Publications by authors named "Ida Moltke"

53 Publications

Origin and expansion of the world's most widespread pinniped: range-wide population genomics of the harbour seal (Phoca vitulina).

Mol Ecol 2022 Jan 23. Epub 2022 Jan 23.

Section for Evolutionary Genomics, Globe Institute, University of Copenhagen, Denmark.

The harbour seal (Phoca vitulina) is the most widely distributed pinniped, occupying a wide variety of habitats and climatic zones across the Northern Hemisphere. Intriguingly, the harbour seal is also one of the most philopatric seals, raising questions as to how it colonised virtually the whole of the Northern Hemisphere. To shed light on the origin, remarkable range expansion, population structure and genetic diversity of this species, we used genotyping-by-sequencing to analyse ~13,500 biallelic SNPs from 286 individuals sampled from 22 localities across the species' range. Our results point to a Northeast Pacific origin, colonisation of the North Atlantic via the Canadian Arctic, and subsequent stepping-stone range expansions across the North Atlantic from North America to Europe, accompanied by a successive loss of genetic diversity. Our analyses further revealed a deep divergence between modern North Pacific and North Atlantic harbour seals, with finer-scale genetic structure at regional and local scales consistent with strong philopatry. The study provides new insights into the harbour seal's remarkable ability to colonise and adapt to a wide range of habitats. Furthermore, it has implications for current harbour seal subspecies delineations and highlights the need for international and national red lists and management plans to ensure the protection of genetically and demographically isolated populations.
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http://dx.doi.org/10.1111/mec.16365DOI Listing
January 2022

Loss of sucrase-isomaltase function increases acetate levels and improves metabolic health in Greenlandic cohorts.

Gastroenterology 2021 Dec 13. Epub 2021 Dec 13.

Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background & Aims: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, an inability to breakdown and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms, when dietary sucrose is introduced. Here we aimed to describe the health of adults with sucrase-isomaltase deficiency.

Methods: Association between c.273_274delAG and phenotypes related to metabolic health was assessed in two cohorts of Greenlandic adults (N=4,922 and N=1,629). A sucrase-isomaltase knock-out (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 BMI (β (SE), -2.0 kg/m (0.5), P=3.1x10), body weight (-4.8 kg (1.4), P=5.1x10), fat percentage (-3.3% (1.0), P=3.7x10), fasting triglyceride (-0.27 mmol/L (0.07), P=2.3x10), and remnant cholesterol (-0.11 mmol/L (0.03), P=4.2x10). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (0.056 mmol/L (0.002), P=2.1x10), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which compared to 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.
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http://dx.doi.org/10.1053/j.gastro.2021.12.236DOI Listing
December 2021

LocalNgsRelate: a software tool for inferring IBD sharing along the genome between pairs of individuals from low-depth NGS data.

Bioinformatics 2021 Oct 28. Epub 2021 Oct 28.

Department of Biology, University of Copenhagen, Copenhagen N, 2200, Denmark.

Motivation: Inference of Identity-by-descent (IBD) sharing along the genome between pairs of individuals has important uses. But all existing inference methods are based on genotypes, which is not ideal for low-depth Next Generation Sequencing (NGS) data from which genotypes can only be called with high uncertainty.

Results: We present a new probabilistic software tool, LocalNgsRelate, for inferring IBD sharing along the genome between pairs of individuals from low-depth NGS data. Its inference is based on genotype likelihoods instead of genotypes, and thereby it takes the uncertainty of the genotype calling into account. Using real data from the 1000 Genomes project, we show that LocalNgsRelate provides more accurate IBD inference for low-depth NGS data than two state-of-the-art genotype based methods, Albrechtsen et al. (2009) and hap-IBD. We also show that the method works well for NGS data down to a depth of 2X.

Availability: LocalNgsRelate is freely available at https://github.com/idamoltke/LocalNgsRelate.

Supplementary Data: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab732DOI Listing
October 2021

Identifying a living great-grandson of the Lakota Sioux leader Tatanka Iyotake (Sitting Bull).

