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Objective: To evaluate the genetic diversity, admixture, genetic relationships, and sex-biased demographic processes in Mexican Mestizo (admixed) populations based on 10 X-chromosome STRs (X-STRs)., Methods: We analyzed the X-STRs Decaplex system in 104 Mexican Native Americans to obtain the ancestral reference needed to complete the demographic analyses above mentioned. We included reported Iberian and Latin American (admixed) populations from Central and South America, as well as datasets from Mexican Mestizos based on Y-linked STRs (Y-STRs), autosomal STRs (A-STRs), and mtDNA., Results: Higher X-linked Native American ancestry was observed among Latin American populations regarding that reported from A-STRs and Y-STRs. The interpopulation differentiation based on ancestry among Mexican Mestizos diminished according to the inheritance pattern: Y-STRs (highest), A-STRs, X-STRs, and mtDNA (lowest). This finding is related to the peculiar admixture process that occurred during and after the Spanish Conquest of Mexico (and most of Latin America), involving a large number of Spanish men (Y-chromosomes) with a lesser proportion of X-chromosomes than autosomes; besides to the limited number of Spanish women (XX) arrived in the Americas in subsequent and shorter periods. Population expansion was detected in Mexican Mestizos from all the country, except those from the southeast region characterized by elevated indigenous ancestry, marginalization, and poorness., Conclusions: Population growth was detected in most Mexican Mestizos, besides more homogeneous and larger Native American ancestry based on X-linked inheritance than that based on autosomal STRs and Y-STRs., (© 2024 Wiley Periodicals LLC.)

There is a collective push to diversify human genetic studies by including underrepresented populations. However, analyzing DNA sequence reads involves the initial step of aligning the reads to the GRCh38/hg38 reference genome which is inadequate for non-European ancestries. In this study, using long-read sequencing technology, we constructed de novo genome assemblies from two indigenous Americans from Arizona (IAZ). Each assembly included ∼17 Mb of DNA sequence not present [nonreference sequence (NRS)] in hg38, which consists mostly of repeat elements. Forty NRSs totaling 240 kb were uniquely anchored to the hg38 primary assembly generating a modified hg38-NRS reference genome. DNA sequence alignment and variant calling were then conducted with whole-genome sequencing (WGS) sequencing data from 387 IAZ using both the hg38 and modified hg38-NRS reference maps. Variant calling with the hg38-NRS map identified ∼50,000 single-nucleotide variants present in at least 5% of the WGS samples which were not detected with the hg38 reference map. We also directly assessed the NRSs positioned within genes. Seventeen NRSs anchored to regions including an identical 187 bp NRS found in both de novo assemblies. The NRS is located in HCN2 79 bp downstream of Exon 3 and contains several putative transcriptional regulatory elements. Genotyping of the HCN2-NRS revealed that the insertion is enriched in IAZ (minor allele frequency = 0.45) compared to other reference populations tested. This study shows that inclusion of population-specific NRSs can dramatically change the variant profile in an underrepresented ethnic groups and thereby lead to the discovery of previously missed common variations., (Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution 2024.)

Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (116 kcal/day) and increased rates of endogenous glucose production during basal (5%) and insulin-stimulated (43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and postabsorptive sleeping metabolic rate., (© 2024 by the American Diabetes Association.)

We sought to identify genetic/immunologic contributors of type 2 diabetes (T2D) in an indigenous American community by genotyping all study participants for both high-resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI <35 kg/m2. Here, we test the interaction of the two loci with a more complete data set and perform a BMI sensitivity test. We defined the risk protection haplotype of SLC16A11, T-C-G-T-T, as allele 2 of a diallelic genetic model with three genotypes, SLC16A11*11, *12, and *22, where allele 1 is the wild type. Both earlier findings were confirmed. Together in the same logistic model with BMI ≥35 kg/m2, DRB1*16:02:01 remains protective (odds ratio [OR] 0.73), while SLC16A11 switches from risk to protection (OR 0.57 [*22] and 0.78 [*12]); an added interaction term was statistically significant (OR 0.49 [*12]). Bootstrapped (b = 10,000) statistical power of interaction, 0.4801, yielded a mean OR of 0.43. Sensitivity analysis demonstrated that the interaction is significant in the BMI range of 30-41 kg/m2. To investigate the epistasis, we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15-mer peptides for both the wild-type and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggested that the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for type 1 diabetes., (© 2024 by the American Diabetes Association.)

Most genetic variants associated with adult height have been identified through large genome-wide association studies (GWASs) in European-ancestry cohorts. However, it is unclear how these variants influence linear growth during adolescence. This study uses anthropometric and genotypic data from a longitudinal study conducted in an American Indian community in Arizona between 1965-2007. Growth parameters (i.e. height, velocity, and timing of growth spurt) were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, in 787 participants with height measurements spanning the whole period of growth. Heritability estimates suggested that genetic factors could explain 25% to 71% of the variance of pubertal growth traits. We performed a GWAS of growth parameters, testing their associations with 5 077 595 imputed or directly genotyped variants. Six variants associated with height at peak velocity (P < 5 × 10-8, adjusted for sex, birth year and principal components). Implicated genes include NUDT3, previously associated with adult height, and PACSIN1. Two novel variants associated with duration of growth spurt (P < 5 × 10-8) in LOC105375344, an uncharacterized gene with unknown function. We finally examined the association of growth parameters with a polygenic score for height derived from 9557 single nucleotide polymorphisms (SNPs) identified in the GIANT meta-analysis for which genotypic data were available for the American Indian study population. Height polygenic score was correlated with the magnitude and velocity of height growth that occurred before and at the peak of the adolescent growth spurt, indicating overlapping genetic architecture, with no influence on the timing of adolescent growth., (Published by Oxford University Press 2024.)

Purpose: Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer., Methods: We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations., Results: We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39)., Conclusions: Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer., (© 2023. The Author(s).)

American Indians (AI) demonstrate the highest rates of both suicidal behaviors (SB) and alcohol use disorders (AUD) among all ethnic groups in the US. Rates of suicide and AUD vary substantially between tribal groups and across different geographical regions, underscoring a need to delineate more specific risk and resilience factors. Using data from over 740 AI living within eight contiguous reservations, we assessed genetic risk factors for SB by investigating: (1) possible genetic overlap with AUD, and (2) impacts of rare and low-frequency genomic variants. Suicidal behaviors included lifetime history of suicidal thoughts and acts, including verified suicide deaths, scored using a ranking variable for the SB phenotype (range 0-4). We identified five loci significantly associated with SB and AUD, two of which are intergenic and three intronic on genes AACSP1, ANK1, and FBXO11. Nonsynonymous rare and low-frequency mutations in four genes including SERPINF1 (PEDF), ZNF30, CD34, and SLC5A9, and non-intronic rare and low-frequency mutations in genes OPRD1, HSD17B3 and one lincRNA were significantly associated with SB. One identified pathway related to hypoxia-inducible factor (HIF) regulation, whose 83 nonsynonymous rare and low-frequency variants on 10 genes were significantly linked to SB as well. Four additional genes, and two pathways related to vasopressin-regulated water metabolism and cellular hexose transport, also were strongly associated with SB. This study represents the first investigation of genetic factors for SB in an American Indian population that has high risk for suicide. Our study suggests that bivariate association analysis between comorbid disorders can increase statistical power; and rare and low-frequency variant analysis in a high-risk population enabled by whole-genome sequencing has the potential to identify novel genetic factors. Although such findings may be population specific, rare functional mutations relating to PEDF and HIF regulation align with past reports and suggest a biological mechanism for suicide risk and a potential therapeutic target for intervention., (© 2023. The Author(s).)

Background: Genome-wide association studies have shown that body mass index (BMI), an estimate of obesity, is highly polygenic. Individual variants typically have small effect sizes, making it challenging to identify unique loci in under-represented ethnic groups which lack statistical power due to their small sample size. Yet obesity is a major health disparity and is particularly prevalent in southwestern American Indians. Here, we identify and characterize a new locus for BMI that was detected by analyzing moderate associations with BMI obtained in a population-based sample of southwestern American Indians together with the well-powered GIANT dataset., Methods: Genotypes for 10.5 million variants were tested for association with BMI in 5870 American Indians and 2600 variants that showed an association P < 10 -3 in the American Indian sample were combined in a meta-analysis with the BMI data reported in GIANT (N = 240,608). The newly identified gene, NFIA-AS2 was functionally characterized, and the impact of its lead associated variant rs1777538 was studied both in-silico and in-vitro., Results: Rs1777538 (T/C; C allele frequency = 0.16 in American Indians and 0.04 in GIANT, meta-analysis P = 5.0 × 10 -7 ) exhibited a large effect in American Indians (1 kg/m 2 decrease in BMI per copy of C allele). NFIA-AS2 was found to be a nuclear localized long non-coding RNA expressed in tissues pertinent to human obesity. Analysis of this variant in human brown preadipocytes showed that NFIA-AS2 transcripts carrying the C allele had increased RNA degradation compared to the T allele transcripts (half-lives = 9 h, 13 h respectively). During brown adipogenesis, NFIA-AS2 featured a stage-specific regulation of nearby gene expression where rs1777538 demonstrated an allelic difference in regulation in the mature adipocytes (the strongest difference was observed for L1TD1, P = 0.007)., Conclusion: Our findings support a role for NFIA-AS2 in regulating pathways that impact BMI., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: Since 2010, genome-wide data from hundreds of ancient Native Americans have contributed to the understanding of Americas' prehistory. However, these samples have never been studied as a single dataset, and distinct relationships among themselves and with present-day populations may have never come to light. Here, we reassess genomic diversity and population structure of 223 ancient Native Americans published between 2010 and 2019., Materials and Methods: The genomic data from ancient Americas was merged with a worldwide reference panel of 278 present-day genomes from the Simons Genome Diversity Project and then analyzed through ADMIXTURE, D -statistics, PCA, t-SNE, and UMAP., Results: We find largely similar population structures in ancient and present-day Americas. However, the population structure of contemporary Native Americans, traced here to at least 10,000 years before present, is noticeably less diverse than their ancient counterparts, a possible outcome of the European contact. Additionally, in the past there were greater levels of population structure in North than in South America, except for ancient Brazil, which harbors comparatively high degrees of structure. Moreover, we find a component of genetic ancestry in the ancient dataset that is closely related to that of present-day Oceanic populations but does not correspond to the previously reported Australasian signal. Lastly, we report an expansion of the Ancient Beringian ancestry, previously reported for only one sample., Discussion: Overall, our findings support a complex scenario for the settlement of the Americas, accommodating the occurrence of founder effects and the emergence of ancestral mixing events at the regional level., Competing Interests: CONFLICT OF INTEREST The authors declare that they have no conflict of interest.

Insulin-like growth factor binding protein 4 (IGFBP4) is involved in adipogenesis, and IGFBP4 null mice have decreased body fat through decreased PPAR-γ expression. In the current study, we assessed whether variation in the IGFBP4 coding region influences body mass index (BMI) in American Indians who are disproportionately affected by obesity. Whole exome sequence data from a population-based sample of 6779 American Indians with longitudinal measures of BMI were used to identify variation in IGFBP4 that associated with BMI. A novel variant that predicts a p.Ser76Thr in IGFBP4 (Thr-allele frequency = 0.02) was identified which associated with the maximum BMI measured during adulthood (BMI 39.8 kg/m 2 for Thr-allele homozygotes combined with heterozygotes vs. 36.2 kg/m 2 for Ser-allele homozygotes, β = 6.7% per Thr-allele, p = 8.0 × 10 -5 , adjusted for age, sex, birth-year and the first five genetic principal components) and the maximum age- and sex-adjusted BMI z-score measured during childhood/adolescence (z-score 0.70 SD for Thr-allele heterozygotes vs. 0.32 SD for Ser-allele homozygotes, β = 0.37 SD per Thr-allele, p = 8.8 × 10 -6 ). In vitro functional studies showed that IGFBP4 with the Thr-allele (BMI-increasing) had a 55% decrease (p = 0.0007) in FOXO-induced transcriptional activity, reflecting increased activation of the PI3K/AKT pathway mediated through increased IGF signaling. Over-expression and knock-down of IGFBP4 in OP9 cells during differentiation showed that IGFBP4 upregulates adipogenesis through PPARγ, CEBPα, AGPAT2 and SREBP1 expression. We propose that this American Indian specific variant in IGFBP4 affects obesity via an increase of IGF signaling., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15-30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4-9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far., (© 2021. The Author(s).)

Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The peopling of the Americas by Native Americans occurred in 4 waves of which the last was Nadene language speakers of whom Athabaskans are the largest group. As the Europeans were entering the Southwestern states of the USA, Athabaskan hunting-gathering tribes were migrating South from Canada along the Rocky Mountains and undergoing potential bottlenecks reflected in autosomal recessive diseases shared by Apaches and Navajos. About 300 years ago, the Navajo developing a sedentary culture learned from Pueblo Indians while the Apache remained hunter-gathers. Although most of the tribe was rounded up and forced to relocate to Bosque Redondo, the adult breeding population was large enough to prevent a genetic bottleneck. However, some Navajo underwent further population bottlenecks while hiding from the brutal US Army action (under Kit Carson's guidance). This led to an increased frequency of other autosomal recessive diseases. Recent advances in population genetics, pathophysiology of the diseases, and social/ethical issues concerning their study are reviewed., (© 2021. Institute of Plant Genetics, Polish Academy of Sciences, Poznan.)

To compare etonogestrel pharmacokinetic and pharmacodynamic outcomes by both self-reported race/ethnicity and genetically determined ancestry among contraceptive implant users. We conducted a secondary analysis of our parent pharmacogenomic study of 350 implant users. We genotyped these reproductive-aged (18-45 years) women for 88 ancestry-informative single nucleotide polymorphisms. We then assigned each participant a proportion value for African (AFR), European (EUR), and Indigenous American (AMR) ancestry based on reference population data. We correlated genetic ancestry with self-reported race/ethnicity and utilized genetic ancestry proportion values as variables for previously performed association analyses with serum etonogestrel concentrations and progestin-related side effects (e.g., bothersome bleeding and subjective weight gain). We successfully estimated genetically determined ancestry for 332 participants. EUR, AFR, and AMR ancestry were each highly correlated with self-reported White/non-Hispanic race (r = 0.64, p = 4.14 × 10 -40 ), Black/African American race (r = 0.88, p = 1.36 × 10 -107 ), and Hispanic/Latina ethnicity (r = 0.68, p = 4.03 × 10 -47 ), respectively. Neither genetically determined ancestry nor self-reported race/ethnicity were significantly associated with serum etonogestrel concentrations. AFR ancestry and self-reported Black race had similar associations with reporting monthly periods (odds ratio [OR] 2.18, p = 0.09 vs. OR 2.22, p = 0.02) and having received treatment for bothersome bleeding (OR 5.19, p = 0.005 vs. OR 4.73, p = 2.0 × 10 -4 ). In multivariable logistic regression for subjective weight gain, AMR ancestry dropped out of the model in preference for self-reported Hispanic/Latina ethnicity. We found no new associations between genetically determined ancestry and contraceptive implant pharmacodynamics/pharmacokinetics. Self-reported race/ethnicity were strong surrogates for genetically determined ancestry among this population of contraceptive implant users. Our data suggest that self-reported race/ethnicity, capturing societal and cultural aspects, remain important to the investigation of progestin-related side effects., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: MATE2-K is an efflux transporter protein of organic cation expressed mainly in the kidney and encoded by the SLC47A2 gene. Different variants of this gene have shown an impact on the pharmacokinetics of various drugs, including metformin, which represents one of the most widely used drugs in treating type 2 diabetes. The SLC47A2 gene variants have been scarcely studied in Mexican populations, especially in Native American groups. For this reason, we analyzed the distribution of the variants rs12943590, rs35263947, and rs9900497 within the SLC47A2 gene in 173 Native Americans (Tarahumara, Huichol, Maya, Puerépecha) and 182 Mestizos (admixed) individuals from Mexico., Methods and Results: Genotypes were determined through TaqMan probes (qPCR). The Hardy-Weinberg agreement was confirmed for all three SLC47A2 gene variants in all the Mexican populations analyzed. When worldwide populations were included for comparison purposes, for alleles and genotypes a relative interpopulation homogeneity was observed for rs35263947 (T allele; range 23.3-51.1%) and rs9900497 (T allele; range 18.6-40.9%). Conversely, heterogeneity was evident for rs12943590 (A allele, range 22.1-59.1%), where the most differentiated population was the Huichol, with high frequencies of the risk genotype associated with decreased response to metformin treatment (A/A = 40.9%)., Conclusions: Although the SLC47A2 gene variants allow predicting favorable response to the metformin treatment in Mexican populations, the probable high frequency of ineffectiveness should be discarded in Huichols., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Metabolic syndrome (MetS) is a complex cluster of risk factors, considered as a polygenic and multifactorial entity. The objective of this study was to determine the association of rs9939609-FTO polymorphism and MetS components in adult women of Mayan communities of Chiapas., Methods: In a cross-sectional study, sociodemographic, anthropometric, clinical, and biochemical data were obtained from 291 adult women from three regions of Chiapas, Mexico. The prevalence of MetS and the allele and genotype frequencies of the rs9939609-FTO were estimated. Multivariate logistic regression models were used to assess the association of the single nucleotide polymorphism (SNP) with each of the MetS components., Results: The MetS prevalence was 60%. We found a statistically significant association between rs9939609-FTO and hyperglycemia in the dominant model (OR 2.6; 95% CI 1.3-5.3; p = 0.007)., Conclusions: Women from Mayan communities of Chiapas presented a high prevalence of MetS and a relevant association of the FTO variant with hyperglycemia. This is the first study carried out in these Mayan indigenous communities from Chiapas., (© 2021. The Author(s).)

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk., (© 2021. The Author(s).)

Background: LCAT (lecithin-cholesterol acyltransferase) deficiency is characterized by two distinct phenotypes, familial LCAT deficiency (FLD) and Fish Eye disease (FED). This is the first systematic review evaluating the ethnic distribution of LCAT deficiency, with particular emphasis on Latin America and the discussion of three Mexican-Mestizo probands., Methods: A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) Statement in Pubmed and SciELO. Articles which described subjects with LCAT deficiency syndromes and an assessment of the ethnic group to which the subject pertained, were included., Results: The systematic review revealed 215 cases (154 FLD, 41 FED and 20 unclassified) pertaining to 33 ethnic/racial groups. There was no association between genetic alteration and ethnicity. The mean age of diagnosis was 42 ± 16.5 years, with fish eye disease identified later than familial LCAT deficiency (55 ± 13.8 vs. 41 ± 14.7 years respectively). The prevalence of premature coronary heart disease was significantly greater in FED vs. FLD. In Latin America, 48 cases of LCAT deficiency have been published from six countries (Argentina (1 unclassified), Brazil (38 FLD), Chile (1 FLD), Columbia (1 FLD), Ecuador (1 FLD) and Mexico (4 FLD, 1 FED and 1 unclassified). Of the Mexican probands, one showed a novel LCAT mutation., Conclusions: The systematic review shows that LCAT deficiency syndromes are clinically and genetically heterogeneous. No association was confirmed between ethnicity and LCAT mutation. There was a significantly greater risk of premature coronary artery disease in fish eye disease compared to familial LCAT deficiency. In FLD, the emphasis should be in preventing both cardiovascular disease and the progression of renal disease, while in FED, cardiovascular risk management should be the priority. The LCAT mutations discussed in this article are the only ones reported in the Mexican- Amerindian population., (© 2021. The Author(s).)

The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup'ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4-mediated 4β-vitamin D hydroxylation activity in Yup'ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele-coupled with low frequency of the functional CYP3A5*1 variant-may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objective: To analyze the genetic origin, relationships, structure, and admixture in Mayan Native American groups from Guatemala and Mexico based on 15 autosomal short tandem repeats (STRs) loci commonly used in human identification (HID)., Methods: We genotyped 513 unrelated Mayan samples from Guatemala based on 15 STR loci (AmpFlSTR® Identifiler kit). Moreover, we included 4408 genotypes previously reported, as following: Mayas from Guatemala and Mexico (n = 1666) and from Latin American, European, and African (n = 2742) populations. Forensic parameters, genetic distances, admixture, and population structure were assessed., Results: Forensic parameters of the 15 STRs in different Mayan groups from Guatemala were reported. Low (Fst = 0.78%; p = 0.000) and non-significant differentiation (Fst = 1.8%; p = 0.108) were observed in Mayas from Guatemala and Mexico, respectively. The relative homogeneity observed among Mayan groups supported theories of extensive pre-Columbian gene flow and trade throughout the Mayan Empire. The distribution of the three Native American ancestries among these Mayan groups did not support the presumable Guatemalan origin of Tojolabal and Lacandon people (South, Mexico). The nonsignificant differentiation between Ladinos and Mayas suggests a relative panmixia in Guatemala. Mestizos from southeastern Mexico and Guatemala constitute a core of Native American ancestry in Latin America related to the Mayan Empire in Central America., Conclusions: The higher European admixture and homogeneity in Mexican Mayas of the Yucatan Peninsula suggest more intensive post-Columbian gene flow in this region than in Guatemalan Mayas., (© 2021 Wiley Periodicals LLC.)

The Mexican-Mestizo population arose following European contact with the Americas due to the admixture of principally Spaniards, Native Americans, and Africans around 500 years ago. Because the paternal lineage distribution of the Mexican population has been poorly investigated, this study inferred the haplogroups of ten populations based on 1859 haplotypes (Y-STR data) using two haplogroup predictor programs. In the Mexican population sample, we found predominantly European ancestry (50.1%), followed by Native American (32.5%), Eurasian (13.4%), African (2.1%), East African-South Eurasian (1.3%), and Asian (0.6%) ancestries. In general, our results support a contrary north-to-south gradient throughout the Mexican territory of European and Native-American ancestries, respectively. Moreover, the presence of West-European R1b and Sub-Saharan African E1b1a haplogroups agrees with historical and genetic data of gene flow during the European conquest. This study represents the effort to analyze these paternal lineages on a large scale by taking advantage of Y-STR haplotype data to determine the distribution and ancestry proportions in this country.

Alcohol and other substance use disorders (AUD and SUD) are complex diseases that are postulated to have a polygenic inheritance and are often comorbid with other disorders. The comorbidities may arise partially through genetic pleiotropy. Identification of specific gene variants accounting for large parts of the variance in these disorders has yet to be accomplished. We describe a flexible strategy that takes a variant-trait association database and determines if a subset of disease/straits are potentially pleiotropic with the disorder under study. We demonstrate its usage in a study of use disorders in two independent cohorts: alcohol, stimulants, cannabis (CUD), and multi-substance use disorders (MSUD) in American Indians (AI) and AUD and CUD in Mexican Americans (MA). Using a machine learning method with variants in GWAS catalog, we identified 229 to 246 pleiotropic variants for AI and 153 to 160 for MA for each SUD. Inflammation was the most enriched for MSUD and AUD in AIs. Neurological disorder was the most significantly enriched for CUD in both cohorts, and for AUD and stimulants in AIs. Of the select pleiotropic genes shared among substances-cohorts, multiple biological pathways implicated in SUD and other psychiatric disorders were enriched, including neurotrophic factors, immune responses, extracellular matrix, and circadian regulation. Shared pleiotropic genes were significantly up-regulated in brain regions playing important roles in SUD, down-regulated in esophagus mucosa, and differentially regulated in adrenal gland. This study fills a gap for pleiotropy detection in understudied admixed populations and identifies pleiotropic variants that may be potential targets of interest for SUD., (© 2020 Society for the Study of Addiction.)

Background: Breast cancer is one of the most common causes of cancer mortality for all women, including American Indian and Alaska Native (AI/AN) women. The use of the 21-gene recurrence score (RS) appears to be predictive of the benefit of chemotherapy for women with estrogen receptor (ER)-positive breast cancer. The objective of the current study was to compare RS testing between AI/AN and non-Hispanic White (NHW) women with breast cancer., Methods: The Surveillance, Epidemiology, and End Results program was used to identify women with ER-positive breast cancer from 2004 through 2015. Multivariable logistic regression was used to evaluate factors associated with RS use, with high-risk RS, and with chemotherapy use among those with a high-risk RS., Results: A total of 363,387 NHW patients and 1951 AI/AN patients with ER-positive breast cancer were identified. AI/AN women were found to be less likely to undergo RS testing and, when tested, were more likely to have a high-risk RS. In the multivariable logistic regression analysis, AI/AN women were found to be significantly more likely to have a high-risk RS (odds ratio,1.28; 95% confidence interval, 1.01-1.66). Among untested women, chemotherapy use was higher for AI/AN women; however, the use of chemotherapy was not found to be significantly different between the groups with a high-risk RS. Using Cox proportional hazards models, AI/AN race was found to be significantly associated with worse overall survival., Conclusions: AI/AN women were less likely to undergo RS testing compared with NHW women and were more likely to have a high-risk RS. Reversing the disparity in genomic expression assay testing is critical to ensure guideline-based breast cancer treatment and improve survival rates for AI/AN women with breast cancer., (© 2020 American Cancer Society.)

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

Background/objectives: Nighttime eating (NE) behavior has a genetic component and predicts weight gain. We hypothesized that some genetic variants, which affect NE would also show an effect on body mass index (BMI). We aimed to determine which known BMI variants associate with NE in Southwestern American Indians (SWAIs), who are at elevated risk for obesity., Methods: Known BMI variants from the GIANT-UK Biobank meta-analysis (N = 700,000) were analysed in SWAIs characterized for NE during an inpatient 3-day protocol. Variants were analysed for association with NE using whole-genome sequence data from 50 SWAIs (23 cases and 27 controls) and selected variants were genotyped in an additional 32 SWAIs (13 NE cases and 19 controls). Variants associated with NE in a meta-analysis of the two SWAI samples were further analysed for association with nightly caloric intake and functionality in hypothalamus, pituitary, and adrenal tissues., Results: Variants were identified where the allele that associated with increased BMI in the GIANT-UK Biobank meta-analysis (P ≤ 1 × 10 -8 ) also had a P < 0.01 for increased NE in the SWAI meta-analysis. These variants were captured by six tagSNPs. Comparison of the nightly calorie intake by genotype and eQTL data from relevant tissues highlighted rs3753612 upstream of HCRTR1., Conclusions: Our strategy led to the HCRTR1 locus, which has previously been linked to sleep regulation and feeding. Although this is an intriguing candidate gene for NE, further studies in larger samples and different populations are required to validate the role of HCRTR1 in NE.

Objective: Hispanic populations typically show a high prevalence of dyslipidemias, especially of low high-density lipoproteins (HDLs) or HDL cholesterol. Highly admixed populations are ideal groups to clarify the role of genetic ancestry on HDL concentrations, isolating it from that of other factors. The objective of this study was to estimate the association between Native American genetic ancestry and HDL-cholesterol levels independent of socioeconomic factors in a representative sample of the Mexican population., Methods: We used data from the Mexican National Health Survey 2000, analyzing 1647 subjects from whom stored DNA samples and HDL measurements were available. To estimate proportional genetic ancestry (Native American, African, and European), we used a 107 genetic ancestry informative marker panel with the software STRUCTURE. To estimate the association between genetic ancestry and low HDL levels, we fitted logistic regression models with the percentage of Native American genetic ancestry, in quartiles, as the main predictor., Results: Mean HDL levels were 38.9 mg/dL, with 62% of subjects having levels below 40 mg/dL. Participants had on average 53.6% Native American, 39% European, and 7.3% African genetic ancestry. Those in the fourth quartile of Native American genetic ancestry had 35% higher odds of having low HDL-cholesterol relative to those in the first quartile (odds ratio, 1.35; 95% confidence interval, 0.99-1.81) after adjustment for socioeconomic level and other covariates, although the association is clearly nonlinear., Conclusion: Native American genetic ancestry seems to play a small but distinct role in the development of low HDL cholesterol levels., (© 2020 Wiley Periodicals, Inc.)

Genomic research raises unique ethical concerns among Alaska Native and American Indian (AN/AI) people and their communities. The Center for the Ethics of Indigenous Genomic Research (CEIGR) was created to foster research that takes these concerns into account while considering the sovereign status of AN/AI tribal nations. Relationships developed within CEIGR have allowed for effective, collaborative research among individuals who come from diverse cultures, political and historical backgrounds, and academic disciplines, and who work for organizations with varying resources, capacities, and expectations. The CEIGR framework may inform other groups seeking to conduct social science research related to genomic research with tribal people and their communities.

Rationale: Puerto Ricans have the highest childhood asthma prevalence in the United States (23.6%); however, the etiology is uncertain. Objectives: In this study, we sought to uncover the genetic architecture of lung function in Puerto Rican youth with and without asthma who were recruited from the island ( n  = 836). Methods: We used admixture-mapping and whole-genome sequencing data to discover genomic regions associated with lung function. Functional roles of the prioritized candidate SNPs were examined with chromatin immunoprecipitation sequencing, RNA sequencing, and expression quantitative trait loci data. Measurements and Main Results: We discovered a genomic region at 1q32 that was significantly associated with a 0.12-L decrease in the lung volume of exhaled air (95% confidence interval, -0.17 to -0.07; P  = 6.62 × 10 -8 ) with each allele of African ancestry. Within this region, two SNPs were expression quantitative trait loci of TMEM9 in nasal airway epithelial cells and MROH3P in esophagus mucosa. The minor alleles of these SNPs were associated with significantly decreased lung function and decreased TMEM9 gene expression. Another admixture-mapping peak was observed on chromosome 5q35.1, indicating that each Native American ancestry allele was associated with a 0.15-L increase in lung function (95% confidence interval, 0.08-0.21; P  = 5.03 × 10 -6 ). The region-based association tests identified four suggestive windows that harbored candidate rare variants associated with lung function. Conclusions: We identified common and rare genetic variants that may play a critical role in lung function among Puerto Rican youth. We independently validated an inflammatory pathway that could potentially be used to develop more targeted treatments and interventions for patients with asthma.

Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations of European and East Asian ancestry, and there were many predicted loss-of-function (pLOF) and nonsynonymous variants that were highly enriched or private in the SWAI population. We used pLOF and nonsynonymous variants in the SWAI population to evaluate gene-burden associations of candidate genes from European genome-wide association studies (GWASs) for type 2 diabetes, body mass index, and four major plasma lipids. We found 19 significant gene-burden associations for 11 genes, providing additional evidence for prioritizing candidate effector genes of GWAS signals. Interestingly, these associations were mainly driven by pLOF and nonsynonymous variants that are unique or highly enriched in the SWAI population. Particularly, we found four pLOF or nonsynonymous variants in APOB, APOE, PCSK9, and TM6SF2 that are private or enriched in the SWAI population and associated with low-density lipoprotein (LDL) cholesterol levels. Their large estimated effects on LDL cholesterol levels suggest strong impacts on protein function and potential clinical implications of these variants in cardiovascular health. In summary, our study illustrates the utility and potential of exome sequencing in genetically unique populations, such as the SWAI population, to prioritize candidate effector genes within GWAS loci and to find additional variants in known disease genes with potential clinical impact., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)

Obesity, a risk factor for multiple diseases (e.g. diabetes, hypertension, cancers) originates through complex interactions between genes and prevailing environment (food habit and lifestyle) that varies across populations. Indians exhibit a unique obesity phenotype with high abdominal adiposity for a given body weight compared to matched white populations suggesting presence of population-specific genetic and environmental factors influencing obesity. However, Indian population-specific genetic contributors for obesity have not been explored yet. Therefore, to identify potential genetic contributors, we performed a two-staged genome-wide association study (GWAS) for body mass index (BMI), a common measure to evaluate obesity in 5973 Indian adults and the lead findings were further replicated in 1286 Indian adolescents. Our study revealed novel association of variants-rs6913677 in BAI3 gene (p = 1.08 × 10 -8 ) and rs2078267 in SLC22A11 gene (p = 4.62 × 10 -8 ) at GWAS significance, and of rs8100011 in ZNF45 gene (p = 1.04 × 10 -7 ) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped genetic data of identified signals with their DNA methylation patterns in 236 Indian individuals and performed methylation quantitative trait loci (meth-QTL) analysis. Further, functional roles of discovered variants and underlying genes were speculated using publicly available gene regulatory databases (ENCODE, JASPAR, GeneHancer, GTEx). The identified variants in BAI3 and SLC22A11 genes were found to dictate methylation patterns at unique CpGs harboring critical cis-regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were located in repressive chromatin, active enhancer, and active chromatin regions, respectively, in human subcutaneous adipose tissue in ENCODE database. Additionally, these genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, GTEx portal identify rs8100011 as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue (p = 1.6 × 10 -7 ), and ZNF45 gene expression in skeletal muscle of Indian subjects showed an inverse correlation with BMI indicating its possible role in obesity. In conclusion, our study discovered 3 novel population-specific functional genetic variants (rs6913677, rs2078267, rs8100011) in 2 novel (SLC22A11 and ZNF45) and 1 earlier reported gene (BAI3) for BMI in Indians. Our study decodes key genomic loci underlying obesity phenotype in Indians that may serve as prospective drug targets in future.

Introduction: Alaska Native and American Indian (AN/AI) populations have higher tobacco use prevalence than other ethnic/racial groups. Pharmacogenetic testing to tailor tobacco cessation treatment may improve cessation rates. This study characterized polymorphic variations among AN/AI people in genes associated with metabolism of nicotine and drugs used for tobacco cessation., Methods: Recruitment of AN/AI individuals represented six subgroups, five geographic subgroups throughout Alaska and a subgroup comprised of AIs from the lower 48 states living in Alaska. We sequenced the CYP2A6 and CYP2B6 genes to identify known and novel gain, reduced, and loss-of-function alleles, including structural variation (eg, gene deletions, duplications, and hybridizations)., Results: Variant allele frequencies differed substantially between AN/AI subgroups. The gene deletion CYP2A6*4 and reduced function CYP2A6*9 alleles were found at high frequency in Northern/Western subgroups and in Lower 48/Interior subgroups, respectively. The reduced function CYP2B6*6 allele was observed in all subgroups and a novel, predicted reduced function CYP2B6 variant was found at relatively high frequency in the Southeastern subgroup., Conclusions: Diverse CYP2A6 and CYP2B6 variation among the subgroups highlight the need for comprehensive pharmacogenetic testing to guide tobacco cessation therapy for AN/AI populations., Implications: Nicotine metabolism is largely determined by CYP2A6 genotype, and variation in CYP2A6 activity has altered the treatment success in other populations. These findings suggest pharmacogenetic-guided smoking cessation drug treatment could provide benefit to this unique population seeking tobacco cessation therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Huastecos or Teenek Amerindians are presently living at North East Mexico (San Luis Potosi State). They have probably one of the most ancient culture of Mexico and Central America together with Mayas and Olmec groups with which also show close relationships. Proximity to Atlantic Ocean/Mexican Gulf originated that Spaniards had very early contact with them at about 1519 CE or before. In the present paper we have aimed to study HLA gene profile which may be useful for HLA and disease epidemiology and transplant programs in Teeneks. HLA-DRB1*04:07, -DRB1*14:06 and -DRB1*04:11 have been found in high frequency like in other Amerindian groups. High frequency typical Amerindians HLA extended haplotypes have been found, such as A*02-B*35-DRB1*04:07-DQB1*03:02; A*68-B*39-DRB1*04:07-DQB1*03:02 and A*02-B*39-DRB1*04:07-DQB1*03:02; also new haplotypes have been described, like A*02-B*52-DRB1*04:11-DQB1*03:02, A*68-B*35-DRB1*14:02-DQB1*03:01 and A*68-B*40-DRB1*16:02-DQB1*03:01. Genetic proximity is observed not only to linguistically close Mayans, but also to Mazatecans, Mixtecans and Zapotecans, who speak an altogether different languages; it shows once more that genes and languages do not correlate. This population was greatly diminished after European contact between 1500 and 1600 years CE; in fact, North and South America First Inhabitants population was brought from 80 down to 8 million people because of diseases (i.e.: measles, smallpox or influenza), slavery and war., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: the CYP2D6 gene is clinically important and is known to have a number of variants. This gene has four distinct metabolization profiles that are determined by the different allelic forms present in the individual. The relative frequency of these profiles varies considerably among human populations around the world. Populations from more isolated regions, such as Native Americans, are still relatively poorly studied, however. Even so, recent advances in genotyping techniques and increasing interest in the study of these populations has led to a progressive increase in publication rates. Given this, the review presented here compiled the principal papers published on the CYP2D6 gene in Amerindian populations to determine the metabolic profile of this group., Methods: a systematic literature review was conducted in three scientific publication platforms (Google Scholar, Science Direct, and Pubmed). The search was run using the keywords "CYP2D6 Amerindians" and "CYP2D6 native Americans"., Results: a total of 13 original papers met the inclusion criteria established for this study. All the papers presented frequencies of the different CYP2D6 alleles in Amerindian populations. Seven of the papers focused specifically on Amerindian populations from Mexico, while the others included populations from Argentina, Chile, Costa Rica, Mexico, Paraguay, Peru, and the United States. The results of the papers reviewed here showed that the extensive metabolization profile was the most prevalent in all Amerindian populations studied to date, followed by the intermediate, slow, and ultra-rapid, in that order., Conclusion: the metabolization profiles of the Amerindian populations reviewed in the present study do not diverge in any major way from those of other populations from around the world. Given the paucity of the data available on Amerindian populations, further research is required to better characterize the metabolization profile of these populations to ensure the development of adequate therapeutic strategies.

In Mexico, the genetic mechanisms underlying childhood obesity are poorly known. We evaluated the effect of loci, known to be associated with childhood body mass index (BMI) in Europeans, in Mexican children from different ethnic groups. We performed linear and logistic analyses of BMI and obesity, respectively, in Mestizos and Amerindians (Seris, Yaquis and Nahuatl speakers) from Northern ( n = 369) and Central Mexico ( n = 8545). We used linear models to understand the effect of degree of Amerindian ancestry (AMA) and genetic risk score (GRS) on BMI z-score. Northern Mexican Mestizos showed the highest overweight-obesity prevalence (47.4%), followed by Seri (36.2%) and Central Mexican (31.5%) children. Eleven loci ( SEC16B /rs543874, OLFM4 /rs12429545/rs9568856, FTO /rs9939609, MC4R /rs6567160, GNPDA2 /rs13130484, FAIM2 /rs7132908, FAM120AOS /rs944990, LMX1B /rs3829849, ADAM23 /rs13387838, HOXB5 /rs9299) were associated with BMI and seven ( SEC16B /rs543874, OLFM4 /rs12429545/rs9568856, FTO /rs9939609, MC4R /rs6567160, GNPDA2 rs13130484, LMX1B /rs3829849) were associated with obesity in Central Mexican children. One SNP was associated with obesity in Northern Mexicans and Yaquis ( SEC16B /rs543874). We found higher BMI z-score at higher GRS (β = 0.11, p = 0.2 × 10 -16 ) and at lower AMA (β = -0.05, p = 6.8 × 10 -7 ). The GRS interacts with AMA to increase BMI (β = 0.03, p = 6.08 × 10 -3 ). High genetic BMI susceptibility increase the risk of higher BMI, including in Amerindian children.

TPMT and NUDT15 polymorphisms are major determinants of tolerance to thiopurine drugs used in leukemias and nonmalignant immunologic disorders. We adopted an extreme discordant phenotype approach to explore the impact of Native American versus European ancestry on the distribution of TPMT and NUDT15 polymorphisms, and inferred metabolic phenotypes in the 1000 Genomes Ad Mixed American superpopulation. Significant differences were observed in the distribution of TPMT and NUDT15 haplotypes (star alleles) between individuals with predominant (>70%) European versus Native ancestry. The largest difference is related to NUDT15 rs116855232. Based on the combined TPMT/NUDT15 metabolic phenotypes, the Clinical Pharmacogenetics Implementation Consortium recommendations for thiopurine dose adjustment applies to 40.1% of individuals with major Native American ancestry, compared to 12.8% of individuals with predominantly European ancestry. These findings may be relevant to the adoption and interpretation of pharmacogenetic tests for thiopurine drugs across Latin America peoples with different European and Native-American ancestries.

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

We analyzed 307 Mexican-Mestizo (admixed) males from Mexico City with the Powerplex® Y23 system. The complete list of Y-STR haplotypes was uploaded into the YHRD database (accession number YA004275). The discriminatory capacity (98.70 %) and gene diversity (D = 99.99 %) were calculated, improving the haplotype diversity regarding previous studies in Mexico based on 17 Y-STRs and 12 Y-STRs. Haplogroup distribution assignment was inferred by means of two different online-available algorithms. The Native American Q* haplogroup was the most frequent (66.2 %), followed by the European R1b lineage (19.5 %). In addition, eight Eurasian (3.9%) and two African (6.6%) haplogroups were observed in this population sample from Mexico City. Interestingly, AMOVA test showed a low but significant differentiation among Mexican-Mestizos (Fst = 1.52%; p = 0.0000), suggesting that four population clusters allow to explain their genetic structure according to geographic criteria: north, west, center, and south.

The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P<0.05). The non-synonymous ADRB2 Glu27 allele (rs1042714G), which is associated with several common conditions, showed the lowest frequency in MAs (0.03) compared to other populations worldwide. Among MEZs, this allele showed a frequency of 0.15, intermediate between that in MAs and in Iberians (0.43). Moreover, Glu27 was the only SNP exhibiting a geographic gradient within the MEZ population (from 0.22 to 0.11), reflecting admixed mestizo ancestry across the country. Population differentiation analysis demonstrated that Glu27 had the highest FST value in MAs compared with Europeans (CEU) (0.71), and the lowest between MAs and Japanese (JPT) (0.01), even lower than that observed between MAs and MEZs (0.08). This analysis demonstrated the genetic diversity among Amerindian ethnicities, with the most extreme FST value (0.34) found between the Nahuatls from Morelos and the Seris. This is the first study of ADRB2 genetic variants among MA ethnicities. Our findings add to our understanding of the genetic contribution to variability in disease susceptibility in admixed populations., Competing Interests: The authors have declared that no competing interests exist.

Mitochondrial haplogroup information can be useful in forensic contexts that rely primarily on mitochondrial DNA (mtDNA) testing, which often involve limited or degraded DNA. Due to the phylogeographic patterning of mtDNA in human populations, mitochondrial haplogroups are indicative of maternal ancestry (as mtDNA is a maternally inherited marker). In certain circumstances, maternal ancestry inferred from mitochondrial haplogrouping could be beneficial to forensic investigations. For example, ancestry information could assist in the identification of unknown service members from past conflicts, such as the World War II Battle of Tarawa involving American and Japanese forces. In this context, it could be useful to distinguish Native American mtDNA from Asian mtDNA to bolster the anthropological and circumstantial evidence leading to an identification or foreign national determination. Although most of the founding Native American haplogroups contain diagnostic variants in the mitochondrial control region (CR), haplogroup B2 does not, and this makes it more difficult to distinguish B2 from the parental B4 and closely related B4b haplogroups found in Asia. In this paper, the amount of mtDNA information required to distinguish Native American haplotypes from Asian haplotypes within haplogroup B was examined. Fifty-six samples belonging to subtypes of B2 and B4 were sequenced for the entire mitogenome. Haplogroups were estimated from three ranges of mitochondrial DNA (HV1 and 2, CR, and full mitogenome). Half of the samples could not be precisely haplogrouped without full mitogenome data, although enough variants were often provided to make an accurate B2 versus B4 distinction. Native American B2 haplotypes were distinguishable using CR data alone in 82% of samples, though the remaining samples required full mitogenome data for haplogroup B2 designation. The use of full mitogenome data consistently enables accurate haplogroup determination, and opens the possibility for gaining information on maternal ancestry., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations., Methods: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses., Results: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4., Conclusion: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation., Competing Interests: MBIRI does not alter our adherence to PLOS ONE policies on sharing data and materials.

European and African descendants settled the continental US during the 17th-19th centuries, coming into contact with established Native American populations. The resulting admixture among these groups yielded a significant reservoir of Native American ancestry in the modern US population. We analyzed the patterns of Native American admixture seen for the three largest genetic ancestry groups in the US population: African descendants, Western European descendants, and Spanish descendants. The three groups show distinct Native American ancestry profiles, which are indicative of their historical patterns of migration and settlement across the country. Native American ancestry in the modern African descendant population does not coincide with local geography, instead forming a single group with origins in the southeastern US, consistent with the Great Migration of the early 20th century. Western European descendants show Native American ancestry that tracks their geographic origins across the US, indicative of ongoing contact during westward expansion, and Native American ancestry can resolve Spanish descendant individuals into distinct local groups formed by more recent migration from Mexico and Puerto Rico. We found an anomalous pattern of Native American ancestry from the US southwest, which most likely corresponds to the Nuevomexicano descendants of early Spanish settlers to the region. We addressed a number of controversies surrounding this population, including the extent of Sephardic Jewish ancestry. Nuevomexicanos are less admixed than nearby Mexican-American individuals, with more European and less Native American and African ancestry, and while they do show demonstrable Sephardic Jewish ancestry, the fraction is no greater than seen for other New World Spanish descendant populations., Competing Interests: The authors have declared that no competing interests exist.

Inorganic arsenic (As) is a toxic xenobiotic and carcinogen associated with severe health conditions. The urban population from the Atacama Desert in northern Chile was exposed to extremely high As levels (up to 600 µg/l) in drinking water between 1958 and 1971, leading to increased incidence of urinary bladder cancer (BC), skin cancer, kidney cancer, and coronary thrombosis decades later. Besides, the Andean Native-American ancestors of the Atacama population were previously exposed for millennia to elevated As levels in water (∼120 µg/l) for at least 5,000 years, suggesting adaptation to this selective pressure. Here, we performed two genome-wide selection tests-PBSn1 and an ancestry-enrichment test-in an admixed population from Atacama, to identify adaptation signatures to As exposure acquired before and after admixture with Europeans, respectively. The top second variant selected by PBSn1 was associated with LCE4A-C1orf68, a gene that may be involved in the immune barrier of the epithelium during BC. We performed association tests between the top PBSn1 hits and BC occurrence in our population. The strongest association (P = 0.012) was achieved by the LCE4A-C1orf68 variant. The ancestry-enrichment test detected highly significant signals (P = 1.3 × 10-9) mapping MAK16, a gene with important roles in ribosome biogenesis during the G1 phase of the cell cycle. Our results contribute to a better understanding of the genetic factors involved in adaptation to the pathophysiological consequences of As exposure., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Purpose: Direct-to-consumer (DTC) genetic ancestry companies have rapidly increased in popularity, with top testing services maintaining genetic databases of several million consumers. While genetic ancestry tests are often characterized as recreational, companies invoke deeply personal concepts of individual identity, group membership, and kinship when marketing their services. In particular, many companies claim to be able to determine Native American heritage, claims that are not supported by the state of the science and may have significant cultural and political consequences for US tribal communities. This study aims to fill the gaps in empirical work on this issue and characterize how genetic ancestry companies articulate indigenous identity through their marketing strategies., Methods: We conducted a qualitative content analysis of the public facing websites for 25 DTC genetic ancestry companies that offer services measuring Native American ancestry., Results: Our findings describe how genetic ancestry companies promote a causal relationship between genetics and self-identity through marketing language such as "Discover Yourself" and "Are you Native American?" and how this may affect US tribal communities., Conclusion: Genetic ancestry company claims regarding genetic ancestry, personal identity, and cultural membership are problematic and challenge how US tribal nations currently identify and create potential obstacles for tribal sovereignty.

Today, practical, functional and symbolic choices inform the selection of raw materials for worked objects. In cases where we can discern the origin of worked bone, tooth, ivory and antler objects in the past, we assume that similar choices are being made. However, morphological species identification of worked objects is often impossible due to the loss of identifying characteristics during manufacture. Here, we describe a novel non-destructive ZooMS (Zooarchaeology by Mass Spectrometry) method which was applied to bone points from Pre-Contact St. Lawrence Iroquoian village sites in southern Quebec, Canada. The traditional ZooMS technique requires destructive analysis of a sample, which can be problematic when dealing with artefacts. Here we instead extracted proteins from the plastic bags in which the points had been stored. ZooMS analysis revealed hitherto unexpected species, notably black bear (Ursus americanus) and human (Homo sapiens sapiens), used in point manufacture. These surprising results (confirmed through genomic sequencing) highlight the importance of advancing biomolecular research in artefact studies. Furthermore, they unexpectedly and exceptionally allow us to identify and explore the tangible, material traces of the symbolic relationship between bears and humans, central to past and present Iroquoian cosmology and mythology.

North and South America were the last continents to be explored and settled by modern humans at the end of the Pleistocene. Genetic data, derived from contemporary populations and ancient individuals, show that the first Americans originated from Asia and after several population splits moved south of the continental ice sheets that covered Canada sometime between ~17.5 and ~14.6 thousand years (ka) ago. Archaeological evidence shows that geographically dispersed populations lived successfully, using biface, blade, and osseous technologies, in multiple places in North and South America between ~15.5 and ~14 ka ago. Regional archaeological complexes emerged by at least ~13 ka ago in North America and ~12.9 ka ago in South America. Current genetic and archaeological data do not support an earlier (pre-17.5 ka ago) occupation of the Americas., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Research misconduct and consequential harms have been inflicted upon American Indian/Alaska Native communities for decades. To protect their people and culture and to retain oversight over research, many Native communities have established tribal health research and institutional review boards. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study showcases a successful, trusting research collaboration with tribal nations and academic investigators in Oklahoma. In 2006, the TODAY Study investigators proposed a modification of the study protocol to collect biological specimens from participants for genomic analyses and indefinite storage. Partnering American Indian tribal nations elected not to participate in the genomics collection and repository proposal. Reasons included 1) protection of cultural values, 2) concerns regarding community anonymity, 3) a potential threat to tribal services eligibility, 4) broad informed consent language, and 5) vague definitions of data access and usage. The nations believed the proposed genomics analyses presented a risk of harm to their people and nations without clear benefit. Since the 2006 proposal and the advancement of genomics research, many tribal communities in Oklahoma, appreciating the potential benefits of genomic research, are developing policies regarding oversight of/access to data and biological specimens to mitigate risks and provide members and communities with opportunities to participate in safe and meaningful genomic research., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2019.)