. 2024 Sep 20;15(1):8251.

doi: 10.1038/s41467-024-52298-2.

CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET

Kwangsik Nho^#^{1

2

3

4}, Shannon L Risacher^#^{1

3}, Liana G Apostolova^{1

3

5

6}, Paula J Bice^{1

3}, Jared R Brosch^{3

5}, Rachael Deardorff^{3

5}, Kelley Faber^{6

7}, Martin R Farlow^{3

5}, Tatiana Foroud^{3

6

7}, Sujuan Gao^{3

8}, Thea Rosewood^{1

2

3}, Jun Pyo Kim^{1

2

3}, Kelly Nudelman^{3

6

7}, Meichen Yu^{1

3}, Paul Aisen⁹, Reisa Sperling¹⁰, Basavaraj Hooli¹¹, Sergey Shcherbinin¹¹, Diana Svaldi¹¹, Clifford R Jack Jr¹², William J Jagust¹³, Susan Landau¹³, Aparna Vasanthakumar¹⁴, Jeffrey F Waring¹⁴, Vincent Doré^{15

16}, Simon M Laws¹⁷, Colin L Masters¹⁸, Tenielle Porter¹⁷, Christopher C Rowe^{16

18}, Victor L Villemagne^{16

19}, Logan Dumitrescu^{20

21}, Timothy J Hohman^{20

21}, Julia B Libby²⁰, Elizabeth Mormino²², Rachel F Buckley¹⁰, Keith Johnson^{10

23}, Hyun-Sik Yang^{10

24}, Ronald C Petersen²⁵, Vijay K Ramanan²⁵, Nilüfer Ertekin-Taner^{26

27}, Prashanthi Vemuri¹², Ann D Cohen¹⁹, Kang-Hsien Fan²⁸, M Ilyas Kamboh²⁸, Oscar L Lopez^{19

29}, David A Bennett³⁰, Muhammad Ali³¹, Tammie Benzinger³², Carlos Cruchaga^{31

33}, Diana Hobbs³², Philip L De Jager³⁴, Masashi Fujita³⁴, Vaishnavi Jadhav^{6

35}, Bruce T Lamb^{3

6

35}, Andy P Tsai^{22

35

36}, Isabel Castanho^{37

38}, Jonathan Mill³⁷, Michael W Weiner^{39

40}; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Andrew J Saykin^{41

42

43

44

45}

Affiliations

¹ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
² Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA.
³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
⁴ Department of BioHealth Informatics, Indiana University, Indianapolis, USA.
⁵ Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
⁷ National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, USA.
⁸ Department of Biostatistics, Indiana University School of Medicine, Indianapolis, USA.
⁹ Department of Neurology, Keck School of Medicine, University of Southern California, San Diego, USA.
¹⁰ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
¹¹ Eli Lilly and Company, Indianapolis, USA.
¹² Department of Radiology, Mayo Clinic, Rochester, USA.
¹³ UC Berkeley Helen Wills Neuroscience Institute, University of California - Berkeley, Berkeley, USA.
¹⁴ Genomics Research Center, AbbVie, North Chicago, USA.
¹⁵ CSIRO Health and Biosecurity, Melbourne, Australia.
¹⁶ Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia.
¹⁷ Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia.
¹⁸ Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Australia.
¹⁹ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA.
²⁰ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, USA.
²¹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, USA.
²² Department of Neurology & Neurological Sciences, Stanford University, Stanford, USA.
²³ Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
²⁴ Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
²⁵ Department of Neurology, Mayo Clinic, Rochester, USA.
²⁶ Department of Neurology, Mayo Clinic, Jacksonville, USA.
²⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, USA.
²⁸ Department of Human Genetics, University of Pittsburgh, Pittsburgh, USA.
²⁹ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
³⁰ Department of Neurological Sciences, Rush Medical College, Rush University, Chicago, USA.
³¹ Department of Psychiatry, Washington University, St. Louis, USA.
³² Department of Radiology, Washington University School of Medicine, St. Louis, USA.
³³ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, USA.
³⁴ Center for Translational and Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, USA.
³⁵ Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, USA.
³⁶ Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, USA.
³⁷ Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
³⁸ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
³⁹ Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, USA.
⁴⁰ Department of Veterans Affairs Medical Center, San Francisco, USA.
⁴¹ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴² Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴⁵ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.

^# Contributed equally.

PMID: 39304655
PMCID: PMC11415491
DOI: 10.1038/s41467-024-52298-2

CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET

Kwangsik Nho et al. Nat Commun. 2024.

. 2024 Sep 20;15(1):8251.

doi: 10.1038/s41467-024-52298-2.

Authors

Affiliations

¹ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA.
² Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA.
³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA.
⁴ Department of BioHealth Informatics, Indiana University, Indianapolis, USA.
⁵ Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA.
⁷ National Centralized Repository for Alzheimer's Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, USA.
⁸ Department of Biostatistics, Indiana University School of Medicine, Indianapolis, USA.
⁹ Department of Neurology, Keck School of Medicine, University of Southern California, San Diego, USA.
¹⁰ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
¹¹ Eli Lilly and Company, Indianapolis, USA.
¹² Department of Radiology, Mayo Clinic, Rochester, USA.
¹³ UC Berkeley Helen Wills Neuroscience Institute, University of California - Berkeley, Berkeley, USA.
¹⁴ Genomics Research Center, AbbVie, North Chicago, USA.
¹⁵ CSIRO Health and Biosecurity, Melbourne, Australia.
¹⁶ Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Australia.
¹⁷ Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia.
¹⁸ Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Australia.
¹⁹ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, USA.
²⁰ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, USA.
²¹ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, USA.
²² Department of Neurology & Neurological Sciences, Stanford University, Stanford, USA.
²³ Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
²⁴ Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.
²⁵ Department of Neurology, Mayo Clinic, Rochester, USA.
²⁶ Department of Neurology, Mayo Clinic, Jacksonville, USA.
²⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, USA.
²⁸ Department of Human Genetics, University of Pittsburgh, Pittsburgh, USA.
²⁹ Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
³⁰ Department of Neurological Sciences, Rush Medical College, Rush University, Chicago, USA.
³¹ Department of Psychiatry, Washington University, St. Louis, USA.
³² Department of Radiology, Washington University School of Medicine, St. Louis, USA.
³³ NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, USA.
³⁴ Center for Translational and Computational Neuroimmunology, Department of Neurology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, USA.
³⁵ Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, USA.
³⁶ Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, USA.
³⁷ Department for Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
³⁸ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
³⁹ Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, USA.
⁴⁰ Department of Veterans Affairs Medical Center, San Francisco, USA.
⁴¹ Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴² Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴³ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.
⁴⁵ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA. asaykin@iu.edu.

^# Contributed equally.

