Ancient genomes reveal insights into ritual life at Chichén Itzá.

The ancient city of Chichén Itzá in Yucatán, Mexico, was one of the largest and most influential Maya settlements during the Late and Terminal Classic periods (AD 600-1000) and it remains one of the most intensively studied archaeological sites in Mesoamerica1-4. However, many questions about the social and cultural use of its ceremonial spaces, as well as its population's genetic ties to other Mesoamerican groups, remain unanswered2. Here we present genome-wide data obtained from 64 subadult individuals dating to around AD 500-900 that were found in a subterranean mass burial near the Sacred Cenote (sinkhole) in the ceremonial centre of Chichén Itzá. Genetic analyses showed that all analysed individuals were male and several individuals were closely related, including two pairs of monozygotic twins. Twins feature prominently in Mayan and broader Mesoamerican mythology, where they embody qualities of duality among deities and heroes5, but until now they had not been identified in ancient Mayan mortuary contexts. Genetic comparison to present-day people in the region shows genetic continuity with the ancient inhabitants of Chichén Itzá, except at certain genetic loci related to human immunity, including the human leukocyte antigen complex, suggesting signals of adaptation due to infectious diseases introduced to the region during the colonial period.

Mexican Biobank advances population and medical genomics of diverse ancestries.

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.

Combined genome-wide association study of 136 quantitative ear morphology traits in multiple populations reveal 8 novel loci.

Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we quantitatively assessed 136 ear morphology traits using deep learning analysis of digital face images in 14,921 individuals from five different cohorts in Europe, Asia, and Latin America. Through GWAS meta-analysis and C-GWASs, a recently introduced method to effectively combine GWASs of many traits, we identified 16 genetic loci involved in various ear phenotypes, eight of which have not been previously associated with human ear features. Our findings suggest that ear morphology shares genetic determinants with other surface ectoderm-derived traits such as facial variation, mono eyebrow, and male pattern baldness. Our results enhance the genetic understanding of human ear morphology and shed light on the shared genetic contributors of different surface ectoderm-derived phenotypes. Additionally, gene editing experiments in mice have demonstrated that knocking out the newly ear-associated gene (Intu) and a previously ear-associated gene (Tbx15) causes deviating mouse ear morphology.

Inbreeding, Native American ancestry and child mortality: linking human selection and paediatric medicine.

The children of related parents show increased risk of early mortality. The Native American genome typically exhibits long stretches of homozygosity, and Latin Americans are highly heterogeneous regarding the individual burden of homozygosity, the proportion and the type of Native American ancestry. We analysed nationwide mortality and genome-wide genotype data from admixed Chileans to investigate the relationship between common causes of child mortality, homozygosity and Native American ancestry. Results from two-stage linear-Poisson regression revealed a strong association between the sum length of runs of homozygosity (SROH) above 1.5 Megabases (Mb) in each genome and mortality due to intracranial non-traumatic haemorrhage of foetus and newborn (5% increased risk of death per Mb in SROH, P = 1 × 10-3) and disorders related to short gestation and low birth weight (P = 3 × 10-4). The major indigenous populations in Chile are Aymara-Quechua in the north of the country and the Mapuche-Huilliche in the south. The individual proportion of Aymara-Quechua ancestry was associated with an increased risk of death due to anencephaly and similar malformations (P = 4 × 10-5), and the risk of death due to Edwards and Patau trisomy syndromes decreased 4% per 1% Aymara-Quechua ancestry proportion (P = 4 × 10-4) and 5% per 1% Mapuche-Huilliche ancestry proportion (P = 2 × 10-3). The present results suggest that short gestation, low birth weight and intracranial non-traumatic haemorrhage mediate the negative effect of inbreeding on human selection. Independent validation of the identified associations between common causes of child death, homozygosity and fine-scale ancestry proportions may inform paediatric medicine.

Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high-incidence country.

Since 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans.

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

Genome-Wide Association Study Identifies a Functional SIDT2 Variant Associated With HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease.

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.

Meta-analysis of genome-wide association studies identifies 8 novel loci involved in shape variation of human head hair.

