Multicenter Study

. 2023 Apr 26;11(1):68.

doi: 10.1186/s40478-023-01563-4.

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

Muhammad Ali^#^{1

2}, Derek B Archer^#³, Priyanka Gorijala^{1

2}, Daniel Western^{1

2}, Jigyasha Timsina^{1

2}, Maria V Fernández^{1

2}, Ting-Chen Wang³, Claudia L Satizabal^{4

5

6}, Qiong Yang⁷, Alexa S Beiser^{7

5

6}, Ruiqi Wang⁸, Gengsheng Chen^{9

10}, Brian Gordon^{9

10}, Tammie L S Benzinger^{9

10}, Chengjie Xiong⁹, John C Morris^{9

11}, Randall J Bateman^{9

11

12}, Celeste M Karch¹, Eric McDade¹¹, Alison Goate¹³, Sudha Seshadri^{6

14}, Richard P Mayeux¹⁵, Reisa A Sperling^{16

17}, Rachel F Buckley^{17

18}, Keith A Johnson¹⁹, Hong-Hee Won²⁰, Sang-Hyuk Jung²⁰, Hang-Rai Kim²¹, Sang Won Seo²², Hee Jin Kim^{20

22}, Elizabeth Mormino¹², Simon M Laws²³, Kang-Hsien Fan²⁴, M Ilyas Kamboh²⁴, Prashanthi Vemuri²⁵, Vijay K Ramanan²⁶, Hyun-Sik Yang^{27

28

29

30}, Allen Wenzel³¹, Hema Sekhar Reddy Rajula³², Aniket Mishra³², Carole Dufouil³², Stephanie Debette^{32

33

34}, Oscar L Lopez³⁵, Steven T DeKosky³⁶, Feifei Tao³⁷, Michael W Nagle³⁷; Knight Alzheimer Disease Research Center (Knight ADRC); Dominantly Inherited Alzheimer Network (DIAN); Alzheimer’s Disease Neuroimaging Initiative (ADNI); ADNI-DOD, A4 Study Team; Australian Imaging Biomarkers, Lifestyle (AIBL) Study; Timothy J Hohman³, Yun Ju Sung^{1

2}, Logan Dumitrescu^#³, Carlos Cruchaga^#^{38

39

40

41

42}

Affiliations

¹ Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.
² NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.
³ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health, San Antonio, TX, 78229, USA.
⁵ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁶ Framingham Heart Study, Framingham, MA, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁸ Boston University, Boston, MA, USA.
⁹ Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.
¹⁰ Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.
¹¹ Department of Neurology, Washington University, St Louis, MO, USA.
¹² Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
¹³ Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Boston University School of Medicine, Boston, MA, USA.
¹⁵ The Department of Neurology, Columbia University, New York, NY, USA.
¹⁶ Department of Neurology, Harvard Medical School, Boston, MA, USA.
¹⁷ Brigham and Women's Hospital and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA.
¹⁹ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
²¹ Department of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Republic of Korea.
²² Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
²³ Centre for Precision Health, Edith Cowan University, 270 Joondalup Dr, Joondalup, WA, 6027, Australia.
²⁴ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
²⁵ Department of Radiology, Mayo Clinic-Minnesota, Rochester, MN, 55905, USA.
²⁶ Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN, 55905, USA.
²⁷ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
²⁸ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
²⁹ Harvard Medical School, Boston, MA, USA.
³⁰ Broad Institute of Harvard and MIT, Cambridge, USA.
³¹ Wisconsin Alzheimer's Institute, Madison, WI, USA.
³² UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, 33000, Bordeaux, France.
³³ Department of Neurology, Boston University School of Medicine, Boston, MA, 2115, USA.
³⁴ Department of Neurology, CHU de Bordeaux, 33000, Bordeaux, France.
³⁵ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
³⁶ Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
³⁷ Neurogenomics, Genetics-Guided Dementia Discovery, Eisai, Inc, Cambridge, MA, USA.
³⁸ Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.
³⁹ NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.
⁴⁰ Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA. cruchagac@wustl.edu.
⁴¹ Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.
⁴² Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, USA. cruchagac@wustl.edu.

^# Contributed equally.

PMID: 37101235
PMCID: PMC10134547
DOI: 10.1186/s40478-023-01563-4

Multicenter Study

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

Muhammad Ali et al. Acta Neuropathol Commun. 2023.

. 2023 Apr 26;11(1):68.

doi: 10.1186/s40478-023-01563-4.

Authors

Affiliations

¹ Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA.
² NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA.
³ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
⁴ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health, San Antonio, TX, 78229, USA.
⁵ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁶ Framingham Heart Study, Framingham, MA, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁸ Boston University, Boston, MA, USA.
⁹ Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA.
¹⁰ Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, USA.
¹¹ Department of Neurology, Washington University, St Louis, MO, USA.
¹² Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
¹³ Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Boston University School of Medicine, Boston, MA, USA.
¹⁵ The Department of Neurology, Columbia University, New York, NY, USA.
¹⁶ Department of Neurology, Harvard Medical School, Boston, MA, USA.
¹⁷ Brigham and Women's Hospital and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA.
¹⁹ Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
²¹ Department of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Republic of Korea.
²² Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
²³ Centre for Precision Health, Edith Cowan University, 270 Joondalup Dr, Joondalup, WA, 6027, Australia.
²⁴ Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
²⁵ Department of Radiology, Mayo Clinic-Minnesota, Rochester, MN, 55905, USA.
²⁶ Department of Neurology, Mayo Clinic-Minnesota, Rochester, MN, 55905, USA.
²⁷ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
²⁸ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
²⁹ Harvard Medical School, Boston, MA, USA.
³⁰ Broad Institute of Harvard and MIT, Cambridge, USA.
³¹ Wisconsin Alzheimer's Institute, Madison, WI, USA.
³² UMR 1219, University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, 33000, Bordeaux, France.
³³ Department of Neurology, Boston University School of Medicine, Boston, MA, 2115, USA.
³⁴ Department of Neurology, CHU de Bordeaux, 33000, Bordeaux, France.
³⁵ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
³⁶ Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
³⁷ Neurogenomics, Genetics-Guided Dementia Discovery, Eisai, Inc, Cambridge, MA, USA.
³⁸ Department of Psychiatry, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.
³⁹ NeuroGenomics and Informatics, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.
⁴⁰ Knight Alzheimer's Disease Research Center, Washington University, St Louis, MO, USA. cruchagac@wustl.edu.
⁴¹ Hope Center for Neurologic Diseases, Washington University, St. Louis, MO, 63110, USA. cruchagac@wustl.edu.
⁴² Department of Genetics, Washington University School of Medicine, St Louis, MO, 63110, USA. cruchagac@wustl.edu.

^# Contributed equally.

PMID: 37101235
PMCID: PMC10134547
DOI: 10.1186/s40478-023-01563-4

Abstract

Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer's disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10^-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10^-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10^-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10^-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10^-08, MAF = 0.006, sex-interaction P = 9.8 × 10^-07) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10^-08, MAF = 0.004, sex-interaction P = 1.3 × 10^-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies.

Keywords: Alzheimer’s disease; Amyloid PET; Brain amyloidosis; GWAS; Meta-analysis; Multi-ethnic.

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Conflict of interest statement

The authors declare that they no competing interests.

Figures

**Fig. 1**
Schematic overview of datasets and performed analyses. Amyloid PET endophenotype and corresponding genotype data was available for 8 different cohorts with a total sample size of 7,557 (NHW = 7036, African = 359, Asian = 162). We also got GWAS summary statistics data from 6 external cohorts having a total sample size of 5852 (NHW = 4520, Asian = 1332). We performed Race-specific linear regression using amyloid PET as a quantitative endophenotype and age, sex, cohort name, and first ten genetic PCs as model covariates. The same analytic pipeline was used by the external cohorts for generating the summary statistics data. We meta-analyzed the results from internal and external summary statistics using a standard error (StdErr)-based meta-analysis approach using METAL software (N = 13,409). Furthermore, different post-GWAS analyses were carried out to identify novel SNPs associated with brain amyloidosis

**Fig. 2**
Multi-ethnic meta-analysis (N = 13,409) identified novel signals in chr 1, 14, and 19 associated with brain amyloidosis. A Manhattan plot showing the p-values in the multi-ethnic meta-analysis. The blue and red lines represent the suggestive (P = 1 × 10⁻⁵) and genome-wide significance thresholds (P = 5 × 10⁻⁸). Variants with a p value below 1 × 10⁻¹⁵ are not shown. Local Manhattan plot for the chr1 (B), chr14 (C), and chr19 (D, E) loci. The relative location of genes and the direction of transcription are shown in the lower portion of the locus zoom plots

**Fig. 3**
Sex stratified analyses identified several female specific signals. A Manhattan plot showing the p-values in the 5195 female and 4625 male participants across 9 cohorts. The blue and red lines represent the suggestive (P = 1 × 10⁻⁵) and genome-wide significance thresholds (P = 5 × 10⁻⁸). Variants with a p value below 1 × 10⁻¹⁵ are not shown. The observed genomic control value (λ) was 1 for both strata. Local Manhattan plot showing the genome-wide significant locus from the chr5 (B) and chr11 (C) for female-specific signals. The relative location of genes and the direction of transcription are shown in the lower portion of the locus zoom plots

**Fig. 4**
Genome-wide genetic covariance results. Genetic covariance between multi-ethnic amyloid PET GWAS (NHW = 11, 816) and 63 complex human traits. Error bars represent 95% confidence intervals

See this image and copyright information in PMC

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Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

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Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease

Authors

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Abstract

Conflict of interest statement

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