Sci Adv 2021 Oct 27;7(44):eabh2013. Epub 2021 Oct 27.

Lundbeck Foundation GeoGenetics Centre, University of Copenhagen, Copenhagen, Denmark.

[Figure: see text].
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http://dx.doi.org/10.1126/sciadv.abh2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550246PMC
October 2021

NGSremix: a software tool for estimating pairwise relatedness between admixed individuals from next-generation sequencing data.

G3 (Bethesda) 2021 08;11(8)

Department of Biology, The Bioinformatics Centre, University of Copenhagen, 2200 Copenhagen N, Denmark.

Estimation of relatedness between pairs of individuals is important in many genetic research areas. When estimating relatedness, it is important to account for admixture if this is present. However, the methods that can account for admixture are all based on genotype data as input, which is a problem for low-depth next-generation sequencing (NGS) data from which genotypes are called with high uncertainty. Here, we present a software tool, NGSremix, for maximum likelihood estimation of relatedness between pairs of admixed individuals from low-depth NGS data, which takes the uncertainty of the genotypes into account via genotype likelihoods. Using both simulated and real NGS data for admixed individuals with an average depth of 4x or below we show that our method works well and clearly outperforms all the commonly used state-of-the-art relatedness estimation methods PLINK, KING, relateAdmix, and ngsRelate that all perform quite poorly. Hence, NGSremix is a useful new tool for estimating relatedness in admixed populations from low-depth NGS data. NGSremix is implemented in C/C++ in a multi-threaded software and is freely available on Github https://github.com/KHanghoj/NGSremix.
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http://dx.doi.org/10.1093/g3journal/jkab174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496226PMC
August 2021

Predictors and trajectories of treatment response to SSRIs in patients suffering from PTSD.

Psychiatry Res 2021 07 26;301:113964. Epub 2021 Apr 26.

H. Lundbeck A/S, Valby, Copenhagen, Denmark.

Paroxetine and sertraline are the only FDA approved drugs for treatment of posttraumatic stress disorder (PTSD). Although both drugs show better outcomes than placebo, not all patients benefit from treatment. We examined predictors and latent classes of SSRI treatment response in patients with PTSD. Symptom severity was measured over a 12-week period in 390 patients suffering from PTSD treated with open-label sertraline or paroxetine and a double-blinded placebo. First, growth curve modeling (GCM) was used to examine population-level predictors of treatment response. Second, growth mixture modeling (GMM) was used to group patients into latent classes based on their treatment response trajectories over time and to investigate predictors of latent class membership. Gender, childhood sexual trauma, and sexual assault as index trauma moderated the population-level treatment response using GCM. GMM identified three classes: fast responders, responders with low pretreatment symptom severity and responders with high pretreatment symptom severity. Class membership was predicted based on time since index trauma, severity of depression, and severity of anxiety. The study shows that higher severity of comorbid disorders does not result in an inferior response to treatment and suggests that patients with longer time since index trauma might particularly benefit from treatment with sertraline or paroxetine.
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http://dx.doi.org/10.1016/j.psychres.2021.113964DOI Listing
July 2021

Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers.

Diabetologia 2021 Aug 29;64(8):1795-1804. Epub 2021 Apr 29.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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 day], p = 6.5 × 10), 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 day], 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.
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http://dx.doi.org/10.1007/s00125-021-05461-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245392PMC
August 2021

A large-scale genome-wide gene expression analysis in peripheral blood identifies very few differentially expressed genes related to antidepressant treatment and response in patients with major depressive disorder.

Neuropsychopharmacology 2021 06 8;46(7):1324-1332. Epub 2021 Apr 8.

The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.

A better understanding of the biological factors underlying antidepressant treatment in patients with major depressive disorder (MDD) is needed. We perform gene expression analyses and explore sources of variability in peripheral blood related to antidepressant treatment and treatment response in patients suffering from recurrent MDD at baseline and after 8 weeks of treatment. The study includes 281 patients, which were randomized to 8 weeks of treatment with vortioxetine (N = 184) or placebo (N = 97). To our knowledge, this is the largest dataset including both gene expression in blood and placebo-controlled treatment response measured by a clinical scale in a randomized clinical trial. We identified three novel genes whose RNA expression levels at baseline and week 8 are significantly (FDR < 0.05) associated with treatment response after 8 weeks of treatment. Among these genes were SOCS3 (FDR = 0.0039) and PROK2 (FDR = 0.0028), which have previously both been linked to depression. Downregulation of these genes was associated with poorer treatment response. We did not identify any genes that were differentially expressed between placebo and vortioxetine groups at week 8 or between baseline and week 8 of treatment. Nor did we replicate any genes identified in previous peripheral blood gene expression studies examining treatment response. Analysis of genome-wide expression variability showed that type of treatment and treatment response explains very little of the variance, a median of <0.0001% and 0.05% in gene expression across all genes, respectively. Given the relatively large size of the study, the limited findings suggest that peripheral blood gene expression might not be the best approach to explore the biological factors underlying antidepressant treatment.
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http://dx.doi.org/10.1038/s41386-021-01002-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134553PMC
June 2021

The genetic history of Greenlandic-European contact.

Curr Biol 2021 05 11;31(10):2214-2219.e4. Epub 2021 Mar 11.

Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark. Electronic address:

The Inuit ancestors of the Greenlandic people arrived in Greenland close to 1,000 years ago. 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. 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.
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http://dx.doi.org/10.1016/j.cub.2021.02.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284823PMC
May 2021

High genetic diversity and low differentiation reflect the ecological versatility of the African leopard.

Curr Biol 2021 05 25;31(9):1862-1871.e5. Epub 2021 Feb 25.

Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark. Electronic address:

Large carnivores are generally sensitive to ecosystem changes because their specialized diet and position at the top of the trophic pyramid is associated with small population sizes. Accordingly, low genetic diversity at the whole-genome level has been reported for all big cat species, including the widely distributed leopard. However, all previous whole-genome analyses of leopards are based on the Far Eastern Amur leopards that live at the extremity of the species' distribution and therefore are not necessarily representative of the whole species. We sequenced 53 whole genomes of African leopards. Strikingly, we found that the genomic diversity in the African leopard is 2- to 5-fold higher than in other big cats, including the Amur leopard, likely because of an exceptionally high effective population size maintained by the African leopard throughout the Pleistocene. Furthermore, we detected ongoing gene flow and very low population differentiation within African leopards compared with those of other big cats. We corroborated this by showing a complete absence of an otherwise ubiquitous equatorial forest barrier to gene flow. This sets the leopard apart from most other widely distributed large African mammals, including lions. These results revise our understanding of trophic sensitivity and highlight the remarkable resilience of the African leopard, likely because of its extraordinary habitat versatility and broad dietary niche.
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http://dx.doi.org/10.1016/j.cub.2021.01.064DOI Listing
May 2021

Population genomics of the Viking world.

Nature 2020 09 16;585(7825):390-396. Epub 2020 Sep 16.

NTNU University Museum, Department of Archaeology and Cultural History, Trondheim, Norway.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history. 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.
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http://dx.doi.org/10.1038/s41586-020-2688-8DOI Listing
September 2020

The derived allele of a novel intergenic variant at chromosome 11 associates with lower body mass index and a favorable metabolic phenotype in Greenlanders.

PLoS Genet 2020 01 24;16(1):e1008544. Epub 2020 Jan 24.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1371/journal.pgen.1008544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001991PMC
January 2020

Fast and accurate relatedness estimation from high-throughput sequencing data in the presence of inbreeding.

Gigascience 2019 05;8(5)

Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen K, Denmark.

Background: The estimation of relatedness between pairs of possibly inbred individuals from high-throughput sequencing (HTS) data has previously not been possible for samples where we cannot obtain reliable genotype calls, as in the case of low-coverage data.

