Mary Revelas1, Anbupalam Thalamuthu1, Christopher Oldmeadow2, Tiffany-Jane Evans2, Nicola J Armstrong3, John B Kwok4, Henry Brodaty5, Peter R Schofield4, Rodney J Scott6, Perminder S Sachdev7, John R Attia8, Karen A Mather9. 1. Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia. 2. Hunter Medical Research Institute, Newcastle, Australia. 3. Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Mathematics and Statistics, Murdoch University, Perth, Australia. 4. Neuroscience Research Australia, Randwick, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia. 5. Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Dementia Centre for Research Collaboration, University of New South Wales, Sydney, Australia. 6. Faculty of Health, University of Newcastle, Newcastle NSW, Australia; Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia. 7. Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW, Australia. 8. Hunter Medical Research Institute, Newcastle, Australia; Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia. 9. Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia. Electronic address: Karen.mather@unsw.edu.au.
Abstract
BACKGROUND: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. METHODS: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. RESULTS: Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). CONCLUSION: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.
BACKGROUND: Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. METHODS: Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85+) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. RESULTS: Five polymorphisms, ACErs4340, APOE ε2/3/4, FOXO3Ars2802292, KLOTHO KL-VS and IL6rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). CONCLUSION: In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.
Authors: Erika J Wolf; Mark W Logue; Xiang Zhao; Nikolaos P Daskalakis; Filomene G Morrison; Shaline Escarfulleri; Annjanette Stone; Steven A Schichman; Regina E McGlinchey; William P Milberg; Cidi Chen; Carmela R Abraham; Mark W Miller Journal: Psychoneuroendocrinology Date: 2020-04-13 Impact factor: 4.905
Authors: Erika J Wolf; Filomene G Morrison; Danielle R Sullivan; Mark W Logue; Rachel E Guetta; Annjanette Stone; Steven A Schichman; Regina E McGlinchey; William P Milberg; Mark W Miller Journal: Brain Behav Immun Date: 2019-03-11 Impact factor: 7.217
Authors: Jiaming Zhang; Nikolay Burnaevskiy; James Annis; Wenyan Han; Deyin Hou; Paula Ladd; Lin Lee; Alexander R Mendenhall; Junko Oshima; George M Martin Journal: J Gerontol A Biol Sci Med Sci Date: 2020-11-13 Impact factor: 6.053