Actionable Genotypes and Their Association with Life Span in Iceland

Brynjar O Jensson; Gudny A Arnadottir; Hildigunnur Katrinardottir; Run Fridriksdottir; Hannes Helgason; Asmundur Oddsson; Gardar Sveinbjornsson; Hannes P Eggertsson; Gísli Hreinn Halldórsson; Bjarni A Atlason; Hakon Jonsson; Gudjon R Oskarsson; Arni Sturluson; Sigurjon A Gudjonsson; Gudmundur A Thorisson; Florian Zink; Kristjan H S Moore; Gunnar Palsson; Asgeir Sigurdsson; Adalbjorg Jonasdottir; Aslaug Jonasdottir; Magnús Karl Magnússon; Anna Helgadottir; Valgerdur Steinthorsdottir; Julius Gudmundsson; Simon N Stacey; Rafn Hilmarsson; Ísleifur Ólafsson; Óskar Þór Jóhannsson; Davíð Ottó Arnar; Jona Saemundsdottir; Olafur T Magnusson; Gisli Masson; Bjarni Vilhjálmur Halldórsson; Agnar Freyr Helgason; Hreinn Stefansson; Ingileif Jónsdóttir; Hilma Holm; Thorunn Rafnar; Unnur Þorsteinsdóttir; Daniel F Gudbjartsson; Kári Stefánsson; Patrick Sulem

doi:10.1056/nejmoa2300792

Actionable Genotypes and Their Association with Life Span in Iceland

Brynjar O Jensson, Gudny A Arnadottir, Hildigunnur Katrinardottir, Run Fridriksdottir, Hannes Helgason, Asmundur Oddsson, Gardar Sveinbjornsson, Hannes P Eggertsson, Gísli Hreinn Halldórsson, Bjarni A Atlason, Hakon Jonsson, Gudjon R Oskarsson, Arni Sturluson, Sigurjon A Gudjonsson, Gudmundur A Thorisson, Florian Zink, Kristjan H S Moore, Gunnar Palsson, Asgeir Sigurdsson, Adalbjorg JonasdottirAslaug Jonasdottir, Magnús Karl Magnússon, Anna Helgadottir, Valgerdur Steinthorsdottir, Julius Gudmundsson, Simon N Stacey, Rafn Hilmarsson, Ísleifur Ólafsson, Óskar Þór Jóhannsson, Davíð Ottó Arnar, Jona Saemundsdottir, Olafur T Magnusson, Gisli Masson, Bjarni Vilhjálmur Halldórsson, Agnar Freyr Helgason, Hreinn Stefansson, Ingileif Jónsdóttir, Hilma Holm, Thorunn Rafnar, Unnur Þorsteinsdóttir, Daniel F Gudbjartsson, Kári Stefánsson, Patrick Sulem

Landspitali, Reykjavik University, University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking.

METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers.

RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span.

CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

Original language	English
Pages (from-to)	1741-1752
Number of pages	12
Journal	The New England journal of medicine
Volume	389
Issue number	19
DOIs	https://doi.org/10.1056/nejmoa2300792
Publication status	Published - 9 Nov 2023

Bibliographical note

Other keywords

Alleles
Breast Cancer
Cancer
Cardiology
Cardiology General
Cardiovascular Diseases/genetics
Disease/genetics
Gastrointestinal Tract Cancer
Genetic Testing
Genetic Variation
Genetics
Genetics General
Genomics
Genotype
Geriatrics/Aging
Geriatrics/Aging General
Gynecologic Oncology
Hematology/Oncology
Hematology/Oncology General
Humans
Iceland/epidemiology
Longevity/genetics
Neoplasms/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1056/nejmoa2300792

Cite this

Jensson, B. O., Arnadottir, G. A., Katrinardottir, H., Fridriksdottir, R., Helgason, H., Oddsson, A., Sveinbjornsson, G., Eggertsson, H. P., Halldórsson, G. H., Atlason, B. A., Jonsson, H., Oskarsson, G. R., Sturluson, A., Gudjonsson, S. A., Thorisson, G. A., Zink, F., Moore, K. H. S., Palsson, G., Sigurdsson, A., ... Sulem, P. (2023). Actionable Genotypes and Their Association with Life Span in Iceland. The New England journal of medicine, 389(19), 1741-1752. https://doi.org/10.1056/nejmoa2300792

@article{7fb7cc4b3d534fdfb452556e559318d5,

title = "Actionable Genotypes and Their Association with Life Span in Iceland",

abstract = "BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking.METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers.RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0\%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span.CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).",

keywords = "Alleles, Breast Cancer, Cancer, Cardiology, Cardiology General, Cardiovascular Diseases/genetics, Disease/genetics, Gastrointestinal Tract Cancer, Genetic Testing, Genetic Variation, Genetics, Genetics General, Genomics, Genotype, Geriatrics/Aging, Geriatrics/Aging General, Gynecologic Oncology, Hematology/Oncology, Hematology/Oncology General, Humans, Iceland/epidemiology, Longevity/genetics, Neoplasms/genetics",

