Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants

doi:10.1016/j.nbd.2020.104972

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants

Research output: Contribution to journal › Review article › peer-review

4 Scopus citations

Abstract

Background: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). Methods: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives. Results: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values =.001 and.0001, respectively). Discussion: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.

Original language	English
Article number	104972
Journal	Neurobiology of Disease
Volume	143
DOIs	https://doi.org/10.1016/j.nbd.2020.104972
State	Published - Sep 2020

Bibliographical note

Funding Information:
We thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute , University of Utah and from the University of Utah 's program in Personalized Health and Center for Clinical and Translational Science .

Funding Information:
We appreciate the contributions of Brigham Young University in supporting this research. This research is supported by RF1AG054052 (PI: Kauwe) and U01AG052411 (PI: Goate). We thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah's program in Personalized Health and Center for Clinical and Translational Science. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL?103010). Alzheimer's Disease Genetics Consortium (ADGC), Data from ADGC was appropriately downloaded from dbGaP (accession: phs000372.v1.p1). We acknowledge the contributions of The members of the Alzheimer's Disease Genetics Consortium are: Marilyn S. Albert1, Roger L. Albin2-4, Liana G. Apostolova5, Steven E. Arnold6, Clinton T. Baldwin7, Robert Barber8, Michael M. Barmada9, Lisa L. Barnes10, 11, Thomas G. Beach12, Gary W. Beecham13, 14, Duane Beekly15, David A. Bennett10, 16, Eileen H. Bigio17, Thomas D. Bird18, Deborah Blacker19,20, Bradley F. Boeve21, James D. Bowen22, Adam Boxer23, James R. Burke24, Joseph D. Buxbaum25, 26, 27, Nigel J. Cairns28, Laura B. Cantwell29, Chuanhai Cao30, Chris S. Carlson31, Regina M. Carney13, Minerva M. Carrasquillo33, Steven L. Carroll34, Helena C. Chui35, David G. Clark36, Jason Corneveaux37, Paul K. Crane38, David H. Cribbs39, Elizabeth A. Crocco40, Carlos Cruchaga41, Philip L. De Jager42,43, Charles DeCarli44, Steven T. DeKosky45, F. Yesim Demirci9, Malcolm Dick46, Dennis W. Dickson33, Ranjan Duara47, Nilufer Ertekin-Taner33,48, Denis Evans49, Kelley M. Faber50, Kenneth B. Fallon34, Martin R. Farlow51, Lindsay A Farrer7,52,76,77,83, Steven Ferris53, Tatiana M. Foroud50, Matthew P. Frosch54, Douglas R. Galasko55, Mary Ganguli56, Marla Gearing57,58, Daniel H. Geschwind59, Bernardino Ghetti60, John R. Gilbert13,14, Sid Gilman2, Jonathan D. Glass61, Alison M. Goate41, Neill R. Graff-Radford33,48, Robert C. Green62, John H. Growdon63, Jonathan L. Haines64, 65, Hakon Hakonarson66, Kara L. Hamilton-Nelson13, Ronald L. Hamilton67, John Hardy68, Lindy E. Harrell36, Elizabeth Head69, Lawrence S. Honig70, Matthew J. Huentelman37, Christine M. Hulette71, Bradley T. Hyman63, Gail P. Jarvik72,73, Gregory A. Jicha74, Lee-Way Jin75, Gyungah Jun7,76,77, M. Ilyas Kamboh9,78, Anna Karydas23, John S.K. Kauwe79, Jeffrey A. Kaye80,81, Ronald Kim82, Edward H. Koo55, Neil W. Kowall83,84, Joel H. Kramer85, Patricia Kramer80,86, Walter A. Kukull87, Frank M. LaFerla88, James J. Lah61, Eric B. Larson38,89, James B. Leverenz90, Allan I. Levey61, Ge Li91, Andrew P. Lieberman92, Chiao-Feng Lin29, Oscar L. Lopez78, Kathryn L. Lunetta76, Constantine G. Lyketsos93, Wendy J. Mack94, Daniel C. Marson36, Eden R. Martin13,14, Frank Martiniuk95, Deborah C. Mash96, Eliezer Masliah55,97, Richard Mayeux70, 109, 110, Wayne C. McCormick38, Susan M. McCurry98, Andrew N. McDavid31, Ann C. McKee83,84, Marsel Mesulam99, Bruce L. Miller23, Carol A. Miller100, Joshua W. Miller75, Thomas J. Montine90, John C. Morris28, 101, Jill R. Murrell50, 60, Amanda J. Myers40, Adam C. Naj13, John M. Olichney44, Vernon S. Pankratz102, Joseph E. Parisi103,104, Margaret A. Pericak-Vance13, 14, Elaine Peskind91, Ronald C. Petersen21, Aimee Pierce39, Wayne W. Poon46, Huntington Potter30, Joseph F. Quinn80, Ashok Raj30, Murray Raskind91, Eric M. Reiman37,105-107, Barry Reisberg53,108, Christiane Reitz70,109,110, John M. Ringman5, Erik D. Roberson36, Ekaterina Rogaeva111, Howard J. Rosen23, Roger N. Rosenberg112, Mary Sano26, Andrew J. Saykin50,113, Gerard D. Schellenberg29, Julie A. Schneider10,114, Lon S. Schneider35,115, William W. Seeley23, Amanda G. Smith30, Joshua A. Sonnen90, Salvatore Spina60, Peter St George-Hyslop111,116, Robert A. Stern83, Rudolph E. Tanzi63, John Q. Trojanowski29, Juan C. Troncoso117, Debby W. Tsuang91, Otto Valladares29, Vivianna M. Van Deerlin29, Linda J. Van Eldik118, Badri N. Vardarajan7, Harry V. Vinters5,119, Jean Paul Vonsattel120, Li-San Wang29, Sandra Weintraub99, Kathleen A. Welsh-Bohmer24, 121, Jennifer Williamson70, Randall L. Woltjer122, Clinton B. Wright123, Steven G. Younkin33, Chang-En Yu38, Lei Yu10. 1Department of Neurology, Johns Hopkins University, Baltimore, Maryland, 2Department of Neurology, University of Michigan, Ann Arbor, Michigan, 3Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, 4Michigan Alzheimer's disease Center, Ann Arbor, Michigan, 5Department of Neurology, University of California Los Angeles, Los Angeles, California, 6Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 7Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, 8Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, 9Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, 10Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, 11Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, 12Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, 13The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, 14Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, 15National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, 16Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, 17Department of Pathology, Northwestern University, Chicago, Illinois, 18Department of Neurology, University of Washington, Seattle, Washington, 19Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 20Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 21Department of Neurology, Mayo Clinic, Rochester, Minnesota, 22Swedish Medical Center, Seattle, Washington, 23Department of Neurology, University of California San Francisco, San Francisco, California, 24Department of Medicine, Duke University, Durham, North Carolina, 25Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, 26Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, 27Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, 28Department of Pathology and Immunology, Washington University, St. Louis, Missouri, 29Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 30USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, 31Fred Hutchinson Cancer Research Center, Seattle, Washington, 32Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, 33Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, 34Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, 35Department of Neurology, University of Southern California, Los Angeles, California, 36Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, 37Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 38Department of Medicine, University of Washington, Seattle, Washington, 39Department of Neurology, University of California Irvine, Irvine, California, 40Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, 41Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, 42Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 43Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, 44Department of Neurology, University of California Davis, Sacramento, California, 45University of Virginia School of Medicine, Charlottesville, Virginia, 46Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California, 47Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, 48Department of Neurology, Mayo Clinic, Jacksonville, Florida, 49Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, 50Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, 51Department of Neurology, Indiana University, Indianapolis, Indiana, 52Department of Epidemiology, Boston University, Boston, Massachusetts, 53Department of Psychiatry, New York University, New York, New York, 54C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, 55Department of Neurosciences, University of California San Diego, La Jolla, California, 56Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 57Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, 58Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, 59Neurogenetics Program, University of California Los Angeles, Los Angeles, California, 60Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, 61Department of Neurology, Emory University, Atlanta, Georgia, 62Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 63Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 64Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, 65Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, 66Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 67Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, 68Institute of Neurology, University College London, Queen Square, London, 69Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, 70Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, 71Department of Pathology, Duke University, Durham, North Carolina, 72Department of Genome Sciences, University of Washington, Seattle, Washington, 73Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, 74Sanders-Brown Center on Aging, Department Neurology, University of Kentucky, Lexington, Kentucky, 75Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, California, 76Department of Biostatistics, Boston University, Boston, Massachusetts, 77Department of Ophthalmology, Boston University, Boston, Massachusetts, 78University of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, Pennsylvania, 79Department of Biology, Brigham Young University, Provo, Utah, 80Department of Neurology, Oregon Health & Science University, Portland, Oregon, 81Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, 82Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, 83Department of Neurology, Boston University, Boston, Massachusetts, 84Department of Pathology, Boston University, Boston, Massachusetts, 85Department of Neuropsychology, University of California San Francisco, San Francisco, California, 86Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, 87Department of Epidemiology, University of Washington, Seattle, Washington, 88Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, 89Group Health Research Institute, Group Health, Seattle, Washington, 90Department of Pathology, University of Washington, Seattle, Washington, 91Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 92Department of Pathology, University of Michigan, Ann Arbor, Michigan, 93Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, 94Department of Preventive Medicine, University of Southern California, Los Angeles, California, 95Department of Medicine - Pulmonary, New York University, New York, New York, 96Department of Neurology, University of Miami, Miami, Florida, 97Department of Pathology, University of California San Diego, La Jolla, California, 98School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, Washington, 99Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois, 100Department of Pathology, University of Southern California, Los Angeles, California, 101Department of Neurology, Washington University, St. Louis, Missouri, 102Department of Biostatistics, Mayo Clinic, Rochester, Minnesota, 103Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, 104Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, 105Arizona Alzheimer's Consortium, Phoenix, Arizona, 106Department of Psychiatry, University of Arizona, Phoenix, Arizona, 107Banner Alzheimer's Institute, Phoenix, Arizona, 108Alzheimer's Disease Center, New York University, New York, New York, 109Gertrude H. Sergievsky Center, Columbia University, New York, New York, 110Department of Neurology, Columbia University, New York, New York, 111Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, 112Department of Neurology, University of Texas Southwestern, Dallas, Texas, 113Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, 114Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, 115Department of Psychiatry, University of Southern California, Los Angeles, California, 116Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, 117Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 118Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, 119Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles, California, 120Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York, 121Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina, 122Department of Pathology, Oregon Health & Science University, Portland, Oregon, 123Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.