Shape variation of human head hair shows striking variation within and between human populations, while its genetic basis is far from being understood. We performed a series of genome-wide association studies (GWASs) and replication studies in a total of 28 964 subjects from 9 cohorts from multiple geographic origins. A meta-analysis of three European GWASs identified 8 novel loci (1p36.23 ERRFI1/SLC45A1, 1p36.22 PEX14, 1p36.13 PADI3, 2p13.3 TGFA, 11p14.1 LGR4, 12q13.13 HOXC13, 17q21.2 KRTAP, and 20q13.33 PTK6), and confirmed 4 previously known ones (1q21.3 TCHH/TCHHL1/LCE3E, 2q35 WNT10A, 4q21.21 FRAS1, and 10p14 LINC00708/GATA3), all showing genome-wide significant association with hair shape (P < 5e-8). All except one (1p36.22 PEX14) were replicated with nominal significance in at least one of the 6 additional cohorts of European, Native American and East Asian origins. Three additional previously known genes (EDAR, OFCC1, and PRSS53) were confirmed at the nominal significance level. A multivariable regression model revealed that 14 SNPs from different genes significantly and independently contribute to hair shape variation, reaching a cross-validated AUC value of 0.66 (95% CI: 0.62-0.70) and an AUC value of 0.64 in an independent validation cohort, providing an improved accuracy compared with a previous model. Prediction outcomes of 2504 individuals from a multiethnic sample were largely consistent with general knowledge on the global distribution of hair shape variation. Our study thus delivers target genes and DNA variants for future functional studies to further evaluate the molecular basis of hair shape in humans.

Obesity, genomic ancestry, and socioeconomic variables in Latin American mestizos.

OBJECTIVES: This article aims to assess the contribution of genomic ancestry and socioeconomic status to obesity in a sample of admixed Latin Americans. METHODS: The study comprised 6776 adult volunteers from Brazil, Chile, Colombia, Mexico, and Peru. Each volunteer completed a questionnaire about socioeconomic variables. Anthropometric variables such as weight, height, waist, and hip circumference were measured to calculate body indices: body mass index, waist-to-hip ratio and waist-to-height ratio (WHtR). Genetic data were extracted from blood samples, and ancestry was estimated using chip genotypes. Multiple linear regression was used to evaluate the relationship between the indices and ancestry, educational level, and economic well-being. The body indices were dichotomized to obesity indices by using appropriate thresholds. Odds ratios were calculated for each obesity index. RESULTS: The sample showed high percentages of obesity by all measurements. However, indices did not overlap consistently when classifying obesity. WHtR resulted in the highest prevalence of obesity. Overall, women with low education level and men with high economic wellness were more likely to be obese. American ancestry was statistically associated with obesity indices, although to a lesser extent than socioeconomic variables. CONCLUSIONS: The proportion of obesity was heavily dependent on the index and the population. Genomic ancestry has a significant influence on the anthropometric measurements, especially on central adiposity. As a whole, we detected a large interpopulation variation that suggests that better approaches to overweight and obesity phenotypes are needed in order to obtain more precise reference values.

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.

Admixture in Latin America: geographic structure, phenotypic diversity and self-perception of ancestry based on 7,342 individuals.

The current genetic makeup of Latin America has been shaped by a history of extensive admixture between Africans, Europeans and Native Americans, a process taking place within the context of extensive geographic and social stratification. We estimated individual ancestry proportions in a sample of 7,342 subjects ascertained in five countries (Brazil, Chile, Colombia, México and Perú). These individuals were also characterized for a range of physical appearance traits and for self-perception of ancestry. The geographic distribution of admixture proportions in this sample reveals extensive population structure, illustrating the continuing impact of demographic history on the genetic diversity of Latin America. Significant ancestry effects were detected for most phenotypes studied. However, ancestry generally explains only a modest proportion of total phenotypic variation. Genetically estimated and self-perceived ancestry correlate significantly, but certain physical attributes have a strong impact on self-perception and bias self-perception of ancestry relative to genetically estimated ancestry.

Characterization of complete mitochondrial genomes of indigenous Mayans in Mexico.

BACKGROUND: The authors have previously published the complete mitochondrial genome (mitogenome) sequences of two indigenous Mesoamerican populations, Mazahua (n = 25) and Zapotec (n = 88). METHODS: This study determined the complete mitogenome sequences of nine unrelated individuals from the indigenous Maya population living in Mexico. RESULTS: Their mitogenome sequences could be classified into either of the haplogroups A2 and C1. Surprisingly, there were no mitogenome sequences (haplotypes) that the Maya, Mazahua, and Zapotec people share in common. CONCLUSIONS: This indicates that no genetic exchange, at least matrilineally, has occurred among them.

[HLA class II in Mexican patients with pemphigus vulgaris: shared epitope for autoimmunity]. / HLA clase II en pacientes mexicanos con pénfigo vulgar: epítopo compartido para autoinmunidad.

INTRODUCTION: Pemphigus is an autoimmune blistering disease of skin and mucous membranes characterized by presence of IgG antibodies against desmoglein 3, and 1. Desmoglein 3 and 1 are presented in pemphigus vulgaris and pemphigus foliaceous, respectively. Desmoglein are transmembrane proteins that form part of cellular junctions called desmosomes. Major histocompatibility complex class II molecules have been related to autoimmune disease; in pemphigus vulgaris, different human lymphocyte antigens (HLA) were associated among different ethnic groups, such as HLA-DR4, HLA-DR14, and HLA-DR1. OBJECTIVE: to determine the allele HLA-DR genetic frequencies in Mexican patients with pemphigus. METHOD: Patients with clinical, histological, and immunofluorescence diagnosis monitored at the Dermatology Department of the Mexican General Hospital were included. DNA was extracted from blood samples and genetic recognition of HLA-DRß1 was performed by polymerase chain reaction and hybridization. Forty-three patients with pemphigus were included: 35 (81.4%) women and eight men (18.6%) between 16 and 85 years old. RESULTS: The HLA-DR14 and HLA-DR1 genetic frequencies were elevated among pemphigus patients and these alleles confer risk to pemphigus 2.2 and 3.3, respectively. CONCLUSION: These findings suggest that pemphigus vulgaris susceptibility is part of a general predisposition to present autoimmune diseases.

Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation.

Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago.

mtDNA diversity of the Zapotec in Mexico suggests a population decline long before the first contact with Europeans.

The New World is the last continent colonized by anatomically modern humans, Homo sapiens. The first migrants entered the New World from Asia through Beringia. It is suggested that there were three streams of Asian gene flow, one major and two additional minor gene flows. The first major migrants took a Pacific coastal route and began spreading to the American continent before the opening of the ice-free corridor. We investigated the diversity of full-length mitochondrial DNA genomes of the Zapotec population, residing in the Mesoamerican region, and reconstructed their demographic history using Bayesian Skyline Plots. We estimated the initial date of gene flow into the New World by Zapotec ancestors at around 17 000­19 000 years ago,which is highly concordant with previous studies. We also show a population decline after the initial expansion. This decline started 4000 years ago, long before European contact with Native Americans. This indicates that other factors including climatec hange should be considered to explain the observed demographic pattern.

Facial asymmetry and genetic ancestry in Latin American admixed populations.

Fluctuating and directional asymmetry are aspects of morphological variation widely used to infer environmental and genetic factors affecting facial phenotypes. However, the genetic basis and environmental determinants of both asymmetry types is far from being completely known. The analysis of facial asymmetries in admixed individuals can be of help to characterize the impact of a genome's heterozygosity on the developmental basis of both fluctuating and directional asymmetries. Here we characterize the association between genetic ancestry and individual asymmetry on a sample of Latin-American admixed populations. To do so, three-dimensional (3D) facial shape attributes were explored on a sample of 4,104 volunteers aged between 18 and 85 years. Individual ancestry and heterozygosity was estimated using more than 730,000 genome-wide markers. Multivariate techniques applied to geometric morphometric data were used to evaluate the magnitude and significance of directional and fluctuating asymmetry (FA), as well as correlations and multiple regressions aimed to estimate the relationship between facial FA scores and heterozygosity and a set of covariates. Results indicate that directional and FA are both significant, the former being the strongest expression of asymmetry in this sample. In addition, our analyses suggest that there are some specific patterns of facial asymmetries characterizing the different ancestry groups. Finally, we find that more heterozygous individuals exhibit lower levels of asymmetry. Our results highlight the importance of including ancestry-admixture estimators, especially when the analyses are aimed to compare levels of asymmetries on groups differing on socioeconomic levels, as a proxy to estimate developmental noise.

Founder effect and ancestral origin of the spinocerebellar ataxia type 7 (SCA7) mutation in Mexican families.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disease characterized by progressive cerebellar ataxia and macular degeneration causing progressive blindness. It accounts for 1 to 11.6 % of spinocerebellar ataxias (SCAs) cases worldwide and for 7.4 % of SCA7 cases in Mexico. We identified a cluster of SCA7 families who resided in a circumscribed area of Veracruz and investigated whether the high incidence of the disease in this region was due to a founder effect. A total of 181 individuals from 20 families were studied. Four microsatellite markers and one SNP flanking the ATNX7 gene were genotyped and the ancestral origin and local ancestry analysis of the SCA7 mutation were evaluated. Ninety individuals from 19 families had the SCA7 mutation; all were found to share a common haplotype, suggesting that the mutation in these families originated from a common ancestor. Ancestral origin and local ancestry analysis of SCA7 showed that the chromosomal segment containing the mutation was of European origin. We here present evidence strongly suggesting that the high frequency of SCA7 in Veracruz is due to a founder effect and that the mutation is most likely of European origin with greatest resemblance to the Finnish population.

Complete mitogenome analysis of indigenous populations in Mexico: its relevance for the origin of Mesoamericans.

