Abstract
Centenarians represent a unique cohort to study the genetic basis for longevity and factors determining the risk of neurodegenerative disorders, including Alzheimer's disease (AD). The estimated genetic contribution to longevity is highest in centenarians and supercententenarians, but few genetic variants have been shown to clearly impact this phenotype. While the genetic risk for AD and other dementias is now well understood, the frequency of known dementia risk variants in centenarians is not fully characterized. To address these questions, we performed whole exome sequencing on 100 individuals of 98-108 years age in search of genes with large effect sizes towards the exceptional aging phenotype. Overall, we were unable to identify a rare protein-altering variant or individual genes with an increased burden of rare variants associated with exceptional longevity. Gene burden analysis revealed three genes of nominal statistical significance associated with extreme aging, including LYST, MDN1, and RBMXL1. Several genes with variants conferring an increased risk for AD and other dementias were identified, including TREM2, EPHA1, ABCA7, PLD3, MAPT, and NOTCH3. Larger centenarian studies will be required to further elucidate the ge...Continue Reading
References
Jan 1, 1992·International Journal of Aging & Human Development·L W PoonS B Thielman
Feb 22, 2002·American Journal of Medical Genetics·Mohammad A KarimRichard A Spritz
Mar 2, 2005·Biological Psychiatry·Loubna Erraji-BenchekrounEtienne Sibille
Apr 22, 2008·Cell·Kristan K SteffenMatt Kaeberlein
Jul 9, 2011·American Journal of Human Genetics·Michael C WuXihong Lin
Jan 27, 2012·PloS One·Paola SebastianiThomas T Perls
May 5, 2012·Human Molecular Genetics·Giovanni CoppolaDaniel H Geschwind
Nov 16, 2012·The New England Journal of Medicine·Rita GuerreiroUNKNOWN Alzheimer Genetic Analysis Group
Dec 18, 2013·Nature·Carlos CruchagaAlison M Goate
Apr 2, 2014·Human Molecular Genetics·Joris DeelenP Eline Slagboom
May 23, 2014·Expert Review of Molecular Diagnostics·Julie W RuttenSaskia A J Lesnik Oberstein
Sep 10, 2014·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Linda BroerJoanne M Murabito
Nov 13, 2014·PloS One·Hinco J GiermanStuart K Kim
Mar 31, 2015·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Paola SebastianiThomas T Perls
Jun 24, 2015·Annals of Neurology·Badri N VardarajanRichard Mayeux
Aug 6, 2015·European Journal of Human Genetics : EJHG·Gaël NicolasDidier Hannequin
Dec 19, 2015·PLoS Genetics·Kristen FortneyStuart K Kim
Mar 27, 2016·Aging·Luke C PillingDavid Melzer
Apr 27, 2016·Cell·Galina A EriksonAli Torkamani
Jun 16, 2016·Lancet Neurology·Elise Cuyvers, Kristel Sleegers
Aug 19, 2016·Nature·Monkol LekUNKNOWN Exome Aggregation Consortium
Nov 5, 2016·Molecular Cell·Nithya RamanStefan Müller
Mar 23, 2017·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Paola SebastianiThomas T Perls
Apr 4, 2017·Bioinformatics·Alessandro RomanelFrancesca Demichelis
Aug 24, 2017·Neuroscience Letters·Victoria Berge-SeidlMathias Toft
Nov 14, 2017·Aging·Fan YangZe Yang
Citations
May 28, 2019·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Joshua M Hare, Isabel Beerman
Jul 29, 2020·Nature Metabolism·Zhengdong D ZhangJan Vijg
Mar 7, 2020·Aging Clinical and Experimental Research·Xiaolan LianLina Zhang
Dec 9, 2020·The Journal of Biological Chemistry·Cedric CappelMarkus Damme
Jan 27, 2021·Mechanisms of Ageing and Development·Serena DatoGiuseppe Passarino
Jan 26, 2021·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Guillermo G TorresAlmut Nebel
Mar 11, 2021·Briefings in Functional Genomics·Maarouf BaghdadiJoris Deelen