Results: We introduce ngsRelateV2, a major revision of ngsRelateV1, a program that originally allowed for estimation of relatedness from HTS data among non-inbred individuals only. The new revised version takes into account the possibility of individuals being inbred by estimating the 9 condensed Jacquard coefficients along with various other relatedness statistics. The program is threaded and scales linearly with the number of cores allocated to the process.

Conclusion: The program is available as an open source C/C++ program under the GPL license and hosted at https://github.com/ANGSD/ngsRelate. To facilitate easy analysis, the program is able to work directly on the most commonly used container formats for raw sequence (BAM/CRAM) and summary data (VCF/BCF).
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http://dx.doi.org/10.1093/gigascience/giz034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488770PMC
May 2019

Ancestry-specific association mapping in admixed populations.

Genet Epidemiol 2019 07 18;43(5):506-521. Epub 2019 Mar 18.

Department of Biology, The Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1002/gepi.22200DOI Listing
July 2019

Author Correction: Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits.

Nat Commun 2018 12 19;9(1):5460. Epub 2018 Dec 19.

Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, United Kingdom.

The original version of this Article contained an error in Fig. 2. In panel a, the two legend items "rare" and "common" were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07730-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300593PMC
December 2018

Allele frequency-free inference of close familial relationships from genotypes or low-depth sequencing data.

Mol Ecol 2019 01;28(1):35-48

Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen N, Denmark.

Knowledge of how individuals are related is important in many areas of research, and numerous methods for inferring pairwise relatedness from genetic data have been developed. However, the majority of these methods were not developed for situations where data are limited. Specifically, most methods rely on the availability of population allele frequencies, the relative genomic position of variants and accurate genotype data. But in studies of non-model organisms or ancient samples, such data are not always available. Motivated by this, we present a new method for pairwise relatedness inference, which requires neither allele frequency information nor information on genomic position. Furthermore, it can be applied not only to accurate genotype data but also to low-depth sequencing data from which genotypes cannot be accurately called. We evaluate it using data from a range of human populations and show that it can be used to infer close familial relationships with a similar accuracy as a widely used method that relies on population allele frequencies. Additionally, we show that our method is robust to SNP ascertainment and applicable to low-depth sequencing data generated using different strategies, including resequencing and RADseq, which is important for application to a diverse range of populations and species.
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http://dx.doi.org/10.1111/mec.14954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850436PMC
January 2019

Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits.

Nat Commun 2018 11 7;9(1):4674. Epub 2018 Nov 7.

Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, United Kingdom.

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10; APOC3 and triglyceride levels, P = 1.5 × 10), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10), indicating a role for this gene in lipid metabolism.
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http://dx.doi.org/10.1038/s41467-018-07070-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220258PMC
November 2018

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

Diabetologia 2018 09 20;61(9):2005-2015. Epub 2018 Jun 20.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.

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), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10) 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.
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http://dx.doi.org/10.1007/s00125-018-4659-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096637PMC
September 2018

Physiological and Genetic Adaptations to Diving in Sea Nomads.

Cell 2018 04;173(3):569-580.e15

Centre for GeoGenetics, University of Copenhagen, Copenhagen 1350, Denmark; Department of Zoology, University of Cambridge, Cambridge, CB2 3EJ, UK; Wellcome Trust, Sanger Institute, Hinxton CB10 1SA, UK. Electronic address:

Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people ("Sea Nomads") of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath-holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2018.03.054DOI Listing
April 2018

Genetic architecture of obesity and related metabolic traits-recent insights from isolated populations.