Mesoamerica has an important role in the expansion of Paleoamericans as the route to South America. In this study, we determined complete mitogenome sequences of 113 unrelated individuals from two indigenous populations of Mesoamerica, Mazahua and Zapotec. All newly sequenced mitogenomes could be classified into haplogroups A2, B2, C1 and D1, but one sequence in Mazahua was D4h3a, a subclade of haplogroup D4. This haplogroup has been mostly found in South America along the Pacific coast. Haplogroup X2a was not found in either population. Genetic similarity obtained using phylogenetic tree construction and principal component analysis showed that these two populations are distantly related to each other. Actually, the Mazahua and the Zapotec shared no sequences (haplotypes) in common, while each also showed a number of unique subclades. Surprisingly, Zapotec formed a cluster with indigenous populations living in an area from central Mesoamerica to Central America. By contrast, the Mazahua formed a group with indigenous populations living in external areas, including southwestern North America and South America. This intriguing genetic relationship suggests the presence of two paleo-Mesoamerican groups, invoking a scenario in which one group had expanded into South America and the other resided in Mesoamerica.

PNPLA3 I148M polymorphism is associated with elevated alanine transaminase levels in Mexican Indigenous and Mestizo populations.

The patatin like phospholipase domain-containing (PNPLA3) I148M variant is the strongest genetic factor associated with elevated alanine transaminase (ALT) levels in different populations, particularly in Hispanics who have the highest 148M risk allele frequency reported to date. It has been suggested that Indigenous ancestry is associated with higher ALT levels in Mexicans. The aim of the present study was to assess the frequency of the PNPLA3 148M risk allele in Mexican indigenous and Mestizo individuals, and to examine its association with serum ALT levels. The study included a total of 1624 Mexican individuals: 919 Indigenous subjects from five different native groups and 705 Mexican Mestizo individuals (141 cases with ALT levels ≥ 40 U/L and 564 controls with ALT <40 U/L). The I148M polymorphism was genotyped by TaqMan assays. The frequency of elevated ALT levels in Indigenous populations was 18.7%, and varied according to obesity status: 14.4% in normal weight, 19.9% in overweight and 24.5% in obese individuals. The Mexican indigenous populations showed the highest reported frequency of the PNPLA3 148M risk allele (mean 0.73). The M148M genotype was significantly associated with elevated ALT levels in indigenous individuals (OR = 3.15, 95 % CI 1.91-5.20; P = 7.1 × 10(-6)) and this association was confirmed in Mexican Mestizos (OR = 2.24, 95% CI 1.50-3.33; P = 8.1 × 10(-5)). This is the first study reporting the association between M148M genotype and elevated ALT levels in Indigenous Mexican populations. The 148M allele risk may be considered an important risk factor for liver damage in Mexican indigenous and Mestizo populations.

Selection scan in Native Americans of Mexico identifies FADS2 rs174616: Evidence of gene-diet interactions affecting lipid levels and Delta-6-desaturase activity.

Searching for positive selection signals across genomes has identified functional genetic variants responding to environmental change. In Native Americans of Mexico, we used the fixation index (Fst) and population branch statistic (PBS) to identify SNPs suggesting positive selection. The 103 most differentiated SNPs were tested for associations with metabolic traits, the most significant association was FADS2/rs174616 with body mass index (BMI). This variant lies within a linkage disequilibrium (LD) block independent of previously reported FADS selection signals and has not been clearly associated with metabolic phenotypes. We tested this variant in two independent cohorts with cardiometabolic data. In the Genetics of Atherosclerotic Disease (GEA) cohort, the derived allele (T) was associated with increased BMI, lower LDL-C levels and a decreased risk of subclinical atherosclerosis in women. Significant gene-diet interactions affected lipid, apolipoprotein and adiponectin levels with differences according to sex, involving mainly total and complex dietary carbohydrate%. In the Genotype-related Effects of PUFA trial, the derived allele was associated with lower Δ-6 desaturase activity and erythrocyte membrane dihomo-gamma-linolenic acid (DGLA) levels, and with increased Δ-5 desaturase activity and eicosapentaenoic acid levels. This variant interacted with dietary carbohydrate% affecting Δ-6 desaturase activity. Notably, the relationship of DGLA and other erythrocyte membrane LC-PUFA indices with HOMA-IR differed according to rs174616 genotype, which has implications regarding how these indices should be interpreted. In conclusion, this observational study identified rs174616 as a signal suggesting selection in an independent linkage disequilibrium block, was associated with cardiometabolic and erythrocyte measurements of LC-PUFA in two independent Mexican cohorts and showed significant gene-diet interactions.