Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups

Yiyi Ma^{1

2

3}, Dolly Reyes-Dumeyer^{1

2

3}, Angel Piriz¹, Patricia Recio⁴, Diones Rivera Mejia^{4

5}, Martin Medrano⁶, Rafael A Lantigua^{1

7}, Jean Paul G Vonsattel^{1

8}, Giuseppe Tosto^{1

2}, Andrew F Teich^{1

3

8}, Benjamin Ciener^{1

3

8}, Sandra Leskinen^{1

3

8}, Sharanya Sivakumar^{1

3

8}, Michael DeTure⁹, Duara Ranjan⁹, Dennis Dickson⁹, Melissa Murray⁹, Edward Lee¹⁰, David A Wolk¹⁰, Lee-Way Jin¹¹, Brittany N Dugger¹¹, Annie Hiniker¹², Robert A Rissman¹², Richard Mayeux^#^{13

14

15}, Badri N Vardarajan^#^{16

17

18}

Affiliations

¹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
² G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
³ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, 630 West 168th street, New York, NY, 10032, USA.
⁴ CEDIMAT, Santo Domingo, Dominican Republic.
⁵ Universidad Pedro Henríquez Urena, Santo Domingo, Dominican Republic.
⁶ Pontíficia Universidad Católica Madre y Maestra (PUCMM), Santiago, Dominican Republic.
⁷ Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, New York, NY, USA.
⁸ Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁹ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
¹⁰ Department of Neurology and Penn Alzheimer's Disease Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Pathology and Laboratory Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
¹² Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
¹³ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. rpm2@cumc.columbia.edu.
¹⁴ G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. rpm2@cumc.columbia.edu.
¹⁵ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, 630 West 168th street, New York, NY, 10032, USA. rpm2@cumc.columbia.edu.
¹⁶ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. bnv2103@cumc.columbia.edu.
¹⁷ G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. bnv2103@cumc.columbia.edu.
¹⁸ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, 630 West 168th street, New York, NY, 10032, USA. bnv2103@cumc.columbia.edu.

^# Contributed equally.

PMID: 39177846
PMCID: PMC11343944
DOI: 10.1007/s00401-024-02778-y

Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups

Yiyi Ma et al. Acta Neuropathol. 2024.

. 2024 Aug 23;148(1):27.

doi: 10.1007/s00401-024-02778-y.

Authors

Affiliations

¹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
² G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
³ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, 630 West 168th street, New York, NY, 10032, USA.
⁴ CEDIMAT, Santo Domingo, Dominican Republic.
⁵ Universidad Pedro Henríquez Urena, Santo Domingo, Dominican Republic.
⁶ Pontíficia Universidad Católica Madre y Maestra (PUCMM), Santiago, Dominican Republic.
⁷ Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, New York, NY, USA.
⁸ Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
⁹ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
¹⁰ Department of Neurology and Penn Alzheimer's Disease Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Department of Pathology and Laboratory Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
¹² Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
¹³ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. rpm2@cumc.columbia.edu.
¹⁴ G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. rpm2@cumc.columbia.edu.
¹⁵ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, 630 West 168th street, New York, NY, 10032, USA. rpm2@cumc.columbia.edu.
¹⁶ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. bnv2103@cumc.columbia.edu.
¹⁷ G.H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. bnv2103@cumc.columbia.edu.
¹⁸ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, The New York Presbyterian Hospital, 630 West 168th street, New York, NY, 10032, USA. bnv2103@cumc.columbia.edu.

^# Contributed equally.

PMID: 39177846
PMCID: PMC11343944
DOI: 10.1007/s00401-024-02778-y

Abstract

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10^-8), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10^-9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10^-8), PVRL2 (Score = 125.86, P = 1.64 × 10^-9), TOMM40 (Score = - 18.58, P = 4.61 × 10^-8), and APOE (Score = 75.12, P = 7.26 × 10^-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.

Keywords: Alzheimer’s disease; CpG-related single nucleotide polymorphism; Epigenetics; Genetics; Hispanics; Non-Hispanic Whites.

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Figures

**Fig. 1**
Sliding CGS window search across the genome for the risk loci of clinical diagnosis of Alzheimer disease in Hispanics and non-Hispanic Whites. The genome-wide sliding-window results for the Hispanics (upper panel in blue) and the non-Hispanic Whites (NHW) (lower panel in green) are shown in the Miami plot. Each dot represents one 1-Kb window, and X and Y axes show its genomic coordinate and − log10 transformed P value. The two horizontal red lines show the Bonferroni-corrected genome-wide significance threshold (P ≤ 5 × 10^–8) and those CGS windows passing the genome-wide significance threshold in either Hispanics or NHW are shown in red dots

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Update of

Multi-omics Characterization of Epigenetic and Genetic Risk of Alzheimer Disease in Autopsied Brains from two Ethnic Groups.
Ma Y, Reyes-Dumeyer D, Piriz A, Recio P, Mejia DR, Medrano M, Lantigua RA, Vonsattel JPG, Tosto G, Teich AF, Ciener B, Leskinen S, Sivakumar S, DeTure M, Ranjan D, Dickson D, Murray M, Lee E, Wolk DA, Jin LW, Dugger BN, Hiniker A, Rissman RA, Mayeux R, Vardarajan BN. Ma Y, et al. medRxiv [Preprint]. 2024 Feb 14:2024.02.12.24302533. doi: 10.1101/2024.02.12.24302533. medRxiv. 2024. Update in: Acta Neuropathol. 2024 Aug 23;148(1):27. doi: 10.1007/s00401-024-02778-y. PMID: 38405911 Free PMC article. Updated. Preprint.

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Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups

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Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups

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