The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance.

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10-3 and p = 3.1×10-24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10-5 in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals' adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.

ASSOCIATION BETWEEN APOE-ε4 CARRIER STATUS AND QUALITATIVE NEUROIMAGING CHARACTERISTICS IN OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT.

BACKGROUND: The pathogenesis of mild cognitive impairment (MCI) is multifactorial and includes the presence of genetic variants such as the ε4 allele of the apolipoprotein E gene (APOE-ε4). Association between the APOE-ε4 carrier status and deleterious structural and functional changes on magnetic resonance imaging (MRI) has been previously described in individuals with Alzheimer's disease. However, the central nervous system changes may possibly develop in earlier stages of cognitive impairment, as reflected in MCI. OBJECTIVE: The objective of the study was to determine the association between APOE-ε4 carrier status and qualitative changes on MRI (medial temporal and parietal atrophy), as well as the detection of white matter hyperintensities (WMH) in older adults with MCI, in the memory clinic of a tertiary care hospital in Mexico City. METHODS: A cross-sectional study of 72 adults aged 60 years or above who underwent an exhaustive clinical, neuroimaging, and neuropsychological evaluation. Multivariate logistic regression models were constructed to determine the association between APOE-ε4 carrier status and qualitative/quantitative changes on MRI. RESULTS: Mean age was 75.2 years (± 7.2) and 64% were female. Twenty-one participants were cognitively normal and 51 had MCI. Almost 56% were APOE-ε4 carriers and were associated with medial-temporal atrophy according to the Scheltens scale (odds ratio [OR]: 20.0, 95% confidence intervals [CI]: 3.03-131.7), parietal atrophy according to the Koedam's score (OR: 6.3; 95% CI 1.03-39.53), and WMH according to the Fazekas scale (OR: 11.7, 95% CI: 1.26-108.2), even after adjusting for age, educational level, and cardiovascular risk factors. CONCLUSION: The APOE-ε4 carrier status was associated with medial temporal and parietal atrophy, as well as WMH. Our findings support the hypothesis suggesting the contribution of this genotype to neurodegeneration and cerebral vascular pathology.

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

A panel of 32 AIMs suitable for population stratification correction and global ancestry estimation in Mexican mestizos.

BACKGROUND: Association studies are useful to unravel the genetic basis of common human diseases. However, the presence of undetected population structure can lead to both false positive results and failures to detect genuine associations. Even when most of the approaches to deal with population stratification require genome-wide data, the use of a well-selected panel of ancestry informative markers (AIMs) may appropriately correct for population stratification. Few panels of AIMs have been developed for Latino populations and most contain a high number of markers (> 100 AIMs). For some association studies such as candidate gene approaches, it may be unfeasible to genotype a numerous set of markers to avoid false positive results. In such cases, methods that use fewer AIMs may be appropriate. RESULTS: We validated an accurate and cost-effective panel of AIMs, for use in population stratification correction of association studies and global ancestry estimation in Mexicans, as well as in populations having large proportions of both European and Native American ancestries. Based on genome-wide data from 1953 Mexican individuals, we performed a PCA and SNP weights were calculated to select subsets of unlinked AIMs within percentiles 0.10 and 0.90, ensuring that all chromosomes were represented. Correlations between PC1 calculated using genome-wide data versus each subset of AIMs (16, 32, 48 and 64) were r2 = 0.923, 0.959, 0.972 and 0.978, respectively. When evaluating PCs performance as population stratification adjustment covariates, no correlation was found between P values obtained from uncorrected and genome-wide corrected association analyses (r2 = 0.141), highlighting that population stratification correction is compulsory for association analyses in admixed populations. In contrast, high correlations were found when adjusting for both PC1 and PC2 for either subset of AIMs (r2 > 0.900). After multiple validations, including an independent sample, we selected a minimal panel of 32 AIMs, which are highly informative of the major ancestral components of Mexican mestizos, namely European and Native American ancestries. Finally, the correlation between the global ancestry proportions calculated using genome-wide data and our panel of 32 AIMs was r2 = 0.972. CONCLUSIONS: Our panel of 32 AIMs accurately estimated global ancestry and corrected for population stratification in association studies in Mexican individuals.

Frequency of the T307A, N680S, and -29G>A single-nucleotide polymorphisms in the follicle-stimulating hormone receptor in Mexican subjects of Hispanic ancestry.

