Genetic associations with dementia-related proteinopathy: Application of item response theory

doi:10.1002/alz.13741

Genetic associations with dementia-related proteinopathy: Application of item response theory

,

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

Original language	English
Pages (from-to)	2906-2921
Number of pages	16
Journal	Alzheimer's and Dementia
Volume	20
Issue number	4
DOIs	https://doi.org/10.1002/alz.13741
State	Published - Apr 2024

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Funding

The Alzheimer's Disease Sequencing Project (ADSP) is comprised of two Alzheimer's Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC).The two AD genetics consortia are the Alzheimer's Disease Genetics Consortium(ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non‐governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak‐Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate, U01AG052410 to Dr. Pericak‐Vance and U01 AG052409 to Drs. Seshadri and Fornage. Sequencing for the Follow Up Study (FUS) is supported through U01AG057659 (to Drs. PericakVance, Mayeux, and Vardarajan) and U01AG062943 (to Drs. Pericak‐Vance and Mayeux). Data generation and harmonization in the Follow‐up Phase is supported by U54AG052427 (to Drs. Schellenberg and Wang). The FUS Phase analysis of sequence data is supported through U01AG058589 (to Drs. Destefano, Boerwinkle, De Jager, Fornage, Seshadri, and Wijsman), U01AG058654 (to Drs. Haines, Bush, Farrer, Martin, and Pericak‐Vance), U01AG058635 (to Dr. Goate), RF1AG058066 (to Drs. Haines, Pericak‐Vance, and Scott), RF1AG057519 (to Drs. Farrer and Jun), R01AG048927 (to Dr. Farrer), and RF1AG054074 (to Drs. Pericak‐Vance and Beecham). The ADGCcohorts include: Adult Changes in Thought (ACT) (UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657), the Alzheimer's Disease Centers (ADC) ( P30AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, and P50 AG047270), the Chicago Health and Aging Project (CHAP) (R01 AG11101, RC4 AG039085, K23 AG030944), Indianapolis Ibadan (R01 AG009956, P30 AG010133), the Memory and Aging Project (MAP) ( R01 AG17917), Mayo Clinic (MAYO) (R01 AG032990, U01 AG046139, R01 NS080820, RF1 AG051504, P50 AG016574), Mayo Parkinson's Disease controls (NS039764, NS071674, 5RC2HG005605), University of Miami (R01 AG027944, R01 AG028786, R01 AG019085, IIRG09133827, A2011048), the Multi‐Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE) (R01 AG09029, R01 AG025259), the National Cell Repository for Alzheimer's Disease (NCRAD) (U24 AG21886), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA‐ LOAD) (R01 AG041797), the Religious Orders Study (ROS) (P30 AG10161, R01 AG15819), the Texas Alzheimer's Research and Care Consortium (TARCC) (funded by the Darrell K Royal Texas Alzheimer's Initiative), Vanderbilt University/Case Western Reserve University (VAN/CWRU)(R01 AG019757, R01 AG021547, R01 AG027944, R01 AG028786, P01 NS026630, and Alzheimer's Association), the Washington Heights‐Inwood Columbia Aging Project (WHICAP) (RF1 AG054023), the University of Washington Families (VA Research Merit Grant, NIA: P50AG005136, R01AG041797, NINDS: R01NS069719), the Columbia University HispanicEstudio Familiar de Influencia Genetica de Alzheimer (EFIGA) (RF1 AG015473), the University of Toronto (UT) (funded by Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research), and