PMID: 39304655
PMCID: PMC11415491
DOI: 10.1038/s41467-024-52298-2

Abstract

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

PubMed Disclaimer

Conflict of interest statement

Dr. Apostolova received grant or other financial support from the National Institutes of Health (NIH), Alzheimer’s Association, AVID Pharmaceuticals, Life Molecular Imaging, Roche Diagnostics, and Eli Lilly. In addition, she has received consulting fees from Biogen, Two Labs, IQIVA, Florida Department of Health, Genentech, NIH Biobank, Eli Lilly, GE Healthcare, Eisai, and Roche Diagnostics. She has also received payment or honoraria from American Academy of Neurology, MillerMed, National Alzheimer’s Coordinating Center CME, CME Institute, APhA, Purdue University, Mayo Clinic, MJH Physician Education Resource, and Ohio State University. She received support for travel from the Alzheimer’s Association. She has served on Data Safety and Monitoring or Advisory Boards for IQVIA, UAB Nathan Schock Center, New Mexico Exploratory ADRC, and NIA R01 AG061111. She has a leadership role in multiple committees, including the Medical Science Council of the Alzheimer’s Association Greater Indiana Chapter, the Alzheimer’s Association Science Program Committee, and the FDA PCNS Advisory Committee. Finally, Dr. Apostolova holds stock in Cassava Neurosciences and Golden Seeds. Dr. Foroud receives support from multiple NIH grants (U24 NS095871, U24 AG021886, U24 AG056270, U01 AA026103, U10 AA008401, P30 AG010133, R01 AG019771, U01 AG032984, P30 AR072581, U01 AG057195, UL1 TR002529, U19 AG063911; U19 AG063744, U19 AG068054, R01 AG069453, U54 CA196519, R01 AG061146, R01 AG073267, R01 AG074971, U19 AG071754, R01 AG055444, R01 AG070349, U19 AG024904, R01 AG076634, U19 AG079774, U54 CA280897, U19 NS120384); the Michael J. Fox Foundation (MJFF001948); Cohen Veterans Biosciences; The Parkinson’s Disease Foundation; Children’s Tumor Foundation; Broad Institute; Lumind Foundation; and Gates Venture (0432-06-120975). Dr. Jagust has served as a consultant for Biogen, Eisai, Lilly, and Bioclinica. He has an equity interest in Optoceuticals. Aparna Vasanthakumar and Jeffrey F. Waring are employees of AbbVie and may own AbbVie stock. Dr. Hohman receives support from multiple NIH grants (U24-AG074855, P20-AG068082, R01-AG061518, R01-AG059716, R01-AG074012, RF1-AG059869). He also sits on the advisory board for Vivid Genomics and is a Senior Associate Editor for Alzheimer’s and Dementia: Translational Research and Clinical Intervention. Hyun-Sik Yang received personal fees (honorarium) from Genentech, Inc outside the submitted work. Dr. Vemuri receives funding support from the NIH. Dr. Cruchaga has received research support from: GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Cruchaga is a member of the advisory board of Vivid Genomics and Circular Genomics. Dr. Saykin receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177 and U19 AG074879). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions USA, Inc. (Dementia Advisory Board); NIH NHLBI (MESA Observational Study Monitoring Board); Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging and Behavior). Dr. Ertekin-Taner receives support from multiple NIH grants (R01 AG061796, U19 AG074879, U01 AG046139, KL2 TR002379), Alzheimer’s Association Zenith Fellows Award and Florida Department of Health. She serves as an advisor to the Framingham Heart Study (NIH NHLBI 75N92019D00031/75N92019F00125). She also has a provisional patent application unrelated to this work. The remaining authors declare no competing interests.

Figures

**Fig. 1. Results of Discovery GWAS for cortical tau deposition.**
Quantile-quantile (QQ) (A), Manhattan (B), and LocusZoom (C) plots of genome-wide association study (GWAS) results from seven discovery cohorts (N = 1446) using a linear regression model with age, sex, two principal component (PC) factors from population stratification, *APOE4* status, and diagnosis as covariates are shown. The genomic inflation factor is λ = 1.025 in the Manhattan plot (B), the horizontal blue and red lines represent the -log₁₀(10⁻⁵) and -log₁₀(5.0 × 10⁻⁸) threshold levels, respectively. Two single nucleotide polymorphisms (SNPs) on chromosome 2 showed highly significant ( < 5.0 × 10⁻⁸) associations with cerebral tau deposition. The regional association plot (C) for the locus that passed genome-wide significance shows the region around the most significant SNP (rs2113389) at the *RMDN2-CYP1B1* locus. SNPs were plotted based on their GWAS −log₁₀ p-values and genomic position. The red color scale of r² values was used to label SNPs based on their degree of linkage disequilibrium with the most significant SNP. Recombination rates calculated from 1000 Genomes Project reference data are also displayed in a blue line corresponding to the right vertical axis. *Note: cerebral tau endophenotype measured as an inverse normal transformed variable of cortical tau SUVR*.