Funding Information:
We appreciate the contributions of Brigham Young University in supporting this research. This research is supported by RF1AG054052 (PI: Kauwe) and U01AG052411 (PI: Goate).

Publisher Copyright:
© 2020

Keywords

Genomics
Longevity
Pedigree
Rare variant sharing
Utah population database

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2020.104972

Cite this

@article{6a82727414964e49ac8e469ee2bd5f12,

title = "Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants",

abstract = "Background: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). Methods: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives. Results: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values =.001 and.0001, respectively). Discussion: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.",

keywords = "Genomics, Longevity, Pedigree, Rare variant sharing, Utah population database",

author = "Miller, {Justin B.} and Elizabeth Ward and Staley, {Lyndsay A.} and Jeffrey Stevens and Teerlink, {Craig C.} and Tavana, {Justina P.} and Matthew Cloward and Madeline Page and Louisa Dayton and Cannon-Albright, {Lisa A.} and Kauwe, {John S.K.}",

note = "Funding Information: We thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute , University of Utah and from the University of Utah 's program in Personalized Health and Center for Clinical and Translational Science . Funding Information: We appreciate the contributions of Brigham Young University in supporting this research. This research is supported by RF1AG054052 (PI: Kauwe) and U01AG052411 (PI: Goate). We thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah's program in Personalized Health and Center for Clinical and Translational Science. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL?103010). Alzheimer's Disease Genetics Consortium (ADGC), Data from ADGC was appropriately downloaded from dbGaP (accession: phs000372.v1.p1). We acknowledge the contributions of The members of the Alzheimer's Disease Genetics Consortium are: Marilyn S. Albert1, Roger L. Albin2-4, Liana G. Apostolova5, Steven E. Arnold6, Clinton T. Baldwin7, Robert Barber8, Michael M. Barmada9, Lisa L. Barnes10, 11, Thomas G. Beach12, Gary W. Beecham13, 14, Duane Beekly15, David A. Bennett10, 16, Eileen H. Bigio17, Thomas D. Bird18, Deborah Blacker19,20, Bradley F. Boeve21, James D. Bowen22, Adam Boxer23, James R. Burke24, Joseph D. Buxbaum25, 26, 27, Nigel J. Cairns28, Laura B. Cantwell29, Chuanhai Cao30, Chris S. Carlson31, Regina M. Carney13, Minerva M. Carrasquillo33, Steven L. Carroll34, Helena C. Chui35, David G. Clark36, Jason Corneveaux37, Paul K. Crane38, David H. Cribbs39, Elizabeth A. Crocco40, Carlos Cruchaga41, Philip L. De Jager42,43, Charles DeCarli44, Steven T. DeKosky45, F. Yesim Demirci9, Malcolm Dick46, Dennis W. Dickson33, Ranjan Duara47, Nilufer Ertekin-Taner33,48, Denis Evans49, Kelley M. Faber50, Kenneth B. Fallon34, Martin R. Farlow51, Lindsay A Farrer7,52,76,77,83, Steven Ferris53, Tatiana M. Foroud50, Matthew P. Frosch54, Douglas R. Galasko55, Mary Ganguli56, Marla Gearing57,58, Daniel H. Geschwind59, Bernardino Ghetti60, John R. Gilbert13,14, Sid Gilman2, Jonathan D. Glass61, Alison M. Goate41, Neill R. Graff-Radford33,48, Robert C. Green62, John H. Growdon63, Jonathan L. Haines64, 65, Hakon Hakonarson66, Kara L. Hamilton-Nelson13, Ronald L. Hamilton67, John Hardy68, Lindy E. Harrell36, Elizabeth Head69, Lawrence S. Honig70, Matthew J. Huentelman37, Christine M. Hulette71, Bradley T. Hyman63, Gail P. Jarvik72,73, Gregory A. Jicha74, Lee-Way Jin75, Gyungah Jun7,76,77, M. Ilyas Kamboh9,78, Anna Karydas23, John S.K. Kauwe79, Jeffrey A. Kaye80,81, Ronald Kim82, Edward H. Koo55, Neil W. Kowall83,84, Joel H. Kramer85, Patricia Kramer80,86, Walter A. Kukull87, Frank M. LaFerla88, James J. Lah61, Eric B. Larson38,89, James B. Leverenz90, Allan I. Levey61, Ge Li91, Andrew P. Lieberman92, Chiao-Feng Lin29, Oscar L. Lopez78, Kathryn L. Lunetta76, Constantine G. Lyketsos93, Wendy J. Mack94, Daniel C. Marson36, Eden R. Martin13,14, Frank Martiniuk95, Deborah C. Mash96, Eliezer Masliah55,97, Richard Mayeux70, 109, 110, Wayne C. McCormick38, Susan M. McCurry98, Andrew N. McDavid31, Ann C. McKee83,84, Marsel Mesulam99, Bruce L. Miller23, Carol A. Miller100, Joshua W. Miller75, Thomas J. Montine90, John C. Morris28, 101, Jill R. Murrell50, 60, Amanda J. Myers40, Adam C. Naj13, John M. Olichney44, Vernon S. Pankratz102, Joseph E. Parisi103,104, Margaret A. Pericak-Vance13, 14, Elaine Peskind91, Ronald C. Petersen21, Aimee Pierce39, Wayne W. Poon46, Huntington Potter30, Joseph