Genetic Differences (GD) (R01 AG007584). The CHARGE cohorts are supported in part by National Heart, Lung, and Blood Institute (NHLBI) infrastructure grant HL105756 (Psaty), RC2HL102419 (Boerwinkle) and the neurology working group is supported by the National Institute on Aging (NIA) R01 grant AG033193. The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS‐Family study, and the Prospective Dementia Registry‐Austria (ASPS/PRODEM‐Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fond (FWF) grant number P20545‐P05 and P13180 and the Medical University of Graz. The ASPS‐Fam is funded by the Austrian Science Fund (FWF) project I904), the EU Joint Programme‐Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM‐Austria is supported by the Austrian Research Promotion agency (FFG) (Project No. 827462) and by the Austrian National Bank (Anniversary Fund, project 15435). ARIC research is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC is collected by U012U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD), and with previous brain MRI examinations funded by R01‐HL70825 from the NHLBI. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the NIA. FHS research is supported by NHLBI contracts N01‐HC‐25195 and HHSN268201500001I. This study was also supported by additional grants from the NIA (R01s AG054076, AG049607 and AG033040 and NINDS (R01 NS017950). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG‐CT‐2006‐01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007‐2013)/grant agreement HEALTH‐F4‐2007‐201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2‐CT‐2002‐01254). High‐throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO‐RFBR047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911‐03‐012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014‐93‐015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project 050‐060‐810. All studies are grateful to their participants, faculty and staff. The content of these manuscripts is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. Department of Health and Human Services. This work was supported by grants the National Institute on Aging RF1AG082339, R01AG082730, R01AG057187, U24AG07122, P01AG078116, the UK‐ADC P30AG072946, the National Institute of Neurological Disorders and Stroke F30NS124136, and the NACC New Investigator Award (https://naccdata.org/nacc‐productivity/new‐investigator‐awards) which are awarded each year to promising early‐career investigators from across the ADRC Program to support their career development and advance their research on Alzheimer's Disease Related Dementia (ADRD). The National Institutes of Health, National Institute on Aging (NIH‐NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions, and at the National Cell Repository Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA funded Alzheimer's Disease Centers (ADCs), and the National Alzheimer's Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations. The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA‐funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI FrankLaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PIEric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI AllanLevey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD). Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24‐AG041689‐01), funded by the National Institute on Aging.