author = "Jensson, \{Brynjar O\} and Arnadottir, \{Gudny A\} and Hildigunnur Katrinardottir and Run Fridriksdottir and Hannes Helgason and Asmundur Oddsson and Gardar Sveinbjornsson and Eggertsson, \{Hannes P\} and Halld{\'o}rsson, \{G{\'i}sli Hreinn\} and Atlason, \{Bjarni A\} and Hakon Jonsson and Oskarsson, \{Gudjon R\} and Arni Sturluson and Gudjonsson, \{Sigurjon A\} and Thorisson, \{Gudmundur A\} and Florian Zink and Moore, \{Kristjan H S\} and Gunnar Palsson and Asgeir Sigurdsson and Adalbjorg Jonasdottir and Aslaug Jonasdottir and Magn{\'u}sson, \{Magn{\'u}s Karl\} and Anna Helgadottir and Valgerdur Steinthorsdottir and Julius Gudmundsson and Stacey, \{Simon N\} and Rafn Hilmarsson and {\'I}sleifur {\'O}lafsson and J{\'o}hannsson, \{{\'O}skar {\TH}{\'o}r\} and Arnar, \{Dav{\'i}{\dh} Ott{\'o}\} and Jona Saemundsdottir and Magnusson, \{Olafur T\} and Gisli Masson and Halld{\'o}rsson, \{Bjarni Vilhj{\'a}lmur\} and Helgason, \{Agnar Freyr\} and Hreinn Stefansson and Ingileif J{\'o}nsd{\'o}ttir and Hilma Holm and Thorunn Rafnar and Unnur {\TH}orsteinsd{\'o}ttir and Gudbjartsson, \{Daniel F\} and K{\'a}ri Stef{\'a}nsson and Patrick Sulem",

note = "Publisher Copyright: {\textcopyright} 2023 Massachusetts Medical Society.",

year = "2023",

month = nov,

day = "9",

doi = "10.1056/nejmoa2300792",

language = "English",

volume = "389",

pages = "1741--1752",

journal = "The New England journal of medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "19",

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Jensson, BO, Arnadottir, GA, Katrinardottir, H, Fridriksdottir, R, Helgason, H, Oddsson, A, Sveinbjornsson, G, Eggertsson, HP, Halldórsson, GH, Atlason, BA, Jonsson, H, Oskarsson, GR, Sturluson, A, Gudjonsson, SA, Thorisson, GA, Zink, F, Moore, KHS, Palsson, G, Sigurdsson, A, Jonasdottir, A, Jonasdottir, A, Magnússon, MK, Helgadottir, A, Steinthorsdottir, V, Gudmundsson, J, Stacey, SN, Hilmarsson, R , Ólafsson, Í , Jóhannsson, ÓÞ , Arnar, DO, Saemundsdottir, J, Magnusson, OT, Masson, G, Halldórsson, BV, Helgason, AF, Stefansson, H, Jónsdóttir, I, Holm, H, Rafnar, T, Þorsteinsdóttir, U, Gudbjartsson, DF, Stefánsson, K & Sulem, P 2023, 'Actionable Genotypes and Their Association with Life Span in Iceland', The New England journal of medicine, vol. 389, no. 19, pp. 1741-1752. https://doi.org/10.1056/nejmoa2300792

TY - JOUR

T1 - Actionable Genotypes and Their Association with Life Span in Iceland

AU - Jensson, Brynjar O

AU - Arnadottir, Gudny A

AU - Katrinardottir, Hildigunnur

AU - Fridriksdottir, Run

AU - Helgason, Hannes

AU - Oddsson, Asmundur

AU - Sveinbjornsson, Gardar

AU - Eggertsson, Hannes P

AU - Halldórsson, Gísli Hreinn

AU - Atlason, Bjarni A

AU - Jonsson, Hakon

AU - Oskarsson, Gudjon R

AU - Sturluson, Arni

AU - Gudjonsson, Sigurjon A

AU - Thorisson, Gudmundur A

AU - Zink, Florian

AU - Moore, Kristjan H S

AU - Palsson, Gunnar

AU - Sigurdsson, Asgeir

AU - Jonasdottir, Adalbjorg

AU - Jonasdottir, Aslaug

AU - Magnússon, Magnús Karl

AU - Helgadottir, Anna

AU - Steinthorsdottir, Valgerdur

AU - Gudmundsson, Julius

AU - Stacey, Simon N

AU - Hilmarsson, Rafn

AU - Ólafsson, Ísleifur

AU - Jóhannsson, Óskar Þór

AU - Arnar, Davíð Ottó

AU - Saemundsdottir, Jona

AU - Magnusson, Olafur T

AU - Masson, Gisli

AU - Halldórsson, Bjarni Vilhjálmur

AU - Helgason, Agnar Freyr

AU - Stefansson, Hreinn

AU - Jónsdóttir, Ingileif

AU - Holm, Hilma

AU - Rafnar, Thorunn

AU - Þorsteinsdóttir, Unnur

AU - Gudbjartsson, Daniel F

AU - Stefánsson, Kári

AU - Sulem, Patrick

PY - 2023/11/9

Y1 - 2023/11/9

N2 - BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking.METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers.RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span.CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

AB - BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking.METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers.RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span.CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

KW - Alleles

KW - Breast Cancer

KW - Cancer

KW - Cardiology

KW - Cardiology General

KW - Cardiovascular Diseases/genetics

KW - Disease/genetics

KW - Gastrointestinal Tract Cancer

KW - Genetic Testing

KW - Genetic Variation

KW - Genetics

KW - Genetics General

KW - Genomics

KW - Genotype

KW - Geriatrics/Aging

KW - Geriatrics/Aging General

KW - Gynecologic Oncology

KW - Hematology/Oncology

KW - Hematology/Oncology General

KW - Humans

KW - Iceland/epidemiology

KW - Longevity/genetics

KW - Neoplasms/genetics

UR - https://www.scopus.com/pages/publications/85176723707

U2 - 10.1056/nejmoa2300792

DO - 10.1056/nejmoa2300792

M3 - Article

C2 - 37937776

SN - 0028-4793

VL - 389

SP - 1741

EP - 1752

JO - The New England journal of medicine

JF - The New England journal of medicine

IS - 19

ER -

Actionable Genotypes and Their Association with Life Span in Iceland

Abstract

Bibliographical note

Other keywords

UN SDGs

Access to Document

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Cite this