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

被引：28

作者：

Lin, Jhih-Rong ^{[1
]}

Sin-Chan, Patrick ^{[2
]}

Napolioni, Valerio ^{[3
]}

Torres, Guillermo G. ^{[4
]}

Mitra, Joydeep ^{[1
]}

Zhang, Quanwei ^{[1
]}

Jabalameli, M. Reza ^{[1
]}

Wang, Zhen ^{[1
]}

Nha Nguyen ^{[1
]}

Gao, Tina ^{[5
]}

Laudes, Matthias ^{[6
]}

Goerg, Siegfried ^{[7
]}

Franke, Andre ^{[4
]}

Nebel, Almut ^{[4
]}

Greicius, Michael D. ^{[8
]}

Atzmon, Gil ^{[5
,9
]}

Ye, Kenny ^{[10
]}

Gorbunova, Vera ^{[11
]}

Ladiges, Warren C. ^{[12
]}

Shuldiner, Alan R. ^{[2
]}

Niedernhofer, Laura J. ^{[13
,14
]}

Robbins, Paul D. ^{[13
,14
]}

Milman, Sofiya ^{[1
,5
]}

Suh, Yousin ^{[1
,15
,16
]}

Vijg, Jan ^{[1
]}

Barzilai, Nir ^{[1
,5
]}

Zhang, Zhengdong D. ^{[1
]}

机构：

[1] Albert Einstein Coll Med, Dept Genet, New York, NY 10461 USA

[2] Regeneron Pharmaceut Inc, New York, NY USA

[3] Univ Camerino, Sch Biosci & Vet Med, Camerino, Italy

[4] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[5] Albert Einstein Coll Med, Dept Med, New York, NY USA

[6] Univ Kiel, Dept Internal Med 1, Div Endocrinol Diabet & Clin Nutr, Kiel, Germany

[7] Univ Hosp Schleswig Holstein, Inst Transfus Med, Lubeck, Germany

[8] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[9] Univ Haifa, Fac Nat Sci, Dept Biol, Haifa, Israel

[10] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA

[11] Univ Rochester, Dept Biol, Rochester, NY 14627 USA

[12] Univ Washington, Sch Med, Dept Comparat Med, Seattle, WA USA

[13] Univ Minnesota, Inst Biol Aging & Metab, Minneapolis, MN USA

[14] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA

[15] Columbia Univ, Dept Obstet & Gynecol, Irving Med Ctr, New York, NY USA

[16] Columbia Univ, Dept Genet & Dev, Irving Med Ctr, New York, NY USA

来源：

NATURE AGING | 2021年 / 1卷 / 09期

关键词：

GENOME-WIDE ASSOCIATION; SET ENRICHMENT ANALYSIS; LIFE-SPAN; CARDIOVASCULAR-DISEASE; APOLIPOPROTEIN-E; WEB SERVER; RISK; EXPRESSION; RESISTANCE; STRESS;

D O I：

10.1038/s43587-021-00108-5

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 factor1 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.

引用

页码：783 / +

页数：22

共 76 条

[1] Remarkable longevity and stress resistance of nematode PI3K-null mutants [J].

Ayyadevara, Srinivas ;

Alla, Ramani ;

Thaden, John J. ;

Reis, Robert J. Shmookler .

AGING CELL, 2008, 7 (01) :13-22

[2] THE ALZHEIMER'S DISEASE SEQUENCING PROJECT: STUDY DESIGN AND SAMPLE SELECTION [J].

Beecham, Gary W. ;

Bis, J. C. ;

Martin, E. R. ;

Choi, S. -H. ;

DeStefano, A. L. ;

van Duijn, C. M. ;

Fornage, M. ;

Gabriel, S. B. ;

Koboldt, D. C. ;

Larson, D. E. ;

Naj, A. C. ;

Psaty, B. M. ;

Salerno, W. ;

Bush, W. S. ;

Foroud, T. M. ;

Wijsman, E. ;

Farrer, L. A. ;

Goate, A. ;

Haines, J. L. ;

Pericak-Vance, Margaret A. ;

Boerwinkle, E. ;

Mayeux, R. ;

Seshadri, S. ;

Schellenberg, G. .

NEUROLOGY-GENETICS, 2017, 3 (05)

[3] GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy [J].