F. Quinn80, Ashok Raj30, Murray Raskind91, Eric M. Reiman37,105-107, Barry Reisberg53,108, Christiane Reitz70,109,110, John M. Ringman5, Erik D. Roberson36, Ekaterina Rogaeva111, Howard J. Rosen23, Roger N. Rosenberg112, Mary Sano26, Andrew J. Saykin50,113, Gerard D. Schellenberg29, Julie A. Schneider10,114, Lon S. Schneider35,115, William W. Seeley23, Amanda G. Smith30, Joshua A. Sonnen90, Salvatore Spina60, Peter St George-Hyslop111,116, Robert A. Stern83, Rudolph E. Tanzi63, John Q. Trojanowski29, Juan C. Troncoso117, Debby W. Tsuang91, Otto Valladares29, Vivianna M. Van Deerlin29, Linda J. Van Eldik118, Badri N. Vardarajan7, Harry V. Vinters5,119, Jean Paul Vonsattel120, Li-San Wang29, Sandra Weintraub99, Kathleen A. Welsh-Bohmer24, 121, Jennifer Williamson70, Randall L. Woltjer122, Clinton B. Wright123, Steven G. Younkin33, Chang-En Yu38, Lei Yu10. 1Department of Neurology, Johns Hopkins University, Baltimore, Maryland, 2Department of Neurology, University of Michigan, Ann Arbor, Michigan, 3Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, 4Michigan Alzheimer's disease Center, Ann Arbor, Michigan, 5Department of Neurology, University of California Los Angeles, Los Angeles, California, 6Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 7Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, 8Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, 9Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, 10Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, 11Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, 12Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, 13The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, 14Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, 15National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, 16Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, 17Department of Pathology, Northwestern University, Chicago, Illinois, 18Department of Neurology, University of Washington, Seattle, Washington, 19Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 20Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 21Department of Neurology, Mayo Clinic, Rochester, Minnesota, 22Swedish Medical Center, Seattle, Washington, 23Department of Neurology, University of California San Francisco, San Francisco, California, 24Department of Medicine, Duke University, Durham, North Carolina, 25Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, 26Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, 27Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, 28Department of Pathology and Immunology, Washington University, St. Louis, Missouri, 29Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 30USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, 31Fred Hutchinson Cancer Research Center, Seattle, Washington, 32Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, 33Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, 34Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, 35Department of Neurology, University of Southern California, Los Angeles, California, 36Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, 37Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 38Department of Medicine, University of Washington, Seattle, Washington, 39Department of Neurology, University of California Irvine, Irvine, California, 40Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, 41Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, 42Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 43Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, 44Department of Neurology, University of California Davis, Sacramento, California, 45University of Virginia School of Medicine, Charlottesville, Virginia, 46Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California, 47Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, 48Department of Neurology, Mayo Clinic, Jacksonville, Florida, 49Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, 50Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, 51Department of Neurology, Indiana University, Indianapolis, Indiana, 52Department of Epidemiology, Boston University, Boston, Massachusetts, 53Department of Psychiatry, New York University, New York, New York, 54C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, 55Department of Neurosciences, University of California San Diego, La Jolla, California, 56Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 57Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, 58Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, 59Neurogenetics Program, University of California