Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders

Andersen, Mette K.; Jørsboe, Emil; Sandholt, Camilla H.; Grarup, Niels; Jørgensen, Marit Eika; Færgeman, Nils J.; Bjerregaard, Peter; Pedersen, Oluf; Moltke, Ida; Hansen, Torben; Albrechtsen, Anders

doi:10.1371/journal.pgen.1006119

Cited by 25 publications

(36 citation statements)

References 67 publications

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“…Thus, uncorrected analyses of our data showed that L479 corresponded to higher levels of high-density lipoprotein and ApoA1 and lower levels of BMI (Table XI in Interestingly, in the final stages of the preparation of this article, a GWAS on erythrocyte membrane fatty acid composition among Greenlanders was published. 27 The study found that the CPT1A variant rs80356779 was associated with the levels of a range of fatty acids in the phospholipid fraction of erythrocyte membranes. These findings complement our serum metabolomics results in understanding the role of the p.Pro479Leu variant in CPT1A in regulating fatty acid levels in different blood components.…”

Section: Discussionmentioning

confidence: 98%

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

Skotte

Koch

Yakimov

et al. 2017

Circ Cardiovasc Genet

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−27). The derived allele (L479) occurred at a frequency of 76.2% in our sample while being absent in most other populations, and we found strong signatures of positive selection at the locus. Furthermore, we found that each copy of L479 reduced height by an average of 2.1 cm (P=1.04×10 −9 ). In exome sequencing data from a sister population, the Nunavik Inuit, we found no other likely causal candidate variant than rs80356779. Conclusion-Our study shows that a common CPT1A missense mutation is strongly associated with a range of metabolic phenotypes and reduced height in Greenlanders. These findings are important from a public health perspective and highlight the usefulness of complex trait genetic studies in isolated populations. (Circ Cardiovasc Genet. 2017;10:e001618.

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Section: Discussionmentioning

confidence: 98%

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

Skotte

Koch

Yakimov

et al. 2017

Circ Cardiovasc Genet

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“…Details about the genotyping procedure and quality control have previously been described [25]. In total, 4674 individuals (IHIT, 2791; B99, 1336; BBH, 547) and 115,182 SNPs passed the quality control.…”

Section: Methodsmentioning

confidence: 99%

Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population

et al. 2018

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Aims/hypothesisIn 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.MethodsWe 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.ResultsUsing 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/interpretationWe 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 availabilityThe Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/) under the accession EGAS00001002641.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4659-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…These discoveries include type 2 diabetes susceptibility variants in ABCC8 identified in Pima Indians , and in TBC1D4 identified in Greenlanders , as well as in SLC16A11 and HNF1A identified in the admixed Mexican population , where also a protective type 2 diabetes variant has been identified in IGF2 . Moreover, variants associated with lower lipid levels in APOC3 and DSCAML1 have been identified in an isolated Greek population , variants associated with levels of fatty acids in ACSL6 and CPT1A have been identified in Greenlanders , as well as variants associated with obesity in CREBRF and ADCY3 in Samoans and Greenlanders, respectively , and increased fasting insulin in AKT2 identified in Finns .…”

Section: Genetic Association Studies Of Metabolic Traits In Isolated mentioning

confidence: 97%

“…e The type 2 diabetes‐associated haplotype comprises rs13342232, rs13342692, rs117767867, rs75418188 and rs75493593 . f Strongest associated fatty acid for each variant .…”

Section: Genetic Association Studies Of Metabolic Traits In Isolated mentioning

confidence: 99%

“…In CPT1A, the positive selection signal seems to be driven by the Pro479Leu missense variant (rs80356779, c.1436C>T) . The T‐allele (479Leu) of this variant is fixed in the ancestral Inuit population, along with the rs174570 variant mapping to FADS2, even though there is around 7 Mb between these two variants . This unusual long‐range LD phenomenon makes it difficult to determine whether the FADS and CPT1A selection signatures represent the same signal or two independent signals.…”

Section: Genetic Association Studies Of Metabolic Traits In Isolated mentioning

confidence: 99%

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Genetics of metabolic traits in Greenlanders: lessons from an isolated population

Andersen

Hansen

2018

J Intern Med

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In this review, we describe the extraordinary population of Greenland, which differs from large outbred populations of Europe and Asia, both in terms of population history and living conditions. Many years in isolation, small population size and an extreme environment have shaped the genetic composition of the Greenlandic population. The unique genetic background combined with the transition from a traditional Inuit lifestyle and diet, to a more Westernized lifestyle, has led to an increase in the prevalence of metabolic conditions like obesity, where the prevalence from 1993 to 2010 has increased from 16.4% to 19.4% among men, and from 13.0% to 25.4% among women, type 2 diabetes and cardiovascular diseases. The genetic susceptibility to metabolic conditions has been explored in Greenlanders, as well as other isolated populations, taking advantage of population-genetic properties of these populations. During the last 10 years, these studies have provided examples of loci showing evidence of positive selection, due to adaption to Arctic climate and Inuit diet, including TBC1D4 and FADS/CPT1A, and have facilitated the discovery of several loci associated with metabolic phenotypes. Most recently, the c.2433-1G>A loss-of-function variant in ADCY3 associated with obesity and type 2 diabetes was described. This locus has provided novel biological insights, as it has been shown that reduced ADCY3 function causes obesity through disrupted function in primary cilia. Future studies of isolated populations will likely provide further genetic as well as biological insights.

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Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders

Cited by 25 publications

References 67 publications

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population

Genetics of metabolic traits in Greenlanders: lessons from an isolated population

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