Whole-Exome Sequencing of an Exceptional Longevity Cohort
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 super-cententenarians, but few...
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| Veröffentlicht in: | The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2019-08, Vol.74 (9), p.1386-1390 |
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| container_title | The journals of gerontology. Series A, Biological sciences and medical sciences |
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| creator | Nygaard, Haakon B Erson-Omay, E Zeynep Wu, Xiujuan Kent, Brianne A Bernales, Cecily Q Evans, Daniel M Farrer, Matthew J Vilariño-Güell, Carles Strittmatter, Stephen M |
| description | 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 super-cententenarians, 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 genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes. |
| doi_str_mv | 10.1093/gerona/gly098 |
| format | Article |
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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 super-cententenarians, 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 genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.</description><identifier>ISSN: 1079-5006</identifier><identifier>ISSN: 1758-535X</identifier><identifier>EISSN: 1758-535X</identifier><identifier>DOI: 10.1093/gerona/gly098</identifier><identifier>PMID: 29750252</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Age Factors ; Aged, 80 and over ; Aging ; Alzheimer Disease - genetics ; Alzheimer's disease ; Cohort Studies ; Dementia - genetics ; Dementia disorders ; Exome Sequencing ; Female ; Genetic diversity ; Genetics ; Genotype & phenotype ; Geriatrics ; Humans ; Longevity ; Longevity - genetics ; Male ; Neurodegenerative diseases ; Older people ; Phenotypes ; Risk Factors ; The Journal of Gerontology: Biological Sciences</subject><ispartof>The journals of gerontology. Series A, Biological sciences and medical sciences, 2019-08, Vol.74 (9), p.1386-1390</ispartof><rights>The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. 2018</rights><rights>The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.</rights><rights>Copyright Oxford University Press Sep 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c448t-e359e5e93f03a29ae258db4f8edd10ebf56b26b442f290b54e3446b39c94a6aa3</citedby><cites>FETCH-LOGICAL-c448t-e359e5e93f03a29ae258db4f8edd10ebf56b26b442f290b54e3446b39c94a6aa3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29750252$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Le Couteur, David</contributor><creatorcontrib>Nygaard, Haakon B</creatorcontrib><creatorcontrib>Erson-Omay, E Zeynep</creatorcontrib><creatorcontrib>Wu, Xiujuan</creatorcontrib><creatorcontrib>Kent, Brianne A</creatorcontrib><creatorcontrib>Bernales, Cecily Q</creatorcontrib><creatorcontrib>Evans, Daniel M</creatorcontrib><creatorcontrib>Farrer, Matthew J</creatorcontrib><creatorcontrib>Vilariño-Güell, Carles</creatorcontrib><creatorcontrib>Strittmatter, Stephen M</creatorcontrib><title>Whole-Exome Sequencing of an Exceptional Longevity Cohort</title><title>The journals of gerontology. Series A, Biological sciences and medical sciences</title><addtitle>J Gerontol A Biol Sci Med Sci</addtitle><description>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 super-cententenarians, 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 genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.</description><subject>Age Factors</subject><subject>Aged, 80 and over</subject><subject>Aging</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer's disease</subject><subject>Cohort Studies</subject><subject>Dementia - genetics</subject><subject>Dementia disorders</subject><subject>Exome Sequencing</subject><subject>Female</subject><subject>Genetic diversity</subject><subject>Genetics</subject><subject>Genotype & phenotype</subject><subject>Geriatrics</subject><subject>Humans</subject><subject>Longevity</subject><subject>Longevity - genetics</subject><subject>Male</subject><subject>Neurodegenerative diseases</subject><subject>Older people</subject><subject>Phenotypes</subject><subject>Risk Factors</subject><subject>The Journal of Gerontology: Biological