**Fig. 2. Association of the most significant SNP (rs2113389) at the *RMDN2-CYP1B1* locus with regional and global cortical tau burden.**
Using an additive model, the minor allele (T) of rs2113389 is associated with higher tau deposition across participants, with both rs2113389 CT and TT individuals showing significantly greater medial temporal lobe (MTL; A) and cortical (B) tau deposition than rs2113389 CC individuals. Similar results are seen using a dominant model. Specifically, individuals with one or more minor alleles of rs2113389 show significantly greater tau deposition in the medial temporal lobe (C) and cortex (D) than rs2113389 CC individuals. One-way ANCOVA models are used with rs2113389 genotype as the independent variable, covaried for age, sex, Aβ positivity, *APOE4* carrier status, and diagnosis. Plots represent mean ± standard error of the mean. Panels include 1,161 individuals (for A, B, 834 CC, 300 CT, 27 TT); for (C,D), 834 CC, 327 CT/TT). Source data are provided as a Source Data file. Aβ amyloid-beta; ANCOVA analysis of covariance; APOE apolipoprotein E; MTL medial temporal lobe; SUVR standardized uptake value ratio. *Note: tau measured as an inverse normal transformed variable of medial temporal and cortical tau SUVR*.

**Fig. 3. Interaction effect of the most significant SNP (rs2113389) at the *RMDN2-CYP1B1* locus with diagnosis, *APOE ε4* carrier status, and Aβ positivity on regional and cortical tau deposition.**
Both diagnosis and rs2113389 dominant genotype are significantly associated with medial temporal lobe (MTL; A) and cortical (B) tau deposition. *APOE4* carrier status and rs2113389 dominant genotype are significantly associated with MTL (C) and cortical (D) tau deposition. Significant effects of both Aβ positivity and rs2113389 dominant genotype on MTL (E) and cortical (F) tau deposition are observed. Two-way ANCOVA models, covaried for age, sex, as well as diagnosis, *APOE4* carrier status, and Aβ positivity where appropriate, are used. Plots are displayed as mean + /−standard error of the mean. Panels (A) and (B) include 1161 participants (568 CN-CC, 222 CN-CT/TT, 195 MCI-CC, 75 MCI-CT/TT, 71 AD-CC, 30 AD-CT/TT); panels (C) and (D) include 1161 participants (468 *APOE4*-/CC, 199 *APOE4*-/CT/TT, 366 *APOE4* + /CC, 128 *APOE4* + /CT/TT); panels (E) and (F) include 1154 participants (338 Aβ-/CC, 131 Aβ-/CT/TT, 491 Aβ + /CC, 194 Aβ + /CT/TT). Source data are provided as a Source Data file. Aβ amyloid-beta; AD Alzheimer’s disease; ANCOVA analysis of covariance; APOE apolipoprotein E; CN cognitively normal; DX diagnosis; Dom rs2113389 dominant genotype (CC vs. CT/TT); Int. interaction; MCI mild cognitive impairment; MTL medial temporal lobe; SUVR standardized uptake value ratio. *Note: tau measured as an inverse normal transformed variable of medial temporal and cortical tau SUVR*.

**Fig. 4. Voxel-wise analysis and visualization of the effect of rs2113389 dominant genotype on tau deposition.**
A Widespread regions of association between rs2113389 dominant genotype and tau deposition are observed in the inferior frontal, parietal, and medial and lateral temporal lobes, such that those with one or more minor alleles (T) at rs2113389 show greater tau deposition than CC rs2113389 individuals. Images are displayed at a voxel-wise threshold of p < 0.05 with family-wise error correction for multiple comparisons and a minimum cluster size (k) = 100 voxels. B Beta-value maps show widespread regions of higher tau deposition in rs2113389-T carriers relative to non-carriers. Specifically, temporal, parietal, and frontal lobe tau is greater in minor allele carriers than non-carriers. A one-way ANCOVA model is used, covaried for age, sex, diagnosis, *APOE4* carrier status, and Aβ positivity. Analyzes include 1154 individuals (829 CC, 325 CT/TT). Aβ amyloid-beta; ANCOVA analysis of covariance; APOE apolipoprotein E.