Los Angeles, Los Angeles, California, 60Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, 61Department of Neurology, Emory University, Atlanta, Georgia, 62Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 63Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 64Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, 65Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, 66Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 67Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, 68Institute of Neurology, University College London, Queen Square, London, 69Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, 70Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, 71Department of Pathology, Duke University, Durham, North Carolina, 72Department of Genome Sciences, University of Washington, Seattle, Washington, 73Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, 74Sanders-Brown Center on Aging, Department Neurology, University of Kentucky, Lexington, Kentucky, 75Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, California, 76Department of Biostatistics, Boston University, Boston, Massachusetts, 77Department of Ophthalmology, Boston University, Boston, Massachusetts, 78University of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, Pennsylvania, 79Department of Biology, Brigham Young University, Provo, Utah, 80Department of Neurology, Oregon Health & Science University, Portland, Oregon, 81Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, 82Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, 83Department of Neurology, Boston University, Boston, Massachusetts, 84Department of Pathology, Boston University, Boston, Massachusetts, 85Department of Neuropsychology, University of California San Francisco, San Francisco, California, 86Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, 87Department of Epidemiology, University of Washington, Seattle, Washington, 88Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, 89Group Health Research Institute, Group Health, Seattle, Washington, 90Department of Pathology, University of Washington, Seattle, Washington, 91Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 92Department of Pathology, University of Michigan, Ann Arbor, Michigan, 93Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, 94Department of Preventive Medicine, University of Southern California, Los Angeles, California, 95Department of Medicine - Pulmonary, New York University, New York, New York, 96Department of Neurology, University of Miami, Miami, Florida, 97Department of Pathology, University of California San Diego, La Jolla, California, 98School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, Washington, 99Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois, 100Department of Pathology, University of Southern California, Los Angeles, California, 101Department of Neurology, Washington University, St. Louis, Missouri, 102Department of Biostatistics, Mayo Clinic, Rochester, Minnesota, 103Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, 104Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, 105Arizona Alzheimer's Consortium, Phoenix, Arizona, 106Department of Psychiatry, University of Arizona, Phoenix, Arizona, 107Banner Alzheimer's Institute, Phoenix, Arizona, 108Alzheimer's Disease Center, New York University, New York, New York, 109Gertrude H. Sergievsky Center, Columbia University, New York, New York, 110Department of Neurology, Columbia University, New York, New York, 111Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, 112Department of Neurology, University of Texas Southwestern, Dallas, Texas, 113Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, 114Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, 115Department of Psychiatry, University of Southern California, Los Angeles, California, 116Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, 117Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 118Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, 119Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles, California, 120Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York, 121Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina, 122Department of Pathology, Oregon Health & Science University, Portland, Oregon, 123Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida. Funding Information: We appreciate the contributions of Brigham Young University in supporting this research. This research is supported by RF1AG054052 (PI: Kauwe) and U01AG052411 (PI: Goate). Publisher Copyright: {\textcopyright} 2020",

year = "2020",

month = sep,

doi = "10.1016/j.nbd.2020.104972",

language = "English",

volume = "143",

}

TY - JOUR

T1 - Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants

AU - Miller, Justin B.

AU - Ward, Elizabeth

AU - Staley, Lyndsay A.

AU - Stevens, Jeffrey

AU - Teerlink, Craig C.

AU - Tavana, Justina P.

AU - Cloward, Matthew

AU - Page, Madeline

AU - Dayton, Louisa

AU - Cannon-Albright, Lisa A.

AU - Kauwe, John S.K.

N1 - Funding Information: We thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute , University of Utah and from the University of Utah 's program in Personalized Health and Center for Clinical and Translational Science . Funding Information: We appreciate the contributions of Brigham Young University in supporting this research. This research is supported by RF1AG054052 (PI: Kauwe) and U01AG052411 (PI: Goate). We thank the Pedigree and Population Resource of Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah's program in Personalized Health and Center for Clinical and Translational Science. The authors would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL?103010). Alzheimer's Disease Genetics Consortium (ADGC), Data from ADGC was appropriately downloaded from dbGaP (accession: phs000372.v1.p1). We acknowledge the contributions of The members of the Alzheimer's Disease Genetics Consortium are: Marilyn S. Albert1, Roger L. Albin2-4, Liana G. Apostolova5, Steven E. Arnold6, Clinton T. Baldwin7, Robert Barber8, Michael M. Barmada9, Lisa L. Barnes10, 11, Thomas G. Beach12, Gary W. Beecham13, 14, Duane Beekly15, David A. Bennett10, 16, Eileen H. Bigio17, Thomas D. Bird18, Deborah Blacker19,20, Bradley F. Boeve21, James D. Bowen22, Adam Boxer23, James R. Burke24, Joseph D. Buxbaum25, 26, 27, Nigel J. Cairns28, Laura B. Cantwell29, Chuanhai Cao30, Chris S. Carlson31, Regina M. Carney13, Minerva M. Carrasquillo33, Steven L. Carroll34, Helena C. Chui35, David G. Clark36, Jason Corneveaux37, Paul K. Crane38, David H. Cribbs39, Elizabeth A. Crocco40, Carlos Cruchaga41, Philip L. De Jager42,43, Charles DeCarli44, Steven T. DeKosky45, F. Yesim Demirci9, Malcolm Dick46, Dennis W. Dickson33, Ranjan Duara47, Nilufer Ertekin-Taner33,48, Denis Evans49, Kelley M. Faber50, Kenneth B. Fallon34, Martin R. Farlow51, Lindsay A Farrer7,52,76,77,83, Steven Ferris53, Tatiana M. Foroud50, Matthew P. Frosch54, Douglas R. Galasko55, Mary Ganguli56, Marla Gearing57,58, Daniel H. Geschwind59, Bernardino Ghetti60, John R. Gilbert13,14, Sid Gilman2, Jonathan D. Glass61, Alison M. Goate41, Neill R. Graff-Radford33,48, Robert C. Green62, John H. Growdon63, Jonathan L. Haines64, 65, Hakon Hakonarson66, Kara L. Hamilton-Nelson13, Ronald L. Hamilton67, John Hardy68, Lindy E. Harrell36, Elizabeth Head69, Lawrence S. Honig70, Matthew J. Huentelman37, Christine M. Hulette71, Bradley T. Hyman63, Gail P. Jarvik72,73, Gregory A. Jicha74, Lee-Way Jin75, Gyungah Jun7,76,77, M. Ilyas Kamboh9,78, Anna Karydas23, John S.K. Kauwe79, Jeffrey A. Kaye80,81, Ronald Kim82, Edward H. Koo55, Neil W. Kowall83,84, Joel H. Kramer85, Patricia Kramer80,86, Walter A. Kukull87, Frank M. LaFerla88, James J. Lah61, Eric B. Larson38,89, James B. Leverenz90, Allan I. Levey61, Ge Li91, Andrew P. Lieberman92, Chiao-Feng Lin29, Oscar L. Lopez78, Kathryn L. Lunetta76, Constantine G. Lyketsos93, Wendy J. Mack94, Daniel C. Marson36, Eden R. Martin13,14, Frank Martiniuk95, Deborah C. Mash96, Eliezer Masliah55,97, Richard Mayeux70, 109, 110, Wayne C. McCormick38, Susan M. McCurry98, Andrew N. McDavid31, Ann C. McKee83,84, Marsel Mesulam99, Bruce L. Miller23, Carol A. Miller100, Joshua W. Miller75, Thomas J. Montine90, John C. Morris28, 101, Jill R. Murrell50, 60, Amanda J. Myers40, Adam C. Naj13, John M. Olichney44, Vernon S. Pankratz102, Joseph E. Parisi103,104, Margaret A. Pericak-Vance13, 14, Elaine Peskind91, Ronald C. Petersen21, Aimee Pierce39, Wayne W. Poon46, Huntington Potter30, Joseph F. Quinn80, Ashok Raj30, Murray Raskind91, Eric M. Reiman37,105-107, Barry Reisberg53,108, Christiane Reitz70,109,110, John M. Ringman5, Erik D. Roberson36, Ekaterina Rogaeva111, Howard J. Rosen23, Roger N. Rosenberg112, Mary Sano26, Andrew J. Saykin50,113, Gerard D. Schellenberg29, Julie A. Schneider10,114, Lon S. Schneider35,115, William W. Seeley23, Amanda G. Smith30, Joshua A. Sonnen90, Salvatore Spina60, Peter St George-Hyslop111,116, Robert A. Stern83, Rudolph E. Tanzi63, John Q. Trojanowski29, Juan C. Troncoso117, Debby W. Tsuang91, Otto Valladares29, Vivianna M. Van Deerlin29, Linda J. Van Eldik118, Badri N. Vardarajan7, Harry V. Vinters5,119, Jean Paul Vonsattel120, Li-San Wang29, Sandra Weintraub99, Kathleen A. Welsh-Bohmer24, 121, Jennifer Williamson70, Randall L. Woltjer122, Clinton B. Wright123, Steven G. Younkin33, Chang-En Yu38, Lei Yu10. 1Department of Neurology, Johns Hopkins University, Baltimore, Maryland, 2Department of Neurology, University of Michigan, Ann Arbor, Michigan, 3Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan, 4Michigan Alzheimer's disease Center, Ann Arbor, Michigan, 5Department of Neurology, University of California Los Angeles, Los Angeles, California, 6Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 7Department of Medicine (Genetics Program), Boston University, Boston, Massachusetts, 8Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, 9Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, 10Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, 11Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, 12Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona, 13The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, 14Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, 15National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, 16Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, 17Department of Pathology, Northwestern University, Chicago, Illinois, 18Department of Neurology, University of Washington, Seattle, Washington, 19Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, 20Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 21Department of Neurology, Mayo Clinic, Rochester, Minnesota, 22Swedish Medical Center, Seattle, Washington, 23Department of Neurology, University of California San Francisco, San Francisco, California, 24Department of Medicine, Duke University, Durham, North Carolina, 25Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, 26Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, 27Departments of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, 28Department of Pathology and Immunology, Washington University, St. Louis, Missouri, 29Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 30USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, 31Fred Hutchinson Cancer Research Center, Seattle, Washington, 32Department of Psychiatry, Vanderbilt University, Nashville, Tennessee, 33Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, 34Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, 35Department of Neurology, University of Southern California, Los Angeles, California, 36Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, 37Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, 38Department of Medicine, University of Washington, Seattle, Washington, 39Department of Neurology, University of California Irvine, Irvine, California, 40Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida, 41Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, Missouri, 42Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology & Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 43Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, 44Department of Neurology, University of California Davis, Sacramento, California, 45University of Virginia School of Medicine, Charlottesville, Virginia, 46Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California, 47Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida, 48Department of Neurology, Mayo Clinic, Jacksonville, Florida, 49Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, 50Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, 51Department of Neurology, Indiana University, Indianapolis, Indiana, 52Department of Epidemiology, Boston University, Boston, Massachusetts, 53Department of Psychiatry, New York University, New York, New York, 54C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, Massachusetts, 55Department of Neurosciences, University of California San Diego, La Jolla, California, 56Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 57Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, 58Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia, 59Neurogenetics Program, University of California Los Angeles, Los Angeles, California, 60Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana, 61Department of Neurology, Emory University, Atlanta, Georgia, 62Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, 63Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, 64Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, 65Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, 66Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 67Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania, 68Institute of Neurology, University College London, Queen Square, London, 69Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky, 70Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York, 71Department of Pathology, Duke University, Durham, North Carolina, 72Department of Genome Sciences, University of Washington, Seattle, Washington, 73Department of Medicine (Medical Genetics), University of Washington, Seattle, Washington, 74Sanders-Brown Center on Aging, Department Neurology, University of