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African antelope diversity is a globally unique vestige of a much richer world-wide Pleistocene megafauna. Despite this, the evolutionary processes leading to the prolific radiation of African antelopes are not well understood. Here, we sequenced 145 whole genomes from both subspecies of the waterbuck (Kobus ellipsiprymnus), an African antelope believed to be in the process of speciation. We investigated genetic structure and population divergence and found evidence of a mid-Pleistocene separation on either side of the eastern Great Rift Valley, consistent with vicariance caused by a rain shadow along the so-called 'Kingdon's Line'. However, we also found pervasive evidence of both recent and widespread historical gene flow across the Rift Valley barrier. By inferring the genome-wide landscape of variation among subspecies, we found 14 genomic regions of elevated differentiation, including a locus that may be related to each subspecies' distinctive coat pigmentation pattern. We investigated these regions as candidate speciation islands. However, we observed no significant reduction in gene flow in these regions, nor any indications of selection against hybrids. Altogether, these results suggest a pattern whereby climatically driven vicariance is the most important process driving the African antelope radiation, and suggest that reproductive isolation may not set in until very late in the divergence process. This has a significant impact on taxonomic inference, as many taxa will be in a gray area of ambiguous systematic status, possibly explaining why it has been hard to achieve consensus regarding the species status of many African antelopes. Our analyses demonstrate how population genetics based on low-depth whole genome sequencing can provide new insights that can help resolve how far lineages have gone along the path to speciation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Systematic Biologists.)

Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (β SD (SE) = -0.22 (0.03), p = 6.5 × 10 -12 ) and total cholesterol (-0.17 (0.03), p = 1.1 × 10 -8 ) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance., (© 2023. The Author(s).)

In Greenland, traditional marine foods are increasingly being replaced by sucrose- and starch-rich foods. A knock-out c.273_274delAG variant in the sucrase-isomaltase ( SI ) gene is relatively common in Greenland, with homozygous carriers being unable to digest sucrose and some starch. The variant is associated with a healthier metabolic phenotype in Greenlanders, which is confirmed by SI -knockout mice. We aim to assess if the healthy phenotype is explained by metabolic and microbial differences and if food and taste preferences differ between SI -genotypes. This paper describes the protocol for a randomised cross-over trial conducted in Greenland in 2022 with two dietary interventions of three days; a traditional meat- and fish-rich diet and a starch-rich Western diet with 11 energy% sucrose. The power calculation showed that 22 homozygous SI -carriers and 22 non-carriers were sufficient to detect a 0.5 mmol/L difference in glycaemic variability (80% power, α=0.05). We enrolled 18 carriers and 20 non-carriers. We examined food preferences at baseline and collected samples before and after each intervention for metabolic, metabolome, and microbiome profiling. Analyses of samples have not been completed yet. The Ethics Committee of Greenland approved the study. Results will be disseminated in international peer-reviewed journals and to the general Greenlandic population. NCT05375656.

Background: The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population., Methods: Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact., Findings: We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = -232 pmol/L, β SD  = -0.695, P = 4.43 × 10 -4 ) and higher 30-min glucose (β = 1.20 mmol/L, β SD  = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10 -6 ) and HbA1c (β = 0.113 HbA1c%, β SD  = 0.205, P = 7.84 × 10 -3 ). The variant explained 2.5% of diabetes variance in Greenland., Interpretation: The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1-3% in large populations., Funding: Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation., Competing Interests: AT has received funding from the 10.13039/501100009708Novo Nordisk Foundation NNF17OC0028328. AA and ZL have received funding from the 10.13039/501100009708Novo Nordisk Foundation (NNF20OC0061343). NG has received funding from the 10.13039/501100009708Novo Nordisk Foundation (NNF16OC0019986). IM has received funding from a Villum Young Investigator grant (19114). MEJ has received research grants from 10.13039/100004325AstraZeneca, 10.13039/100019944Sanofi Aventis, 10.13039/100002429AMGEN, 10.13039/100001003Boehringer Ingelheim and Novo Nordisk A/S. FFS has received funding from the 10.13039/501100001734University of Copenhagen. The population surveys of Greenland were funded by the Department of Health, Greenland, The 10.13039/501100009708Novo Nordisk Foundation (NNF17OC0028136 & NNF17SH0027192), The 10.13039/501100004836Independent Research Fund Denmark, and 10.13039/501100004046Karen Elise Jensen's Foundation. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the 10.13039/501100009708Novo Nordisk Foundation (NNF18CC0034900). None of the funding agencies had any role in study design or collection, analysis, or interpretation of data. The authors have no further conflicts of interest to declare., (© 2022 The Author(s).)

The common Arctic-specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this, we aimed to investigate the effect of p.G137S on metabolic health and cardiovascular disease risk among Greenlanders to quantify its impact on the population. In a population-based Greenlandic cohort (n = 5,063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. In addition, we explored the variant's impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n = 1,629); 29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of serum LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischemic heart disease (HR [95% CI], 1.51 [1.18-1.92], p = 0.00096), peripheral artery disease (1.69 [1.01-2.82], p = 0.046), and coronary operations (1.78 [1.21-2.62], p = 0.0035). Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations., Competing Interests: The authors declare no competing interests., (© 2022.)

Background & Aims: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency., Methods: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings., Results: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], -2.0 [0.5] kg/m 2 ; P = 3.1 × 10 -5 ), body weight (-4.8 [1.4] kg; P = 5.1 × 10 -4 ), fat percentage (-3.3% [1.0%]; P = 3.7 × 10 -4 ), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10 -6 ), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10 -5 ). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10 -26 ), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test., Conclusions: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Association studies using genetic data from SNP-chip-based imputation or low-depth sequencing data provide a cost-efficient design for large-scale association studies. We explore methods for performing association studies applicable to such genetic data and investigate how using different priors when estimating genotype probabilities affects the association results. Our proposed method, ANGSD-asso's latent model, models the unobserved genotype as a latent variable in a generalized linear model framework. The software is implemented in C/C++ and can be run multi-threaded. ANGSD-asso is based on genotype probabilities, which can be estimated using either the sample allele frequency or the individual allele frequencies as a prior. We explore through simulations how genotype probability-based methods compare with using genetic dosages. Our simulations show that in a structured population using the individual allele frequency prior has better power than the sample allele frequency. In scenarios with sequencing depth and phenotype correlation ANGSD-asso's latent model has higher statistical power and less bias than using dosages. Adding additional covariates to the linear model of ANGSD-asso's latent model has higher statistical power and less bias than other methods that accommodate genotype uncertainty, while also being much faster. This is shown with imputed data from UK Biobank and simulations., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Aims/hypothesis: The common muscle-specific TBC1D4 p.Arg684Ter loss-of-function variant defines a subtype of non-autoimmune diabetes in Arctic populations. Homozygous carriers are characterised by elevated postprandial glucose and insulin levels. Because 3.8% of the Greenlandic population are homozygous carriers, it is important to explore possibilities for precision medicine. We aimed to investigate whether physical activity attenuates the effect of this variant on 2 h plasma glucose levels after an oral glucose load., Methods: In a Greenlandic population cohort (n = 2655), 2 h plasma glucose levels were obtained after an OGTT, physical activity was estimated as physical activity energy expenditure and TBC1D4 genotype was determined. We performed TBC1D4-physical activity interaction analysis, applying a linear mixed model to correct for genetic admixture and relatedness., Results: Physical activity was inversely associated with 2 h plasma glucose levels (β[main effect of physical activity] -0.0033 [mmol/l] / [kJ kg -1  day -1 ], p = 6.5 × 10 -5 ), and significantly more so among homozygous carriers of the TBC1D4 risk variant compared with heterozygous carriers and non-carriers (β[interaction] -0.015 [mmol/l] / [kJ kg -1  day -1 ], p = 0.0085). The estimated effect size suggests that 1 h of vigorous physical activity per day (compared with resting) reduces 2 h plasma glucose levels by an additional ~0.7 mmol/l in homozygous carriers of the risk variant., Conclusions/interpretation: Physical activity improves glucose homeostasis particularly in homozygous TBC1D4 risk variant carriers via a skeletal muscle TBC1 domain family member 4-independent pathway. This provides a rationale to implement physical activity as lifestyle precision medicine in Arctic populations., Data Repository: The Greenlandic Cardio-Metabochip data for the Inuit Health in Transition study has been deposited at the European Genome-phenome Archive ( https://www.ebi.ac.uk/ega/dacs/EGAC00001000736 ) under accession EGAD00010001428.

The Inuit ancestors of the Greenlandic people arrived in Greenland close to 1,000 years ago. 1 Since then, Europeans from many different countries have been present in Greenland. Consequently, the present-day Greenlandic population has ∼25% of its genetic ancestry from Europe. 2 In this study, we investigated to what extent different European countries have contributed to this genetic ancestry. We combined dense SNP chip data from 3,972 Greenlanders and 8,275 Europeans from 14 countries and inferred the ancestry contribution from each of these 14 countries using haplotype-based methods. Due to the rapid increase in population size in Greenland over the past ∼100 years, we hypothesized that earlier European interactions, such as pre-colonial Dutch whalers and early German and Danish-Norwegian missionaries, as well as the later Danish colonists and post-colonial immigrants, all contributed European genetic ancestry. However, we found that the European ancestry is almost entirely Danish and that a substantial fraction is from admixture that took place within the last few generations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Several recent studies have found signs of recent selection on the carnitine palmitoyl-transferase 1A (CPT1A) gene in the ancestors of Arctic populations likely as a result of their traditional diet. CPT1A is involved in fatty acid transportation and is known to affect circulating fatty acid profiles in Inuit as does the unique traditional diet rich in marine animals. We aimed to assess which fatty acids may have driven the selection of rs80356779, a c.1436C>T (p.(Pro479Leu)) variant in CPT1A, by analyzing a potential interaction between the variant and traditional Inuit diet. We included 3005 genome-wide genotyped individuals living in Greenland, who had blood cell membrane fatty acid levels measured. Consumption of 25 traditional food items was expressed as percentage of total energy intake. We tested for CPT1A × traditional diet interaction while taking relatedness and admixture into account. Increasing intakes of traditional diet was estimated to attenuate the effect of 479L on 20:3 omega-6 levels (p = 0.000399), but increase the effect of the variant on 22:5 omega-3 levels (p = 0.000963). The 479L effect on 22:5 omega-3 more than doubled in individuals with a high intake of traditional diet (90% percentile) compared with individuals with a low intake (10% percentile). Similar results were found when assessing interactions with marine foods. Our results suggest that the association between traditional diet and blood cell fatty acid composition is affected by the CPT1A genotype, or other variants in linkage disequilibrium, and support the hypothesis that omega-3 fatty acids may have been important for adaptation to the Arctic diet.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history 1,2 . Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.

The genetic architecture of the small and isolated Greenlandic population is advantageous for identification of novel genetic variants associated with cardio-metabolic traits. We aimed to identify genetic loci associated with body mass index (BMI), to expand the knowledge of the genetic and biological mechanisms underlying obesity. Stage 1 BMI-association analyses were performed in 4,626 Greenlanders. Stage 2 replication and meta-analysis were performed in additional cohorts comprising 1,058 Yup'ik Alaska Native people, and 1,529 Greenlanders. Obesity-related traits were assessed in the stage 1 study population. We identified a common variant on chromosome 11, rs4936356, where the derived G-allele had a frequency of 24% in the stage 1 study population. The derived allele was genome-wide significantly associated with lower BMI (beta (SE), -0.14 SD (0.03), p = 3.2x10-8), corresponding to 0.64 kg/m2 lower BMI per G allele in the stage 1 study population. We observed a similar effect in the Yup'ik cohort (-0.09 SD, p = 0.038), and a non-significant effect in the same direction in the independent Greenlandic stage 2 cohort (-0.03 SD, p = 0.514). The association remained genome-wide significant in meta-analysis of the Arctic cohorts (-0.10 SD (0.02), p = 4.7x10-8). Moreover, the variant was associated with a leaner body type (weight, -1.68 (0.37) kg; waist circumference, -1.52 (0.33) cm; hip circumference, -0.85 (0.24) cm; lean mass, -0.84 (0.19) kg; fat mass and percent, -1.66 (0.33) kg and -1.39 (0.27) %; visceral adipose tissue, -0.30 (0.07) cm; subcutaneous adipose tissue, -0.16 (0.05) cm, all p<0.0002), lower insulin resistance (HOMA-IR, -0.12 (0.04), p = 0.00021), and favorable lipid levels (triglyceride, -0.05 (0.02) mmol/l, p = 0.025; HDL-cholesterol, 0.04 (0.01) mmol/l, p = 0.0015). In conclusion, we identified a novel variant, where the derived G-allele possibly associated with lower BMI in Arctic populations, and as a consequence also leaner body type, lower insulin resistance, and a favorable lipid profile., Competing Interests: The authors have declared that no competing interests exist.

During the last decade genome-wide association studies have proven to be a powerful approach to identifying disease-causing variants. However, for admixed populations, most current methods for association testing are based on the assumption that the effect of a genetic variant is the same regardless of its ancestry. This is a reasonable assumption for a causal variant but may not hold for the genetic variants that are tested in genome-wide association studies, which are usually not causal. The effects of noncausal genetic variants depend on how strongly their presence correlate with the presence of the causal variant, which may vary between ancestral populations because of different linkage disequilibrium patterns and allele frequencies. Motivated by this, we here introduce a new statistical method for association testing in recently admixed populations, where the effect size is allowed to depend on the ancestry of a given allele. Our method does not rely on accurate inference of local ancestry, yet using simulations we show that in some scenarios it gives a substantial increase in statistical power to detect associations. In addition, the method allows for testing for difference in effect size between ancestral populations, which can be used to help determine if a given genetic variant is causal. We demonstrate the usefulness of the method on data from the Greenlandic population., (© 2019 Wiley Periodicals, Inc.)

