GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia- Shade et al. 2024

Description

Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated loci. However, the clinical outcomes used in most prior studies belie the complex nature of underlying neuropathologies. Here, we performed GWAS on eleven ADRD-related neuropathology endophenotypes with participants drawn from three sources.

National Alzheimer’s Coordinating Center (NACC), Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP), and Adult Changes in Thought (ACT; n =7,804 total autopsied participants across all four studies). Deceased patients with genotype and brain autopsy data available were included. Patients of predominantly non-European ancestry were excluded due to small sample sizes. In NACC, patients with rare brain pathologies such as traumatic brain injuries or brain cancers were excluded.

NACC draws participants from over 30 Alzheimer’s Disease Research Centers (ADRC) across the United States. Each ADRC has its own inclusion/exclusion and recruitment criteria, but their participants are typically drawn from clinical or local eldery community populations. ROS recruits elderly brothers and sisters in the Catholic Church, while MAP recruits elderly participants from the greater Chicago area. ACT recruits participants without dementia from the greater Seattle area without dementia at time of enrollment.

Included neuropathology endophenotypes are neuritic plaques, tau neurofibrillary tangles, cerebral amyloid angiography, amyloid-beta plaques, TDP-43 deposits, Lewy body deposits, cerebral atherosclerosis, cerebral arteriolosclerosis, gross infarcts, microinfarcts, and hippocampal sclerosis.

GWAS of neuropathology endophenotypes will confirm known ADRD risk loci and identify novel neuropathology risk loci.

We identified eight independent significantly associated loci of which four were novel (COL4A1, PIK3R5, LZTS1, APOC2). Testing the remaining known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false discovery rate adjustment.

Principal Investigators

David W Fardo — University of Kentucky
Peter T Nelson — University of Kentucky
Shubhabrata Mukherjee — University of Washington
Linda Van Eldik — University of Kentucky

Funding Sources

This study was funded by RF1AG082339, R01AG082730, and P30AG072946.

Publications

Shade LMP. GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia. Nature genetics. 2024 Nov. PubMed link

Acknowledgment statement for any data distributed by NIAGADS:

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), funded by the National Institute on Aging.

For investigators using GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia- Shade et al. 2024 data:

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: RF1AG082339 (to Yuriko Katsumata, Steven A Claas, Mark TW Ebbert, Peter T Nelson, and David W Fardo), R56AG057191 (to Yuriko Katsumata, Steven A Claas, and David W Fardo), F30NS124136 (to Lincoln MP Shade), P30 AG028383 (to Peter T Nelson), R35GM138636 (to Bernardo Aguzzoli Heberle, J Antony Brandon, Madeline L Page, and Mark TW Ebbert), R01AG068331 (to Bernardo Aguzzoli Heberle, J Antony Brandon, Madeline L Page, and Mark TW Ebbert), U01AG058654 (to Jonathan L Haines), P01AG078116 (to Yuriko Katsumata and Khine Zin Aung), R01AG082730 (to David W Fardo), R01LM012535 (to Kwangsik Nho), U19AG024904 (to Andrew J Saykin), U01AG068057 (to Andrew J Saykin), U01AG072177 (to Andrew J Saykin), U19AG074879 (to Kwangsik Nho and Andrew J Saykin), U24AG072122 (to Walter A Kukull), P30AG072976 (to Andrew J Saykin), the BrightFocus Foundation (A2020161S to Mark TW Ebbert), Alzheimer’s Association (2019-AARG-644082 to Mark TW Ebbert), the University of Kentucky Center for Clinical and Translational Science TL-1 Fellowship (TL1TR0019970), the National Center for Advancing Translational Sciences (UL1TR001998) and the Dean of the College of Medicine, University of Kentucky. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH), the University of Kentucky or other participating institutions. The NACC database is funded by NIA/NIH under grant U01AG016976. NACC data are contributed by the NIA-funded ADCs—P30 AG019610 (E Reiman), P30 AG013846 (N Kowall), P50 AG008702 (S Small), P50 AG025688 (A Levey), P50 AG047266 (T Golde), P30 AG010133 (A Saykin), P50 AG005146 (M Albert), P50 AG005134 (B Hyman), P50 AG016574 (R Petersen), P50 AG005138 (M Sano), P30 AG008051 (T Wisniewski), P30 AG013854 (R Vassar), P30 AG008017 (J Kaye), P30 AG010161 (D Bennett), P50 AG047366 (V Henderson), P30 AG010129 (C DeCarli), P50 AG016573 (F LaFerla), P50 AG005131 (J Brewer), P50 AG023501 (B Miller), P30 AG035982 (R Swerdlow), P30 AG028383 (L Van Eldik), P30 AG053760 (H Paulson), P30 AG010124 (J Trojanowski), P50 AG005133 (O Lopez), P50 AG005142 (H Chui), P30 AG012300 (R Rosenberg), P30 AG049638 (S Craft), P50 AG005136 (T Grabowski), P50 AG033514 (S Asthana), P50 AG005681 (J Morris) and P50 AG047270 (S Strittmatter). The results published here are in part based on data obtained from the AD Knowledge Portal. Genotyping was supported by the ADGC through the National Institute of Aging (U01AG032984 and RC2AG036528). Samples from the National Cell Repository for Alzheimer’s Disease, which receives government support under a cooperative agreement grant (U24AG21886) awarded by the NIA, were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families whose help and participation made this work possible. 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 (U24AG041689-01). We thank the study participants and staff of the Rush Alzheimer’s Disease Center. The ROS and the Rush MAP are supported by grants from the NIH (P30AG10161, P30AG72975, R01AG15819, R01AG17917, R01AG22018, R01AG33678, R01AG34374, R01AG36042, R01AG40039, R01AG042210, U01AG46152, U01AG61356, R01AG47976, R01AG43379, RF1AG54057, R01AG56352, R01NS78009 and UH2NS100599) and the Illinois Department of Public Health. The ACT study was funded by the NIA (U19AG066567). Data collection for this work was additionally supported, in part, by previous funding from the NIA (U01AG006781). All statements in this report, including its findings and conclusions, are solely those of the authors and do not necessarily represent the views of the NIA or the NIH. We thank the participants of the ACT study for the data they have provided and the many ACT investigators and staff who steward that data. You can learn more about ACT at https:// actagingstudy.org/.