Funders	Funder number
Columbia University HispanicEstudio Familiar de Influencia Genetica de Alzheimer
Alzheimer's Association
Texas Alzheimer's Research and Care Consortium
Medizinische Universität Graz
UK Medical Research Council, Engineering and Physical Sciences Research Council
NIA/NIH
Erasmus Universiteit Rotterdam
Ministry of Science, ICT and Future Planning
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Membership of the Alzheimer's Disease Genetics Consortium is provided in the Acknowledgments
Toronto Western Hospital University of Toronto
University of Utah Gastroenterology Division in the Department of Internal Medicine
Research Institute for Diseases in the Elderly
EU Joint Programme – Neurodegenerative Disease Research
VAN
Ministerie van Volksgezondheid, Welzijn en Sport
Steiermärkische Krankenanstalten Gesellschaft
University of Washington Families
ZonMw Memorabel
U.S. National Library of Medicine
Darrell K Royal Texas Alzheimer's Initiative
RIDE2
EUROSPAN
Ministerie van Onderwijs, Cultuur en Wetenschap
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center
Sociale en Geesteswetenschappen, NWO
Alzheimer's Disease Related Dementia
National Cell Repository for Alzheimer's Disease	U24 AG21886
Austrian Science Fund/FWF	I 904, P20545‐P05, P13180, P 20545
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01AG20098, R01AG023629, AG033040, AG049607, R01NS069719, R01 NS017950, R01s AG054076, N01‐HC‐25195, R01AG15928, F30NS124136
U.S. Department of Veterans Affairs	R01 AG041797, P50 AG005136
Canadian Institutes of Health Research	RC2HL102419, R01 AG007584, HL105756
Not added	201413
National Institutes of Health (NIH)	UO1 AG006781, UO1 HG006375, U24 AG072122, UO1 HG004610, U01 HG008657
National Heart, Lung, and Blood Institute (NHLBI)	2U01HL096899, 2U01HL096902, 2U01HL096814, 2U01HL096917, U012U01HL096812
Seventh Framework Programme	340755, HEALTH‐F4‐2007‐201413
Cohorts for Heart and Aging Research in Genomic	R01 AG033193
National Alzheimer's Coordinating Center	U01AG016976
National Institute on Aging	R01AG057187, U24AG07122, AG033193, R01AG082730, RF1AG082339, P01AG078116
EFIGA	RF1 AG015473
ADGC	RC2 AG036528, U01 AG032984
Miami Clinical and Translational Science Institute, University of Miami	A2011048, IIRG09133827, R01 AG019085, R01 AG027944, R01 AG09029, R01 AG025259, R01 AG028786
Mayo Clinic Rochester	5RC2HG005605, NS039764, NS071674, R01 NS080820, U01 AG046139, RF1 AG051504, R01 AG032990
Russian Foundation for Basic Research	NWO‐RFBR047.017.043
National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site	U24AG041689
Netherlands Organization of Scientific Research NWO	175.010.2005.011, 911‐03‐012
Sixth Framework Programme	018947, LSHG‐CT‐2006‐01947
National Institute on Deafness and Other Communication Disorders	U01HL080295, N01HC85081, N01HC85082, HHSN268201100006C, N01HC85080, N01HC85086, N01HC85083, N01HC85079, HHSN268200800007C, R01‐HL70825, U01HL130114, N01HC55222
Quality of Life and Management of the Living Resources” of 5th Framework Programme	QLG2‐CT‐2002‐01254
National Institute on Aging Late Onset Alzheimer's Disease Family Study	R01 AG15819, P30 AG10161
Netherlands Consortium for Healthy Aging	050‐060‐810
Washington Heights-Inwood Columbia Aging Project	RF1 AG054023
Erasmus Medisch Centrum	014‐93‐015
Case Western Reserve University	R01 AG021547, R01 AG019757, P01 NS026630
Chicago Health and Aging Project	R01 AG11101, R01 AG009956, R01 AG17917, RC4 AG039085, K23 AG030944
Not added	066133
Österreichische Forschungsförderungsgesellschaft	827462
Alzheimer's Disease Centers	P30 AG013846, P30 AG028383, P30 AG008017, P50 AG005146, P30 AG010133, P50 AG033514, P50 AG005681, P50 AG005142, P50 AG047366, P50 AG047266, P50 AG023501, P30 AG008051, P30 AG010129, P50 AG005138, P50 AG008702, P30 AG012300, P50 AG005134, P50 AG025688, P50 AG047270, P30 AG035982, P30 AG010161, P50 AG005131, P50 AG005133, P30AG013854, P30AG010124, P50 AG016574, P30AG019610, P50 AG016573, P50 AG016570
Oesterreichische Nationalbank	15435
UK-ADC	P30AG072946
The Pennsylvania State University	U24‐AG041689‐01

