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Actionable Genotypes and Their Association with Life Span in Iceland.

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  • 1From deCODE Genetics-Amgen (B.O.J., G.A.A., H.K., R.F., H. Helgason, A.O., G.S., H.P.E., G.H.H., B.A.A., H.J., G.R.O., A. Sturluson, S.A.G., G.A.T., F.Z., K.H.S.M., G.P., A. Sigurdsson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, M.K.M., A. Helgadottir, V.S., J.G., S.N.S., D.O.A., J.S., O.T.M., G.M., B.V.H., A. Helgason, H.S., I.J., H. Holm, T.R., U.T., D.F.G., K.S., P.S.), the Faculty of Medicine, School of Health Sciences (G.A.A., M.K.M., R.H., D.O.A., I.J., U.T., K.S.), the Department of Anthropology (K.H.S.M., A. Helgason), and the School of Engineering and Natural Sciences (H. Helgason, G.H.H., D.F.G.), University of Iceland, the Departments of Urology (R.H.), Clinical Biochemistry (I.O.), Oncology (O.T.J.), Medicine (D.O.A.), and Immunology (I.J.), Landspitali-the National University Hospital of Iceland, and the School of Science and Engineering, Reykjavik University (B.V.H.) - all in Reykjavik, Iceland.

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Summary

Approximately 1 in 25 Icelanders carry actionable genotypes, which are genetic variants linked to diseases. Carrying these actionable genotypes is associated with a reduced lifespan, particularly for cancer-related genes.

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Area of Science:

  • Genomics
  • Medical Genetics
  • Population Health

Background:

  • The American College of Medical Genetics and Genomics (ACMG) recommends reporting actionable genotypes in 73 genes.
  • Preventive or therapeutic measures are available for diseases associated with these actionable genotypes.
  • Research evaluating the link between actionable genotypes and lifespan is limited.

Purpose of the Study:

  • To assess the prevalence of actionable genotypes in the Icelandic population.
  • To investigate the association between actionable genotypes and lifespan.
  • To examine causes of death among carriers of actionable genotypes.

Main Methods:

  • Analyzed genomes of 57,933 Icelanders for variants in ACMG Secondary Findings (SF) v3.0 genes.
  • Manually curated variants, assigning pathogenicity using ClinVar, variant frequency, and disease association.
  • Assessed the relationship between actionable genotypes and lifespan, and analyzed causes of death.

Main Results:

  • Identified 235 actionable genotypes in 53 genes.
  • 4.0% of participants (2306 individuals) carried at least one actionable genotype.
  • Carrying actionable genotypes was linked to a shorter median survival, with cancer gene variants reducing lifespan by 3 years.

Conclusions:

  • About 1 in 25 Icelanders carry actionable genotypes according to ACMG SF v3.0 guidelines.
  • Carrying actionable genotypes is associated with a reduced lifespan.
  • Findings highlight the clinical significance of actionable genotypes in a population context.