Background: Iberian primitive breeds exhibit a remarkable phenotypic diversity over a very limited geographical space. While genomic data are accumulating for most commercial cattle, it is still lacking for these primitive breeds. Whole genome data is key to understand the consequences of historic breed formation and the putative role of earlier admixture events in the observed diversity patterns., Results: We sequenced 48 genomes belonging to eight Iberian native breeds and found that the individual breeds are genetically very distinct with F ST values ranging from 4 to 16% and have levels of nucleotide diversity similar or larger than those of their European counterparts, namely Jersey and Holstein. All eight breeds display significant gene flow or admixture from African taurine cattle and include mtDNA and Y-chromosome haplotypes from multiple origins. Furthermore, we detected a very low differentiation of chromosome X relative to autosomes within all analyzed taurine breeds, potentially reflecting male-biased gene flow., Conclusions: Our results show that an overall complex history of admixture resulted in unexpectedly high levels of genomic diversity for breeds with seemingly limited geographic ranges that are distantly located from the main domestication center for taurine cattle in the Near East. This is likely to result from a combination of trading traditions and breeding practices in Mediterranean countries. We also found that the levels of differentiation of autosomes vs sex chromosomes across all studied taurine and indicine breeds are likely to have been affected by widespread breeding practices associated with male-biased gene flow.

Aims/hypothesis: In a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects., Methods: We investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model., Results: Using a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10 -8 ), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10 -7 ). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10 -8 ) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations., Conclusions/interpretation: We demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations., Data Availability: The Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/ ) under the accession EGAS00001002641.

We have identified a variant in ADCY3 (encoding adenylate cyclase 3) associated with markedly increased risk of obesity and type 2 diabetes in the Greenlandic population. The variant disrupts a splice acceptor site, and carriers have decreased ADCY3 RNA expression. Additionally, we observe an enrichment of rare ADCY3 loss-of-function variants among individuals with type 2 diabetes in trans-ancestry cohorts. These findings provide new information on disease etiology relevant for future treatment strategies.

Motivation: Estimation of admixture proportions and principal component analysis (PCA) are fundamental tools in populations genetics. However, applying these methods to low- or mid-depth sequencing data without taking genotype uncertainty into account can introduce biases., Results: Here we present fastNGSadmix, a tool to fast and reliably estimate admixture proportions and perform PCA from next generation sequencing data of a single individual. The analyses are based on genotype likelihoods of the input sample and a set of predefined reference populations. The method has high accuracy, even at low sequencing depth and corrects for the biases introduced by small reference populations., Availability and Implementation: The admixture estimation method is implemented in C ++ and the PCA method is implemented in R. The code is freely available at http://www.popgen.dk/software/index.php/FastNGSadmix., Contact: emil.jorsboe@bio.ku.dk., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Fatty acids (FAs) are involved in cellular processes important for normal body function, and perturbation of FA balance has been linked to metabolic disturbances, including type 2 diabetes. An individual's level of FAs is affected by diet, lifestyle, and genetic variation. We aimed to improve the understanding of the mechanisms and pathways involved in regulation of FA tissue levels, by identifying genetic loci associated with inter-individual differences in erythrocyte membrane FA levels. We assessed the levels of 22 FAs in the phospholipid fraction of erythrocyte membranes from 2,626 Greenlanders in relation to single nucleotide polymorphisms genotyped on the MetaboChip or imputed. We identified six independent association signals. Novel loci were identified on chromosomes 5 and 11 showing strongest association with oleic acid (rs76430747 in ACSL6, beta (SE): -0.386% (0.034), p = 1.8x10-28) and docosahexaenoic acid (rs6035106 in DTD1, 0.137% (0.025), p = 6.4x10-8), respectively. For a missense variant (rs80356779) in CPT1A, we identified a number of novel FA associations, the strongest with 11-eicosenoic acid (0.473% (0.035), p = 2.6x10-38), and for variants in FADS2 (rs174570), LPCAT3 (rs2110073), and CERS4 (rs11881630) we replicated known FA associations. Moreover, we observed metabolic implications of the ACSL6 (rs76430747) and CPT1A (rs80356779) variants, which both were associated with altered HbA1c (0.051% (0.013), p = 5.6x10-6 and -0.034% (0.016), p = 3.1x10-4, respectively). The latter variant was also associated with reduced insulin resistance (HOMA-IR, -0.193 (0.050), p = 3.8x10-6), as well as measures of smaller body size, including weight (-2.676 kg (0.523), p = 2.4x10-7), lean mass (-1.200 kg (0.271), p = 1.7x10-6), height (-0.966 cm (0.230), p = 2.0x10-5), and BMI (-0.638 kg/m2 (0.181), p = 2.8x10-4). In conclusion, we have identified novel genetic determinants of FA composition in phospholipids in erythrocyte membranes, and have shown examples of links between genetic variants associated with altered FA membrane levels and changes in metabolic traits.