Keywords

ARHGEF28
Alzheimer's Coordinating Center
Alzheimer's Disease Neuroimaging Initiative
Alzheimer's Disease Sequencing Project
Alzheimer's disease neuropathologic changes (ADNC)
Item response theory
Lewy
RGNEF
Religious Orders Study
Rush Memory and Aging Project (MAP)
SDHAF1
TMEM68
neuropathology

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/alz.13741

Cite this

@article{9229d6c38a9240a08f90c023ffaf31e9,

title = "Genetic associations with dementia-related proteinopathy: Application of item response theory",

abstract = "INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.",

keywords = "ARHGEF28, Alzheimer's Coordinating Center, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Sequencing Project, Alzheimer's disease neuropathologic changes (ADNC), Item response theory, Lewy, RGNEF, Religious Orders Study, Rush Memory and Aging Project (MAP), SDHAF1, TMEM68, neuropathology",

author = "Yuriko Katsumata and Fardo, \{David W.\} and Shade, \{Lincoln M.P.\} and Xian Wu and Karanth, \{Shama D.\} and Hohman, \{Timothy J.\} and Schneider, \{Julie A.\} and Bennett, \{David A.\} and Farfel, \{Jose M.\} and Kathryn Gauthreaux and Charles Mock and Kukull, \{Walter A.\} and Abner, \{Erin L.\} and Nelson, \{Peter T.\} and Maria Carrillo and Reiman, \{Eric M.\} and Kewei Chen and Donna Masterman and Green, \{Robert C.\} and Carole Ho and Adam Fleisher and Saykin, \{Andrew J.\} and Kwangsik Nho and Apostolova, \{Liana G.\} and Risacher, \{Shannon L.\} and Jonathan Jackson and Arvin Forghanian-Arani and Bret Borowski and Chad Ward and Christopher Schwarz and Jack, \{Clifford R.\} and David Jones and Jeff Gunter and Kejal Kantarci and Matthew Senjem and Prashanthi Vemuri and Robert Reid and Ronald Petersen and Hsiao, \{John K.\} and William Potter and Eliezer Masliah and Hsiao, \{John K.\} and Laurie Ryan and Marie Bernard and Nina Silverberg and Adrienne Kormos and Cat Conti and Dallas Veitch and Derek Flenniken and Sacrey, \{Diana Truran\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = apr,

doi = "10.1002/alz.13741",

language = "English",

volume = "20",

pages = "2906--2921",

number = "4",

}

TY - JOUR

T1 - Genetic associations with dementia-related proteinopathy

T2 - Application of item response theory

AU - Katsumata, Yuriko

AU - Fardo, David W.

AU - Shade, Lincoln M.P.

AU - Wu, Xian

AU - Karanth, Shama D.

AU - Hohman, Timothy J.

AU - Schneider, Julie A.

AU - Bennett, David A.

AU - Farfel, Jose M.

AU - Gauthreaux, Kathryn

AU - Mock, Charles

AU - Kukull, Walter A.

AU - Abner, Erin L.

AU - Nelson, Peter T.

AU - Carrillo, Maria

AU - Reiman, Eric M.

AU - Chen, Kewei

AU - Masterman, Donna

AU - Green, Robert C.

AU - Ho, Carole

AU - Fleisher, Adam

AU - Saykin, Andrew J.

AU - Nho, Kwangsik

AU - Apostolova, Liana G.

AU - Risacher, Shannon L.

AU - Jackson, Jonathan

AU - Forghanian-Arani, Arvin

AU - Borowski, Bret

AU - Ward, Chad

AU - Schwarz, Christopher

AU - Jack, Clifford R.

AU - Jones, David

AU - Gunter, Jeff

AU - Kantarci, Kejal

AU - Senjem, Matthew

AU - Vemuri, Prashanthi

AU - Reid, Robert

AU - Petersen, Ronald

AU - Hsiao, John K.

AU - Potter, William

AU - Masliah, Eliezer

AU - Hsiao, John K.

AU - Ryan, Laurie

AU - Bernard, Marie

AU - Silverberg, Nina

AU - Kormos, Adrienne

AU - Conti, Cat

AU - Veitch, Dallas

AU - Flenniken, Derek

AU - Sacrey, Diana Truran

PY - 2024/4

Y1 - 2024/4

N2 - INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

AB - INTRODUCTION: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete. METHODS: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43. RESULTS: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility. DISCUSSION: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies. Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.

KW - ARHGEF28

KW - Alzheimer's Coordinating Center

KW - Alzheimer's Disease Neuroimaging Initiative

KW - Alzheimer's Disease Sequencing Project

KW - Alzheimer's disease neuropathologic changes (ADNC)

KW - Item response theory

KW - Lewy

KW - RGNEF

KW - Religious Orders Study

KW - Rush Memory and Aging Project (MAP)

KW - SDHAF1

KW - TMEM68

KW - neuropathology

UR - https://www.scopus.com/pages/publications/85187865746

UR - https://www.scopus.com/inward/citedby.url?scp=85187865746&partnerID=8YFLogxK

U2 - 10.1002/alz.13741

DO - 10.1002/alz.13741

M3 - Article

C2 - 38460116

AN - SCOPUS:85187865746

SN - 1552-5260

VL - 20

SP - 2906

EP - 2921

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 4

ER -

Genetic associations with dementia-related proteinopathy: Application of item response theory

Abstract

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UN SDGs

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Genetic associations with dementia-related proteinopathy: Application of item response theory

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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S'ORCe Collaborative Group (RENEWED)

Statistical ‘Omics Research Collaborative (S'ORCe)

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