Broer, Linda ;

Buchman, Aron S. ;

Deelen, Joris ;

Evans, Daniel S. ;

Faul, Jessica D. ;

Lunetta, Kathryn L. ;

Sebastiani, Paola ;

Smith, Jennifer A. ;

Smith, Albert V. ;

Tanaka, Toshiko ;

Yu, Lei ;

Arnold, Alice M. ;

Aspelund, Thor ;

Benjamin, Emelia J. ;

De Jager, Philip L. ;

Eirkisdottir, Gudny ;

Evans, Denis A. ;

Garcia, Melissa E. ;

Hofman, Albert ;

Kaplan, Robert C. ;

Kardia, Sharon L. R. ;

Kiel, Douglas P. ;

Oostra, Ben A. ;

Orwoll, Eric S. ;

Parimi, Neeta ;

Psaty, Bruce M. ;

Rivadeneira, Fernando ;

Rotter, Jerome I. ;

Seshadri, Sudha ;

Singleton, Andrew ;

Tiemeier, Henning ;

Uitterlinden, Andre G. ;

Zhao, Wei ;

Bandinelli, Stefania ;

Bennett, David A. ;

Ferrucci, Luigi ;

Gudnason, Vilmundur ;

Harris, Tamara B. ;

Karasik, David ;

Launer, Lenore J. ;

Perls, Thomas T. ;

Slagboom, P. Eline ;

Tranah, Gregory J. ;

Weir, David R. ;

Newman, Anne B. ;

van Duijn, Cornelia M. ;

Murabito, Joanne M. .

JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, 2015, 70 (01) :110-118

[4] Human premature aging, DNA repair and RecQ helicases [J].

Brosh, Robert M., Jr. ;

Bohr, Vilhelm A. .

NUCLEIC ACIDS RESEARCH, 2007, 35 (22) :7527-7544

[5] From discoveries in ageing research to therapeutics for healthy ageing [J].

Campisi, Judith ;

Kapahi, Pankaj ;

Lithgow, Gordon J. ;

Melov, Simon ;

Newman, John C. ;

Verdin, Eric .

NATURE, 2019, 571 (7764) :183-192

[6] Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells [J].

Caruso, Alessandra ;

Motolese, Marta ;

Iacovelli, Luisa ;

Caraci, Filippo ;

Copani, Agata ;

Nicoletti, Ferdinando ;

Terstappen, Georg C. ;

Gaviraghi, Giovanni ;

Caricasole, Andrea .

JOURNAL OF NEUROCHEMISTRY, 2006, 98 (02) :364-371

[7] Exome sequencing of three cases of familial exceptional longevity [J].

Cash, Timothy P. ;

Pita, Guillermo ;

Dominguez, Orlando ;

Alonso, Maria R. ;

Moreno, Leticia T. ;

Borras, Consuelo ;

Rodriguez-Manas, Leocadio ;

Santiago, Catalina ;

Garatachea, Nuria ;

Lucia, Alejandro ;

Avellana, Juan A. ;

Vina, Jose ;

Gonzalez-Neira, Anna ;

Serrano, Manuel .

AGING CELL, 2014, 13 (06) :1087-1090

[8] Second-generation PLINK: rising to the challenge of larger and richer datasets [J].

Chang, Christopher C. ;

Chow, Carson C. ;

Tellier, Laurent C. A. M. ;

Vattikuti, Shashaank ;

Purcell, Shaun M. ;

Lee, James J. .

GIGASCIENCE, 2015, 4

[9] Comprehensive assessment of computational algorithms in predicting cancer driver mutations [J].

Chen, Hu ;

Li, Jun ;

Wang, Yumeng ;

Ng, Patrick Kwok-Shing ;

Tsang, Yiu Huen ;

Shaw, Kenna R. ;

Mills, Gordon B. ;

Liang, Han .

GENOME BIOLOGY, 2020, 21 (01)

[10] ToppGene Suite for gene list enrichment analysis and candidate gene prioritization [J].

Chen, Jing ;

Bardes, Eric E. ;

Aronow, Bruce J. ;

Jegga, Anil G. .

NUCLEIC ACIDS RESEARCH, 2009, 37 :W305-W311

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