Sciences</subject><issn>1079-5006</issn><issn>1758-535X</issn><issn>1758-535X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctLw0AQxhdRbK0evUrAi5fYzb6yexGk1AcUPKjobdmkkzQlzdZNUtr_3i2p9XFxLjMwP76Zjw-h8whfR1jRYQ7OVmaYlxus5AHqRzGXIaf8_dDPOFYhx1j00Eldz_G2ODlGPaJijgknfaTeZraEcLy2Cwie4aOFKi2qPLBZYKpgvE5h2RT-QBlMbJXDqmg2wcjOrGtO0VFmyhrOdn2AXu_GL6OHcPJ0_zi6nYQpY7IJgXIFHBTNMDVEGSBcThOWSZhOIwxJxkVCRMIYyYjCCWdAGRMJValiRhhDB-im0122yQKmKVSNM6VeumJh3EZbU-jfm6qY6dyutBBKxIR6gaudgLPeX93oRVGnUJamAtvWmmAqSRxFsfDo5R90blvn3XuKSKq4ZJJ4Kuyo1Nm6dpDtn4mw3oaiu1B0F4rnL3462NNfKXx_aNvlP1qfrZaYXw</recordid><startdate>20190816</startdate><enddate>20190816</enddate><creator>Nygaard, Haakon B</creator><creator>Erson-Omay, E Zeynep</creator><creator>Wu, Xiujuan</creator><creator>Kent, Brianne A</creator><creator>Bernales, Cecily Q</creator><creator>Evans, Daniel M</creator><creator>Farrer, Matthew J</creator><creator>Vilariño-Güell, Carles</creator><creator>Strittmatter, Stephen M</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190816</creationdate><title>Whole-Exome Sequencing of an Exceptional Longevity Cohort</title><author>Nygaard, Haakon B ; Erson-Omay, E Zeynep ; Wu, Xiujuan ; Kent, Brianne A ; Bernales, Cecily Q ; Evans, Daniel M ; Farrer, Matthew J ; Vilariño-Güell, Carles ; Strittmatter, Stephen M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c448t-e359e5e93f03a29ae258db4f8edd10ebf56b26b442f290b54e3446b39c94a6aa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Age Factors</topic><topic>Aged, 80 and over</topic><topic>Aging</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer's disease</topic><topic>Cohort Studies</topic><topic>Dementia - genetics</topic><topic>Dementia disorders</topic><topic>Exome Sequencing</topic><topic>Female</topic><topic>Genetic diversity</topic><topic>Genetics</topic><topic>Genotype & phenotype</topic><topic>Geriatrics</topic><topic>Humans</topic><topic>Longevity</topic><topic>Longevity - genetics</topic><topic>Male</topic><topic>Neurodegenerative diseases</topic><topic>Older people</topic><topic>Phenotypes</topic><topic>Risk Factors</topic><topic>The Journal of Gerontology: Biological Sciences</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nygaard, Haakon B</creatorcontrib><creatorcontrib>Erson-Omay, E Zeynep</creatorcontrib><creatorcontrib>Wu, Xiujuan</creatorcontrib><creatorcontrib>Kent, Brianne A</creatorcontrib><creatorcontrib>Bernales, Cecily Q</creatorcontrib><creatorcontrib>Evans, Daniel M</creatorcontrib><creatorcontrib>Farrer, Matthew J</creatorcontrib><creatorcontrib>Vilariño-Güell, Carles</creatorcontrib><creatorcontrib>Strittmatter, Stephen M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The journals of gerontology. Series A, Biological sciences and medical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nygaard, Haakon B</au><au>Erson-Omay, E Zeynep</au><au>Wu, Xiujuan</au><au>Kent, Brianne A</au><au>Bernales, Cecily Q</au><au>Evans, Daniel M</au><au>Farrer, Matthew J</au><au>Vilariño-Güell, Carles</au><au>Strittmatter, Stephen M</au><au>Le Couteur, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Whole-Exome Sequencing of an Exceptional Longevity Cohort</atitle><jtitle>The journals of gerontology. Series A, Biological sciences and medical sciences</jtitle><addtitle>J Gerontol A Biol Sci Med Sci</addtitle><date>2019-08-16</date><risdate>2019</risdate><volume>74</volume><issue>9</issue><spage>1386</spage><epage>1390</epage><pages>1386-1390</pages><issn>1079-5006</issn><issn>1758-535X</issn><eissn>1758-535X</eissn><abstract>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 super-cententenarians, 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 genetic basis for longevity, and factors conferring protection against age-dependent neurodegenerative syndromes.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>29750252</pmid><doi>10.1093/gerona/gly098</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Age Factors Aged, 80 and over Aging Alzheimer Disease - genetics Alzheimer's disease Cohort Studies Dementia - genetics Dementia disorders Exome Sequencing Female Genetic diversity Genetics Genotype & phenotype Geriatrics Humans Longevity Longevity - genetics Male Neurodegenerative diseases Older people Phenotypes Risk Factors The Journal of Gerontology: Biological Sciences |
| title | Whole-Exome Sequencing of an Exceptional Longevity Cohort |
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