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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.)