Curr Opin Genet Dev 2018 06 3;50:74-78. Epub 2018 Mar 3.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address:

In this mini-review, we give an overview of what is known about the genetic architecture of obesity and related metabolic traits with a primary focus on recent insights from studies of historically small and isolated populations. We start by briefly explaining what genetic architecture is and why studies of isolated populations in general are valuable if we want a complete picture of the genetic architecture of diseases and other traits among humans. Then we contrast what is known about the genetic architecture of obesity and related metabolic traits among large outbred populations, like Europeans, with results from recent studies of isolated populations. Finally, we briefly discuss the perspectives of studying isolated populations to gain insight into genetic architecture in humans.
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http://dx.doi.org/10.1016/j.gde.2018.02.010DOI Listing
June 2018

Genetic determinants of glycated hemoglobin levels in the Greenlandic Inuit population.

Eur J Hum Genet 2018 06 26;26(6):868-875. Epub 2018 Feb 26.

The Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

We previously showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at discovering novel genetic determinants for glycated hemoglobin (HbA) and at estimating the effect of known HbA-associated loci in the Greenlandic population. We analyzed genotype data from 4049 Greenlanders generated using the Illumina Cardio-Metabochip. We performed the discovery association analysis by an additive linear mixed model. To estimate the effect of known HbA-associated loci, we modeled the effect in the European and Inuit ancestry proportions of the Greenlandic genome (EAPGG and IAPGG, respectively). After correcting for multiple testing, we found no novel significant associations. When we investigated loci known to associate with HbA levels, we found that the lead variant in the GCK locus associated significantly with HbA levels in the IAPGG ([Formula: see text]). Furthermore, for 10 of 15 known HbA loci, the effects in IAPGG were similar to the previously reported effects. Interestingly, the ANK1 locus showed a statistically significant ancestral population differential effect, with opposing directions of effect in the two ancestral populations. In conclusion, we found only 1 of the 15 known HbA loci to be significantly associated with HbA levels in the IAPGG and that two-thirds of the loci showed similar effects in Inuit as previously found in European and East Asian populations. Our results shed light on the genetic effects across ethnicities.
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http://dx.doi.org/10.1038/s41431-018-0109-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974304PMC
June 2018

Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes.

Nat Genet 2018 02 8;50(2):172-174. Epub 2018 Jan 8.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1038/s41588-017-0022-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828106PMC
February 2018

Archaic Adaptive Introgression in TBX15/WARS2.

Mol Biol Evol 2017 03;34(3):509-524

Department of Integrative Biology, University of California Berkeley, Berkeley, CA.

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.
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http://dx.doi.org/10.1093/molbev/msw283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430617PMC
March 2017

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit.

Genetics 2017 02 30;205(2):787-801. Epub 2016 Nov 30.

Department of Biology, Section for Computational and RNA Biology, University of Copenhagen, 2200 Copenhagen N, Denmark

The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit we show that the Inuit have undergone a severe ∼20,000-year-long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population tested to date, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation. When comparing proxies for genetic load that assume an additive effect of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. Specifically, we observe <4% increase in the number of derived deleterious alleles in the Inuit. In contrast, proxies for genetic load under a recessive model suggest that the Inuit have a significantly higher load (20% increase or more) compared to other less bottlenecked human populations. Forward simulations under realistic models of demography support our empirical findings, showing up to a 6% increase in the genetic load for the Inuit population across all models of dominance. Further, the Inuit population carries fewer deleterious variants than other human populations, but those that are present tend to be at higher frequency than in other populations. Overall, our results show how recent demographic history has affected patterns of deleterious variants in human populations.
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http://dx.doi.org/10.1534/genetics.116.193821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289852PMC
February 2017

A genomic history of Aboriginal Australia.

Nature 2016 Oct 21;538(7624):207-214. Epub 2016 Sep 21.

Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, 1350 Copenhagen, Denmark.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.
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http://dx.doi.org/10.1038/nature18299DOI Listing
October 2016

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

PLoS Genet 2016 06 24;12(6):e1006119. Epub 2016 Jun 24.

The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1371/journal.pgen.1006119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920407PMC
June 2016

Genetics of Type 2 Diabetes: the Power of Isolated Populations.

Curr Diab Rep 2016 07;16(7):65

The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1, 2100, Copenhagen, Denmark.

Type 2 diabetes (T2D) affects millions of people worldwide. Improving the understanding of the underlying mechanisms and ultimately improving the treatment strategies are, thus, of great interest. To achieve this, identification of genetic variation predisposing to T2D is important. A large number of variants have been identified in large outbred populations, mainly from Europe and Asia. However, to elucidate additional variation, isolated populations have a number of advantageous properties, including increased amounts of linkage disequilibrium, and increased probability for presence of high frequency disease-associated variants due to genetic drift. Collectively, this increases the statistical power to detect association signals in isolated populations compared to large outbred populations. In this review, we elaborate on why isolated populations are a powerful resource for the identification of complex disease variants and describe their contributions to the understanding of the genetics of T2D.
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http://dx.doi.org/10.1007/s11892-016-0757-zDOI Listing
July 2016

Diabetes in Population Isolates: Lessons from Greenland.

Rev Diabet Stud 2015 Fall-Winter;12(3-4):320-9. Epub 2016 Feb 10.

Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Type 2 diabetes (T2D) is an increasing health problem worldwide with particularly high occurrence in specific subpopulations and ancestry groups. The high prevalence of T2D is caused both by changes in lifestyle and genetic predisposition. A large number of studies have sought to identify the genetic determinants of T2D in large, open populations such as Europeans and Asians. However, studies of T2D in population isolates are gaining attention as they provide several advantages over open populations in genetic disease studies, including increased linkage disequilibrium, homogeneous environmental exposure, and increased allele frequency. We recently performed a study in the small, historically isolated Greenlandic population, in which the prevalence of T2D has increased to more than 10%. In this study, we identified a common nonsense variant in TBC1D4, which has a population-wide impact on glucose-stimulated plasma glucose, serum insulin levels, and T2D. The variant defines a specific subtype of non-autoimmune diabetes characterized by decreased post-prandial glucose uptake and muscular insulin resistance. These and other recent findings in population isolates illustrate the value of performing medical genetic studies in genetically isolated populations. In this review, we describe some of the advantages of performing genetic studies of T2D and related cardio-metabolic traits in a population isolate like the Greenlandic, and we discuss potentials and perspectives for future research into T2D in this population.
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http://dx.doi.org/10.1900/RDS.2015.12.320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5275757PMC
July 2018

New evidence for hybrid zones of forest and savanna elephants in Central and West Africa.

Mol Ecol 2015 12 12;24(24):6134-47. Epub 2015 Dec 12.

Center for Conservation Biology, Department of Biology, University of Washington, Box 351800, Seattle, WA, 98195-1800, USA.

The African elephant consists of forest and savanna subspecies. Both subspecies are highly endangered due to severe poaching and habitat loss, and knowledge of their population structure is vital to their conservation. Previous studies have demonstrated marked genetic and morphological differences between forest and savanna elephants, and despite extensive sampling, genetic evidence of hybridization between them has been restricted largely to a few hybrids in the Garamba region of northeastern Democratic Republic of Congo (DRC). Here, we present new genetic data on hybridization from previously unsampled areas of Africa. Novel statistical methods applied to these data identify 46 hybrid samples--many more than have been previously identified--only two of which are from the Garamba region. The remaining 44 are from three other geographically distinct locations: a major hybrid zone along the border of the DRC and Uganda, a second potential hybrid zone in Central African Republic and a smaller fraction of hybrids in the Pendjari-Arli complex of West Africa. Most of the hybrids show evidence of interbreeding over more than one generation, demonstrating that hybrids are fertile. Mitochondrial and Y chromosome data demonstrate that the hybridization is bidirectional, involving males and females from both subspecies. We hypothesize that the hybrid zones may have been facilitated by poaching and habitat modification. The localized geography and rarity of hybrid zones, their possible facilitation from human pressures, and the high divergence and genetic distinctness of forest and savanna elephants throughout their ranges, are consistent with calls for separate species classification.
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http://dx.doi.org/10.1111/mec.13472DOI Listing
December 2015
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