Multi-ancestry meta-analysis and fine-mapping in Alzheimer's disease

Julie Lake; Caroline Warly Solsberg; Jonggeol Jeffrey Kim; Juliana Acosta-Uribe; Mary B Makarious; Zizheng Li; Kristin Levine; Peter Heutink; Chelsea X Alvarado; Dan Vitale; Sarang Kang; Jungsoo Gim; Kun Ho Lee; Stefanie D Pina-Escudero; Luigi Ferrucci; Andrew B Singleton; Cornelis Blauwendraat; Mike A Nalls; Jennifer S Yokoyama; Hampton L Leonard

doi:10.1038/s41380-023-02089-w

Multi-ancestry meta-analysis and fine-mapping in Alzheimer's disease

Mol Psychiatry. 2023 Jul;28(7):3121-3132. doi: 10.1038/s41380-023-02089-w. Epub 2023 May 18.

Authors

Julie Lake^#¹, Caroline Warly Solsberg^#^{2

3

4}, Jonggeol Jeffrey Kim^{1

5}, Juliana Acosta-Uribe^{6

7}, Mary B Makarious^{1

8

9}, Zizheng Li^{2

3}, Kristin Levine^{10

11}, Peter Heutink¹², Chelsea X Alvarado^{1

10

11}, Dan Vitale^{1

10

11}, Sarang Kang^{13

14}, Jungsoo Gim^{13

14

15}, Kun Ho Lee^{13

14

15

16}, Stefanie D Pina-Escudero^{2

3

4}, Luigi Ferrucci¹⁷, Andrew B Singleton^{1

11}, Cornelis Blauwendraat^{11

18}, Mike A Nalls^{1

10

11}, Jennifer S Yokoyama^#^{2

3

4

19}, Hampton L Leonard^#^{20

21

22

23}

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
² Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA, USA.
³ Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
⁴ Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
⁵ Preventive Neurology Unit, Centre for Prevention Diagnosis and Detection, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
⁶ Neuroscience Research Institute and the department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA.
⁷ Neuroscience Group of Antioquia, University of Antioquia, Medellín, Colombia.
⁸ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
⁹ UCL Movement Disorders Centre, University College London, London, UK.
¹⁰ Data Tecnica International LLC, Washington, DC, USA.
¹¹ Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA.
¹² Alector, Inc. 131 Oyster Point Blvd, Suite 600, South San Francisco, CA, 94080, USA.
¹³ Gwangju Alzheimer's disease and Related Dementia Cohort Research Center, Chosun University, Gwangju, 61452, Korea.
¹⁴ BK FOUR Department of Integrative Biological Sciences, Chosun University, Gwangju, 61452, Korea.
¹⁵ Department of Biomedical Science, Chosun University, Gwangju, 61452, Korea.
¹⁶ Korea Brain Research Institute, Daegu, 41062, Korea.
¹⁷ Longitudinal Studies Section, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
¹⁸ Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹⁹ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
²⁰ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. leonardhl@nih.gov.
²¹ Data Tecnica International LLC, Washington, DC, USA. leonardhl@nih.gov.
²² Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA. leonardhl@nih.gov.
²³ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. leonardhl@nih.gov.

^# Contributed equally.

Abstract

Genome-wide association studies (GWAS) of Alzheimer's disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer's disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer's disease and related dementias.

Publication types

Meta-Analysis

MeSH terms

Alzheimer Disease* / ethnology
Alzheimer Disease* / genetics
Black or African American / genetics
Caribbean People / genetics
East Asian People / genetics
European People / genetics
Genetic Predisposition to Disease* / genetics
Genome-Wide Association Study / methods
Genotype
Hispanic or Latino / genetics
Humans
Polymorphism, Single Nucleotide / genetics
South American People / genetics

Supplementary concepts

Colombian people

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding