Sex differences in the genetic predictors of Alzheimer's pathology

Logan Dumitrescu; Lisa L Barnes; Madhav Thambisetty; Gary Beecham; Brian Kunkle; William S Bush; Katherine A Gifford; Lori B Chibnik; Shubhabrata Mukherjee; Philip L De Jager; Walter Kukull; Paul K Crane; Susan M Resnick; C Dirk Keene; Thomas J Montine; Gerard D Schellenberg; Yuetiva Deming; Michael J Chao; Matt Huentelman; Eden R Martin; Kara Hamilton-Nelson; Leslie M Shaw; John Q Trojanowski; Elaine R Peskind; Carlos Cruchaga; Margaret A Pericak-Vance; Alison M Goate; Nancy J Cox; Jonathan L Haines; Henrik Zetterberg; Kaj Blennow; Eric B Larson; Sterling C Johnson; Marilyn Albert; David A Bennett; Julie A Schneider; Angela L Jefferson; Timothy J Hohman

doi:10.1093/brain/awz206

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Sex differences in the genetic predictors of Alzheimer's pathology

Journal article

Open access

Peer reviewed

Sex differences in the genetic predictors of Alzheimer's pathology

Logan Dumitrescu, Lisa L Barnes, Madhav Thambisetty, Gary Beecham, Brian Kunkle, William S Bush, Katherine A Gifford, Lori B Chibnik, Shubhabrata Mukherjee, Philip L De Jager, …

Brain (London, England : 1878), Vol.142(9), pp.2581-2589

2019-09-01

DOI: https://doi.org/10.1093/brain/awz206

PMID: 31497858

Abstract

Genetic Predisposition to Disease - genetics

Humans

Male

Sex Characteristics

Alzheimer Disease - diagnosis

tau Proteins - genetics

Amyloid beta-Peptides - genetics

Aged, 80 and over

Polymorphism, Single Nucleotide - genetics

Alzheimer Disease - epidemiology

Female

Aged

Alzheimer Disease - genetics

Genetic Predisposition to Disease - epidemiology

Genome-Wide Association Study - methods

Cohort Studies

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.60 Dementia
Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: Sex differences in the genetic predictors of Alzheimer's pathology
Creators: Logan Dumitrescu - Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Lisa L Barnes - Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
Madhav Thambisetty - Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
Gary Beecham - John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA
Brian Kunkle - John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA
William S Bush - Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
Katherine A Gifford - Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA
Lori B Chibnik - Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
Shubhabrata Mukherjee - Department of Medicine, University of Washington, Seattle, WA, USA
Philip L De Jager - Cell Circuits Program, Broad Institute, Cambridge MA, USA
Walter Kukull - Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
Paul K Crane - Department of Medicine, University of Washington, Seattle, WA, USA
Susan M Resnick - Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
C Dirk Keene - Department of Pathology, University of Washington, Seattle, WA, USA
Thomas J Montine - Department of Pathology, Stanford University, Stanford, CA, USA
Gerard D Schellenberg - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Yuetiva Deming - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Michael J Chao - Ronald M Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Matt Huentelman - Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
Eden R Martin - John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA
Kara Hamilton-Nelson - John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA
Leslie M Shaw - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
John Q Trojanowski - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Elaine R Peskind - Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
Carlos Cruchaga - Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
Margaret A Pericak-Vance - John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA
Alison M Goate - Ronald M Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Nancy J Cox - Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Jonathan L Haines - Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
Henrik Zetterberg - UK Dementia Research Institute at UCL, London, UK
Kaj Blennow - Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
Eric B Larson - Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
Sterling C Johnson - Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Marilyn Albert - Department of Neurology, the Johns Hopkins University School of Medicine, Baltimore, MD
David A Bennett - Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
Julie A Schneider - Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
Angela L Jefferson - Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA
Timothy J Hohman - Vanderbilt Genetics Institute, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Publication Details: Brain (London, England : 1878), Vol.142(9), pp.2581-2589
Publisher: England
Grant note: P30 AG062421 / NIA NIH HHS P50 AG005131 / NIA NIH HHS U01 AG049505 / NIA NIH HHS R01 AG030146 / NIA NIH HHS P30 AG019610 / NIA NIH HHS T32 AG000213 / NIA NIH HHS UL1 TR000445 / NCATS NIH HHS P50 AG005136 / NIA NIH HHS P50 AG008702 / NIA NIH HHS RF1 AG058501 / NIA NIH HHS T32 MH014677 / NIMH NIH HHS P50 AG005681 / NIA NIH HHS U54 HD083211 / NICHD NIH HHS RF1 AG027161 / NIA NIH HHS P30 AG008017 / NIA NIH HHS R01 AG019085 / NIA NIH HHS R01 AG056534 / NIA NIH HHS U01 HG006375 / NHGRI NIH HHS U01 AG058654 / NIA NIH HHS K25 AG055620 / NIA NIH HHS P50 AG005146 / NIA NIH HHS UH3 NS100605 / NINDS NIH HHS P50 AG016573 / NIA NIH HHS R01 AG027161 / NIA NIH HHS R01 NS100980 / NINDS NIH HHS P50 AG016570 / NIA NIH HHS U01 HG004610 / NHGRI NIH HHS P50 AG005134 / NIA NIH HHS P50 AG033514 / NIA NIH HHS R01 AG021155 / NIA NIH HHS R01 HL111516 / NHLBI NIH HHS P30 AG010161 / NIA NIH HHS K12 HD043483 / NICHD NIH HHS P30 AG013854 / NIA NIH HHS U24 AG041689 / NIA NIH HHS TL1 TR000447 / NCATS NIH HHS R01 AG054076 / NIA NIH HHS R01 AG015819 / NIA NIH HHS RF1 AG057519 / NIA NIH HHS R01 AG059716 / NIA NIH HHS RF1 AG053303 / NIA NIH HHS R01 AG048015 / NIA NIH HHS U01 AG046152 / NIA NIH HHS RF1 AG015819 / NIA NIH HHS R21 AG059941 / NIA NIH HHS R01 AG044546 / NIA NIH HHS P30 AG012300 / NIA NIH HHS P30 AG010129 / NIA NIH HHS P30 AG066507 / NIA NIH HHS P30 AG062715 / NIA NIH HHS P30 AG010133 / NIA NIH HHS P50 AG005133 / NIA NIH HHS P50 AG005142 / NIA NIH HHS P50 AG025688 / NIA NIH HHS U24 AG056270 / NIA NIH HHS R01 AG034962 / NIA NIH HHS P01 AG003991 / NIA NIH HHS S10 OD023680 / NIH HHS P30 AG010124 / NIA NIH HHS U24 AG021886 / NIA NIH HHS R01 AG017917 / NIA NIH HHS P30 AG013846 / NIA NIH HHS KL2 TR000446 / NCATS NIH HHS P50 AG005138 / NIA NIH HHS P30 AG008051 / NIA NIH HHS U01 AG032984 / NIA NIH HHS K01 AG049164 / NIA NIH HHS R01 NS085419 / NINDS NIH HHS P50 AG016574 / NIA NIH HHS U01 AG006781 / NIA NIH HHS R01 AG035083 / NIA NIH HHS P30 AG035982 / NIA NIH HHS R01 AG037639 / NIA NIH HHS
Academic Unit: Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 31497858
Record Identifier: 991031578462302976