**Fig. 5. Gene expression analysis of *RMDN2* and *CYP1B1* and expression quantitative trait locus (eQTL) and DNA methylation QTL (meQTL) analysis of rs2113389.**
AD patients show downregulated expression of *RMDN2* in the parahippocampal gyri (A) and upregulated expression of *CYP1B1* in the temporal cortex (B) relative to CN using brain tissue-based RNA-Seq data from the AMP-AD project (Panel (A), n = 135 (26 CN, 109 AD); Panel (B), n = 151 (71 CN, 80 AD)). C In an eQTL analysis, the identified SNP (rs2113389) is associated with *CYP1B1* expression levels in the temporal cortex (n = 257 (188 CC, 69 CT/TT)). One-way ANCOVA models are used in Panels (A–C), and plots represent the mean ± standard error of the mean. Source data are provided for panels (A–C) as a Source Data file. Cell type-specific expression levels (D) and eQTL in the excitatory neuron (E) of *CYP1B1* gene (N = 424) are shown. In (D), the x-axis is cell types in ROSMAP DLPFC single-nucleus RNA-Seq data. The y-axis is the log₂ of counts per million mapped reads (CPM) of *CYP1B1* gene. Expression levels are computed at the donor level by aggregating cells from the same donor. Rare cell types are observed only in a small fraction of donors. Areas of violin plots are scaled to the number of donors. Fibroblasts (Fib) has the highest expression of *CYP1B1* gene. Among major cell types, excitatory neurons (Exc) has the highest expression. In (E), the minor allele (T) of rs2113389 is associated with higher cell type-specific *CYP1B1* expression levels in the excitatory neuron (p-value = 0.035). F DNA methylation QTL analysis (*cis*-meQTL) of rs2113389 with CpGs in *CYP1B1* measured in blood samples from 634 ADNI participants demonstrate three CpGs, located in the *CYP1B1* gene body region, as significantly associated with rs2113389 (p-value = 7.04 × 10⁻⁸, 5.43 × 10⁻⁹, and 4.73 × 10⁻¹², respectively). G *Cyp1b1* expression (relative mRNA expression levels by qPCR) is increased in the cortex of 6-month-old hTAU mice consistent with our findings in human LOAD (p-value = 0.038). The error bars represent the standard error of the mean. H *Cyp1b1* expression (normalized RNA-Seq read counts) significantly changes with time (genotype*age) in TG rTg4510 mice, suggesting *Cyp1b1* is associated with disease progression in the rTg4510 model. I *Cyp1b1* expression (normalized RNA-Seq read counts) does not change with time (genotype*age) in J20 mice, suggesting that *Cyp1b1* is not associated with amyloid pathology progression. AD Alzheimer’s disease; ADNI Alzheimer’s Disease Neuroimaging Initiative; AMP-AD Accelerating Medicines Partnership-AD; ANCOVA analysis of covariance; *cis*-meQTL DNA methylation quantitative trait loci; CN cognitively normal; CpG cytosines followed by guanine residues; CPM counts per million; DLPFC dorsolateral prefrontal cortex; DNA Deoxyribonucleic acid; eQTL expression quantitative trait loci; Exc excitatory neurons; Fib fibroblasts; hTAU humanized tau; ROSMAP Religious Orders Study/Memory and Aging Project; RNA-Seq Ribonucleic acid sequencing; SNP single nucleotide polymorphism.

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CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET

Affiliations

CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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