Kentucky, Lexington, Kentucky, 75Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, California, 76Department of Biostatistics, Boston University, Boston, Massachusetts, 77Department of Ophthalmology, Boston University, Boston, Massachusetts, 78University of Pittsburgh Alzheimer's Disease Research Center, Pittsburgh, Pennsylvania, 79Department of Biology, Brigham Young University, Provo, Utah, 80Department of Neurology, Oregon Health & Science University, Portland, Oregon, 81Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon, 82Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, 83Department of Neurology, Boston University, Boston, Massachusetts, 84Department of Pathology, Boston University, Boston, Massachusetts, 85Department of Neuropsychology, University of California San Francisco, San Francisco, California, 86Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, Oregon, 87Department of Epidemiology, University of Washington, Seattle, Washington, 88Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, 89Group Health Research Institute, Group Health, Seattle, Washington, 90Department of Pathology, University of Washington, Seattle, Washington, 91Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, 92Department of Pathology, University of Michigan, Ann Arbor, Michigan, 93Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland, 94Department of Preventive Medicine, University of Southern California, Los Angeles, California, 95Department of Medicine - Pulmonary, New York University, New York, New York, 96Department of Neurology, University of Miami, Miami, Florida, 97Department of Pathology, University of California San Diego, La Jolla, California, 98School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, Washington, 99Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois, 100Department of Pathology, University of Southern California, Los Angeles, California, 101Department of Neurology, Washington University, St. Louis, Missouri, 102Department of Biostatistics, Mayo Clinic, Rochester, Minnesota, 103Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota, 104Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, 105Arizona Alzheimer's Consortium, Phoenix, Arizona, 106Department of Psychiatry, University of Arizona, Phoenix, Arizona, 107Banner Alzheimer's Institute, Phoenix, Arizona, 108Alzheimer's Disease Center, New York University, New York, New York, 109Gertrude H. Sergievsky Center, Columbia University, New York, New York, 110Department of Neurology, Columbia University, New York, New York, 111Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, 112Department of Neurology, University of Texas Southwestern, Dallas, Texas, 113Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, Indiana, 114Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, Illinois, 115Department of Psychiatry, University of Southern California, Los Angeles, California, 116Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, 117Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 118Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, 119Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles, California, 120Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York, 121Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina, 122Department of Pathology, Oregon Health & Science University, Portland, Oregon, 123Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida. Funding Information: We appreciate the contributions of Brigham Young University in supporting this research. This research is supported by RF1AG054052 (PI: Kauwe) and U01AG052411 (PI: Goate). Publisher Copyright: © 2020

PY - 2020/9

Y1 - 2020/9

N2 - Background: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). Methods: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives. Results: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values =.001 and.0001, respectively). Discussion: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.

AB - Background: Longevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB). Methods: From an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives. Results: Fifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values =.001 and.0001, respectively). Discussion: This unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation.

KW - Genomics

KW - Longevity

KW - Pedigree

KW - Rare variant sharing

KW - Utah population database

UR - http://www.scopus.com/inward/record.url?scp=85086838889&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85086838889&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2020.104972

DO - 10.1016/j.nbd.2020.104972

M3 - Review article

C2 - 32574725

AN - SCOPUS:85086838889

VL - 143

M1 - 104972

ER -

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants

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