 48.4 and 45.2pmol/l (p = 9.2 × 10-5), while mean 30min insulin was 559.8, 553.5 and 358.8pmol/l, respectively (p =5.7 × 10-8). FST across all markers was 0.130, while PST for liability to diabetes, adjusted for age and sex, was 0.149 (p = 0.35 for difference with FST). PST was 0.094 for BMI (p = 0.54), 0.095 for fasting insulin (p = 0.54) and 0.216 (p = 0.18) for 30min insulin. For type 2 diabetes and BMI, the maximum divergence between populations was observed between American Indians and European Americans (PST-MAX = 0.22, p = 0.37, and PST-MAX = 0.14, p = 0.61), which suggests that a relatively modest 22% or 14% of the genetic variance, respectively, can potentially be explained by differential selection (assuming the absence of neutral drift). These analyses suggest that while type 2 diabetes and related traits differ significantly among continental ancestry groups, the differences are consistent with neutral expectations based on heritability and genetic distances. While these analyses do not exclude a modest role for natural selection, they do not support the hypothesis that differential natural selection is necessary to explain the phenotypic differences among these ancestry groups. Graphical abstract.

The Eskimo-Aleut Dentition: Crown and Root Morphology.

Objective of workThis paper provides an overview of crown and root morphology in Eskimo-Aleut populations of the American Arctic. For context, Eskimo-Aleut dental variation is compared to closely related American Indians and distantly related Europeans.Material and methodsThe characterization of dental trait frequency variation is based on observations made on approximately 10,000 dentitions scored by the late Christy G. Turner II and the author. Sixteen crown and five root traits were scored following the conventions outlined in the Arizona State University Dental Anthropology System.ResultsOf the 21 dental traits considered, only three showed slight differences among Eskimo-Aleuts, American Indians, and Europeans (UM1 cusp 5, LM2 groove pattern, LM2 root number). For the remaining traits, there was typically a dramatic contrast between the two New World populations and Europeans. While generally similar, Eskimo-Aleuts and American Indians showed differences in UI1 winging, shoveling, and double shoveling, UM1 Carabelli trait, 2-cusped UM2, 3-rooted UM2, and especially 3-rooted LM1.ConclusionThe differences between the three groups are likely a product of genetic drift and founder effect although recent work on the EDAR V370A allele suggests some dental variables like shoveling and lower molar cusp number may indirectly reflect natural selection operating on other variables influenced by this allele.Key wordsTooth Crown; Tooth Root; Alaska Natives; North American Indians; European Continental Ancestry Group

Distribution and linkage disequilibrium of the enhancer SNP rs5758550 among Latin American populations: influence of continental ancestry.

A single nucleotide polymorphism (SNP), rs5758550, in a critical enhancer region downstream of the CYP2D6 promoter was proposed to modulate CYP2D6 activity, depending on its linkage disequilibrium (LD) with the common CYP2D6 SNP, rs16947. We examined the influence of individual biogeographical ancestry on the frequency distribution of rs5758550 and its LD with rs16947 in Latin American populations. We then inferred the impact of rs5758550 on the predictive accuracy of CYP2D6 metabolizer status based on CYP2D6 haplotypes. The study cohorts consisted of the Admixed American (AMR) superpopulation of the 1000 Genomes Project (n = 347) plus an admixed Brazilian (BR) cohort (N = 224). Individual proportions of Native, African and European ancestry estimated by ADMIXTURE analysis, were used to design four sub-cohorts, in which one of the three ancestral roots predominated largely (>6 fold) over the other two: AMR-NAT and AMR-EUR, comprised 80 AMR individuals each, with >70% Native or >70% European ancestry, BR-EUR and BR-AFR comprised Brazilians with >90% European (n = 80) or >70% African ancestry (n = 64), respectively. CYP2D6 haplotypes were inferred based on 10 commonly reported CYPD6 variants with or without addition of the enhancer rs5758550 SNP, pairwise LD was assessed by the R parameter, and activity scores were used to infer CYP2D6 metabolizer status. Minor allele frequency (MAF) of all CYP2D6 SNPs, except the rare (<0.02) rs5030656 and rs35742688, differed significantly across sub-cohorts, whereas no difference was observed for rs5758550. The R values for LD between rs5758550 and rs16947 ranged from 0.15 (BR-AFR) to 0.85 (AMR-NAT), with intermediate values in the predominantly European sub-cohorts (0.34-0.67). As a consequence, distribution of CYP2D6 haplotypes containing the rs16947 SNP plus rs5758550 wild-type (A) or variant (G) allele differed markedly across sub-cohorts. Comparison of the CYP2D6 activity scores assigned to the wild-type (CYP2D6*1) and the rs16947-containing haplotypes with or without inclusion of rs5758550, showed that knowledge of the rs5758550 genotype has negligible impact on predicted CYP2D6 phenotypes in AMR-EUR and AMR-NAT, but affects prediction in 10.7 and 21.6% of BR-EUR and BR-AFR individuals, respectively. Collectively, the present results reveal potential pharmacogenomic (PGx) implications of the population diversity in Latin America, affecting a major drug-metabolizing pathway. Thus, the influence of enhancer rs5758550 on assignment of CYP2D6 metabolic phenotypes varies markedly, according to the individual proportions of Native, European and African ancestry. This conclusion reinforces the notion that extrapolation of PGx data across the heterogeneous Latin American is risky, if not inappropriate.