Rare genetic coding variants associated with human longevity and protection against age-related diseases

Regeneron Genetics Center

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms.

Original languageEnglish (US)
Pages (from-to)783-794
Number of pages12
JournalNature Aging
Volume1
Issue number9
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
This work was supported by NIH grant nos. R01 HG008153 (Z.D.Z.), R01 AG061155 (S.M.), R01 AG060747 (M.D.G.), R01 AG057909 (N.B. and Z.D.Z.), P01 AG017242 (J.V.) and U19 AG056278 (J.V., P.D.R., L.J.N., Y.S. and W.C.L.) and a Career Scientist Award from the Irma T. Hirschl Trust to Z.D.Z. We thank the the Popgen Biobank and the Popgen 2.0 Network at Kiel University for help with recruitment of some of the long-lived individuals. G.G.T. was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) through project no. 390870439 (EXC 2150 – ROOTS). We thank T. Wang (Albert Einstein College of Medicine) for comments and suggestions. We thank the Management and Leadership Team at RGC for contributing to securing funding, study design and oversight and reviewing the manuscript (G. Abecasis, A. Baras, M. Cantor, G. Coppola, A. Deubler, A. Economides, L. A. Lotta, J. D. Overton, J. G. Reid and A. Shuldiner). We thank Sequencing and Lab Operations at RGC for performing and being responsible for sample sequencing (J. Marcovici, E. Weihenig, A. Lopez and J. D. Overton); for performing and being responsible for exome sequencing (A. DeVito, J. LaRosa, L. Widom, C. Beechert, C. Forsythe, E. D. Fuller, M. Lattari, M. Sotiropoulos Padilla, S. E. Wolf, A. Lopez and J. D. Overton); for conceiving and being responsible for laboratory automation (T. D. Schleicher, Z. Gu, A. Lopez and J. D. Overton); and for being responsible for sample tracking and the library information management system (M. Pradhan, K. Manoochehri, R. H. Ulloa and J. D. Overton). We thank Genome Informatics at RGC for performing, and being responsible for, the analysis needed to produce exome and genotype data (X. Bai, A. Hawes, W. Salerno and J. G. Reid); for providing computing infrastructure development and operational support (G. Eom and J. G. Reid); for providing variant and gene annotations and their functional interpretation of variants (S. Balasubramanian and J. G. Reid); and for conceiving and being responsible for creating, developing and deploying analysis platforms and computational methods for analysis of genomic data (E. K. Maxwell, J. C. Staples, L. Habegger and J. G. Reid). We thank Research Program Management at RGC for contributing to the management and coordination of all research activities, planning, execution and reviewing of the manuscript (M. B. Jones and L. J. Mitnaul).

Funding Information:
This work was supported by NIH grant nos. R01 HG008153 (Z.D.Z.), R01 AG061155 (S.M.), R01 AG060747 (M.D.G.), R01 AG057909 (N.B. and Z.D.Z.), P01 AG017242 (J.V.) and U19 AG056278 (J.V., P.D.R., L.J.N., Y.S. and W.C.L.) and a Career Scientist Award from the Irma T. Hirschl Trust to Z.D.Z. We thank the the Popgen Biobank and the Popgen 2.0 Network at Kiel University for help with recruitment of some of the long-lived individuals. G.G.T. was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) through project no. 390870439 (EXC 2150 – ROOTS). We thank T. Wang (Albert Einstein College of Medicine) for comments and suggestions. We thank the Management and Leadership Team at RGC for contributing to securing funding, study design and oversight and reviewing the manuscript (G. Abecasis, A. Baras, M. Cantor, G. Coppola, A. Deubler, A. Economides, L. A. Lotta, J. D. Overton, J. G. Reid and A. Shuldiner). We thank Sequencing and Lab Operations at RGC for performing and being responsible for sample sequencing (J. Marcovici, E. Weihenig, A. Lopez and J. D. Overton); for performing and being responsible for exome sequencing (A. DeVito, J. LaRosa, L. Widom, C. Beechert, C. Forsythe, E. D. Fuller, M. Lattari, M. Sotiropoulos Padilla, S. E. Wolf, A. Lopez and J. D. Overton); for conceiving and being responsible for laboratory automation (T. D. Schleicher, Z. Gu, A. Lopez and J. D. Overton); and for being responsible for sample tracking and the library information management system (M. Pradhan, K. Manoochehri, R. H. Ulloa and J. D. Overton). We thank Genome Informatics at RGC for performing, and being responsible for, the analysis needed to produce exome and genotype data (X. Bai, A. Hawes, W. Salerno and J. G. Reid); for providing computing infrastructure development and operational support (G. Eom and J. G. Reid); for providing variant and gene annotations and their functional interpretation of variants (S. Balasubramanian and J. G. Reid); and for conceiving and being responsible for creating, developing and deploying analysis platforms and computational methods for analysis of genomic data (E. K. Maxwell, J. C. Staples, L. Habegger and J. G. Reid). We thank Research Program Management at RGC for contributing to the management and coordination of all research activities, planning, execution and reviewing of the manuscript (M. B. Jones and L. J. Mitnaul).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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