Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
Abstract Life expectancy has steadily increased in the last two centuries, while healthspan has been lagging behind. Survival into extreme ages strongly clusters within families which often exhibit a delayed onset of (multi)morbidity, yet the underlying protective genetic mechanisms are still largely undefined. We performed affected sib-pair linkage analysis in 212 sibships enriched for ancestral longevity and identified four genomic regions (LOD max ≥3.0) at 1q21 . 1 , 6p24.3, 6q14.3, and 19p13.3 . Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes ( NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2, and SH2D3A ) located in longevity-associated loci. Notably, a missense variant in CGAS (rs200818241), was present in two sibships. Using human- and mouse-based cell models, we showed that rs200818241 reduced protein stability and attenuated activation of the canonical cGAS-STING pathway in a cell-type specific manner. This dampened signalling mitigated inflammation and delayed cellular senescence, mechanisms that may contribute to the survival advantage of CGAS variant carriers. Our findings indicate novel rare variants and candidate genes linked to familial longevity and highlight the cGAS-STING pathway as a potential contributor to the protective mechanisms underlying human longevity.
Authors 19
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Leiden University · Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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Columbia University Irving Medical Center · Columbia University
Affiliation as printed
Department of Obstetrics and Gynaecology, Columbia University Irving Medical Centre, New York, USA
Dept. of Obstetrics and Gynaecology, Columbia University Irving Medical Centre
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Leiden University · University of Antwerp · Leiden University Medical Center
Affiliation as printed
Laboratory of Applied Microbiology and Biotechnology, Department of Bioscience Engineering, University of Antwerp, Antwerp, Belgium
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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Christian-Albrechts-Universität zu Kiel
Affiliation as printed
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Institute of Clinical Molecular Biology, Kiel University
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Columbia University Irving Medical Center · Columbia University
Affiliation as printed
Department of Obstetrics and Gynaecology, Columbia University Irving Medical Centre, New York, USA
Dept. of Obstetrics and Gynaecology, Columbia University Irving Medical Centre
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Columbia University Irving Medical Center · Columbia University
Affiliation as printed
Department of Obstetrics and Gynaecology, Columbia University Irving Medical Centre, New York, USA
Dept. of Obstetrics and Gynaecology, Columbia University Irving Medical Centre
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Columbia University Irving Medical Center · Columbia University
Affiliation as printed
Department of Obstetrics and Gynaecology, Columbia University Irving Medical Centre, New York, USA
Dept. of Obstetrics and Gynaecology, Columbia University Irving Medical Centre
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Leiden University · Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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Leiden University · Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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Leiden University · Leiden University Medical Center
Affiliation as printed
Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
Gerontology and Geriatrics, Dept. of Internal Medicine, Leiden University Medical Centre
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Max Planck Institute for Biology of Ageing
Affiliation as printed
Max Planck Institute for Biology of Ageing, Cologne, Germany
Max Planck Institute for Biology of Ageing
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Max Planck Institute for Biology of Ageing
Affiliation as printed
Max Planck Institute for Biology of Ageing, Cologne, Germany
Max Planck Institute for Biology of Ageing
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University of Cologne · Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases · Max Planck Institute for Biology of Ageing
Affiliation as printed
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Max Planck Institute for Biology of Ageing, Cologne, Germany
Max Planck Institute for Biology of Ageing
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Leiden University · Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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Christian-Albrechts-Universität zu Kiel
Affiliation as printed
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
Institute of Clinical Molecular Biology, Kiel University
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Leiden University · Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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Columbia University Irving Medical Center · Columbia University
Affiliation as printed
Department of Genetics and Development, Columbia University Irving Medical Centre, New York, USA
Department of Obstetrics and Gynaecology, Columbia University Irving Medical Centre, New York, USA
Dept. of Obstetrics and Gynaecology, Columbia University Irving Medical Centre
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Leiden University · Leiden University Medical Center · Max Planck Institute for Biology of Ageing
Affiliation as printed
Max Planck Institute for Biology of Ageing, Cologne, Germany
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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Leiden University · University of Cologne · Leiden University Medical Center · Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases · Max Planck Institute for Biology of Ageing
Affiliation as printed
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Max Planck Institute for Biology of Ageing, Cologne, Germany
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, The Netherlands
Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre
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