• Le 03 juin 2019
    Institut de Recherche en Santé - 8 quai Moncousu - Nantes
    Amphithéâtre Denis Escande
  • 11h30

Genetic architecture of metabolic traits in Greenlandic Inuit

Genetic architecture of metabolic traits in Greenlandic Inuit

Anders ALBRECHTSEN, PhD, invited by Christian Dina (Eq I)

Associate professor
University of Copenhagen, Section for computational and RNA biology
Copenhagen, Denmark

ABSTRACT

Based on SNP chip data of 5000 Greenlandic Inuit and sequencing data for a subset we have shown 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 population interesting for investigating the effect of a bottleneck on patterns of deleterious variation and for inferring disease causing variants. When comparing genetic load of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. However, 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 leading to a large increase in recessive genetic load. Overall, our results show how recent demographic history has fundamentally changed the patterns of deleterious variants in this population. 

Using a mixture of Genome-wide association mapping and novel candidate loss-of-function variation found using sequencing we Identify a large amount of causal variation affecting many metabolic traits such as lipids, glucose levels, fatty acids, and obesity. Using DNA and RNA sequencing, metabolomics and small functional studies we infer some of the key biological mechanism of the causal SNPs and infer why they affect the metabolics traits.

These variations are all common variations with very large effect sizes. This is in sharp contrast to the variations found to affect complex diseases in large well studied populations such as Europeans or East Asian, where the effects sizes of common variations are low. This genetic architecture is fairly unique for human populations and may be the key to developing precision medicine and personalized treatment. Preliminary studies of several of the variants already show promise for personalized clinical intervention.

Selected references

  • Grarup et al., (2018). Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population. Diabetologia,
  • Grarup et al., (2018). Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nat. Genet.
  • Pedersen et al., (2017). The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit. Genetics
  • Andersen et al. (2016). Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders. PLoS Genet
  • Fumagalli et al., (2015). Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science,
  • Moltke et al. (2015). Uncovering the genetic history of the present-day Greenlandic population. Am. J. Hum. Genet
  • Moltke et al. (2014). A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature