GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia

Lincoln M P Shade; Yuriko Katsumata; Erin L Abner; Khine Zin Aung; Steven A Claas; Qi Qiao; Bernardo Aguzzoli Heberle; J Anthony Brandon; Madeline L Page; Timothy J Hohman; Shubhabrata Mukherjee; Richard P Mayeux; Lindsay A Farrer; Gerard D Schellenberg; Jonathan L Haines; Walter A Kukull; Kwangsik Nho; Andrew J Saykin; David A Bennett; Julie A Schneider; National Alzheimer’s Coordinating Center; Mark T W Ebbert; Peter T Nelson; David W Fardo

doi:10.1038/s41588-024-01939-9

GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia

Nat Genet. 2024 Nov;56(11):2407-2421. doi: 10.1038/s41588-024-01939-9. Epub 2024 Oct 8.

Authors

Lincoln M P Shade¹, Yuriko Katsumata^{1

2}, Erin L Abner^{2

3}, Khine Zin Aung^{1

2}, Steven A Claas¹, Qi Qiao^{1

2}, Bernardo Aguzzoli Heberle^{2

4}, J Anthony Brandon^{2

4}, Madeline L Page^{2

4}, Timothy J Hohman^{5

6}, Shubhabrata Mukherjee⁷, Richard P Mayeux⁸, Lindsay A Farrer^{9

10

11

12

13}, Gerard D Schellenberg^{14

15}, Jonathan L Haines^{16

17}, Walter A Kukull¹⁸, Kwangsik Nho^{19

20

21}, Andrew J Saykin^{20

22}, David A Bennett^{23

24}, Julie A Schneider^{23

24

25}; National Alzheimer’s Coordinating Center; Mark T W Ebbert^{2

4

26}, Peter T Nelson^{2

27}, David W Fardo^{28

29}

Collaborators

National Alzheimer’s Coordinating Center:
Walter A Kukull, Andrew J Saykin, David A Bennett, Erin L Abner, Subhabrata Mukherjee, Richard P Mayeux, Lindsay A Farrer, Gerard D Schellenberg, Jonathan L Haines, David A Bennett, Julie A Schneider

Affiliations

¹ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
² Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, University of Kentucky, Lexington, KY, USA.
³ Department of Epidemiology and Environmental Health, College of Public Health, University of Kentucky, Lexington, KY, USA.
⁴ Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA.
⁵ Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷ Department of Medicine, University of Washington, Seattle, WA, USA.
⁸ Department of Neurology, Columbia University, New York City, NY, USA.
⁹ Department of Medicine (Biomedical Genetics), Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
¹⁰ Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
¹¹ Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
¹² Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
¹³ Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA.
¹⁴ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁵ Penn Neurodegeneration Genomics Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁶ Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
¹⁷ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
¹⁸ National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁹ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
²⁰ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
²¹ Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
²² Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
²³ Department of Neurological Sciences, Rush Medical College, Chicago, IL, USA.
²⁴ Rush Alzheimer's Disease Center, Rush Medical College, Chicago, IL, USA.
²⁵ Department of Pathology, Rush Medical College, Chicago, IL, USA.
²⁶ Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
²⁷ Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
²⁸ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA. david.fardo@uky.edu.
²⁹ Sanders-Brown Center on Aging and Alzheimer's Disease Research Center, University of Kentucky, Lexington, KY, USA. david.fardo@uky.edu.

Abstract

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Dementia* / genetics
Dementia* / pathology
Endophenotypes*
Female
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Male
Neuropathology
Polymorphism, Single Nucleotide
Quantitative Trait Loci*
Risk Factors

Abstract

MeSH terms

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