BACKGROUND: FSHR SNPs may influence the ovarian sensitivity to endogenous and exogenous FSH stimulation. Given the paucity of data on the FSHR c.919A > G, c.2039A > G and - 29G > A SNPs in Hispanic population, we here analyzed their frequency distribution in Mexican mestizo women. METHODS: Samples from 224 Mexican mestizo women enrolled in an IVF program as well as a genotype database from 8182 Mexican mestizo subjects, were analyzed for FSHR SNPs at positions c.919, c.2039 and - 29G > A. Association between the genetic variants and reproductive outcomes was assessed. RESULTS: The c.919 and c.2039 SNPs were in strong linkage disequilibrium and their corresponding genotype frequencies in the IVF group were: AA 46.8%, AG 44.2%, and GG 8.9%, and AA 41.9%, AG 48.2% and GG 9.8%, respectively. For the -29G > A SNP, genotype frequencies were 27% (GG), 50% (GA) and 23% (AA). In normal oocyte donors with the c.2039 GG genotype, the number of oocytes recovered after ovarian stimulation (COS) were significantly (p < 0.01) lower than in those bearing other genotypes in this or the -29G > A SNP. Analysis of the large scale database revealed that both allelic and genotype frequencies for the three SNPs were very similar to those detected in the IVF cohort (p ≥ 0.38) and that female carriers of the c.2039 G allele tended to present lower number of pregnancies than women bearing the AA genotype; this trend was stronger when women with more Native American ancestry was separately analyzed (OR = 2.0, C.I. 95% 1.03-3.90, p = 0.04). There were no differences or trends in the number of pregnancies among the different genotypes of the -29G > A SNP. CONCLUSIONS: The frequency of the GG/GG combination genotype for the c.919 and c.2039 SNPs in Mexican hispanics is among the lowest reported. The GG genotype is associated with decreased number of oocytes recovered in response to COS as well as to lower pregnancy rates in Hispanic women from the general population. The absence of any effect of the -29AA genotype on the response to COS, indicates that there is no need to perform this particular genotype testing in Hispanic women with the purpose of providing an individually-tailored COS protocol.

Reconstructing Native American population history.

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.

Molecular Characterization of the Lipid Genome-Wide Association Study Signal on Chromosome 18q11.2 Implicates HNF4A-Mediated Regulation of the TMEM241 Gene.

OBJECTIVE: We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region. APPROACH AND RESULTS: We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856). CONCLUSIONS: The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans.

Genome-wide association study of colorectal cancer in Hispanics.

Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10(-8) Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10(-6)) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47-2.36); P = 2.5×10(-7)], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21-1.55); P = 4.0×10(-7)), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36-2.01); P = 4.1×10(-7)) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37-2.08); P=7.8×10(-7)]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10(-5)) and 11q12.2 (P = 6.8×10(-5)), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations.

Rare intronic variants of TCF7L2 arising by selective sweeps in an indigenous population from Mexico.

BACKGROUND: Genetic variations of the TCF7L2 gene are associated with the development of Type 2 diabetes (T2D). The associated mutations have demonstrated an adaptive role in some human populations, but no studies have determined the impact of evolutionary forces on genetic diversity in indigenous populations from Mexico. Here, we sequenced and analyzed the variation of the TCF7L2 gene in three Amerindian populations and compared the results with whole-exon-sequencing of Mestizo populations from Sigma and the 1000 Genomes Project to assess the roles of selection and recombination in diversity. RESULTS: The diversity in the indigenous populations was biased to intronic regions. Most of the variation was low frequency. Only mutations rs77961654 and rs61724286 were located on exon 15. We did not observe variation in intronic region 4-6 in any of the three indigenous populations. In addition, we identified peaks of selective sweeps in the mestizo samples from the Sigma Project within this region. By replicating the analysis of association with T2D between case-controls from the Sigma Project, we determined that T2D was most highly associated with the rs7903146 risk allele and to a lesser extent with the other six variants. All associated markers were located in intronic region 4-6, and their r(2) values of linkage disequilibrium were significantly higher in the Mexican population than in Africans from the 1000 Genomes Project. We observed reticulations in both the haplotypes network analysis from seven marker associates and the neighborNet tree based on 6061 markers in the TCF7L2 gene identified from all samples of the 1000 Genomes Project. Finally, we identified two recombination hotspots in the upstream region and 3' end of the TCF7L2 gene. CONCLUSIONS: The lack of diversity in intronic region 4-6 in Indigenous populations could be an effect of selective sweeps generated by the selection of neighboring rare variants at T2D-associated mutations. The survivors' variants make the intronic region 4-6 the area of the greatest population differentiation within the TCF7L2 gene. The abundance of selective peak sweeps in the downstream region of the TCF7L2 gene suggests that the TCF7L2 gene is part of a region that is in constant recombination between populations.

Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci.

BACKGROUND: The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. METHODS AND FINDINGS: We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4361), and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann-Pick type C1 protein gene (p=2.43×10(-08)). Furthermore, three European loci for TGs (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We used cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalised to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. CONCLUSIONS: This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; used the interpopulation heterogeneity to significantly restrict three previously known European GWA signals, and surveyed whether the European lipid GWA SNPs extend to the Mexican population.