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Admixture Mapping of Alzheimer’s disease in Caribbean Hispanics identifies a new locus on 22q13.1

Molecular Psychiatry volume 27, pages 2813–2820 (2022)Cite this article

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Abstract

Late-onset Alzheimer’s disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD (“admixture mapping”) to identify LOAD-associated ancestral blocks, separately for ancestral components (European [EUR], African [AFR], Native American[NA]) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-β42 Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.

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Fig. 1: Joint admixture mapping analyses.
Fig. 2: Chromosome 22 ancestral block.
Fig. 3: GCAT protein is dysregulated in late onset Alzheimer’s disease.
Fig. 4: GCAT exacerbates Amyloid-β mediated toxicity in vivo.

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Acknowledgements

The National Institutes of Health (NIH), National Institute on Aging (NIH-NIA) and National Institute of Neurological Disorders and Stroke supported this work through the following grants: R56AG069118, R56AG066889, R56AG059756, R01AG056531, and R01NS095922. For WHICAP: Data collection and sharing for this project was supported by the Washington Heights-Inwood Columbia Aging Project (WHICAP, R01AG037212, RF1AG054023, RF1AG066107) funded by the NIH-NIA and by the National Center for Advancing Translational Sciences, NIH, through Grant Number UL1TR001873. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. We acknowledge the WHICAP study participants and the WHICAP research and support staff for their contributions to this study. For EFIGA: Data collection for this project was supported by the Genetic Studies of Alzheimer’s disease in Caribbean Hispanics (EFIGA) funded by the NIH-NIA and by the NIH (5R37AG015473, RF1AG015473, R56AG051876, R01AG067501, R56AG063908, RF1AG015473. We acknowledge the EFIGA study participants and the EFIGA research and support staff for their contributions to this study. For ADI 10/66 PR Alzheimer’s Disease International Epidemiological Study: Data collection for this project was supported by a recurrent PR Legislature grant, Pfizer Co. Grant # GA9001NE, and for PR Apo-E labs: Human Genetics Core Award from Columbia University Irving Institute for Clinical and Translational Research. Zebrafish work was supported by grants from Helmholtz Association (VH-NG-1021) and Schaefer Research Scholars Award. We thank Drs. Mehmet Ilyas Cosacak and Prabesh Bhattarai for gene expression analyses in zebrafish.

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  1. These authors contributed equally: Caghan Kizil, Sanjeev Sariya.

Authors and Affiliations

  1. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West168 th Street, New York, NY, 10032, USA

    Caghan Kizil, Sanjeev Sariya, Yoon A. Kim, Dolly Reyes-Dumeyer, Badri Vardarajan, Richard Mayeux, Ismael Santa-Maria & Giuseppe Tosto

  2. Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, 10032, USA

    Caghan Kizil, Sanjeev Sariya, Dolly Reyes-Dumeyer, Badri Vardarajan, Richard Mayeux & Giuseppe Tosto

  3. German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Tatzberg 41, 01307, Dresden, Germany

    Caghan Kizil

  4. The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, 10032, USA

    Sanjeev Sariya, Dolly Reyes-Dumeyer, Badri Vardarajan, Richard Mayeux & Giuseppe Tosto

  5. Department of Pathology & Cell Biology, Columbia University, New York, NY, USA

    Yoon A. Kim & Ismael Santa-Maria

  6. John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA

    Farid Rajabli & Eden Martin

  7. Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA

    Eden Martin

  8. Department of Medicine, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR, 00936, USA

    Aleyda Maldonado & Ivonne Z. Jiménez-Velázquez

  9. Department of Population & Quantitative Health Sciences, Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA

    Jonathan L. Haines

  10. Department of Medicine, College of Physicians and Surgeons, Columbia University, and the New York Presbyterian Hospital, 630 West 168th Street, New York, NY, 10032, USA

    Richard Mayeux

  11. Department of Psychiatry, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, New York, NY, 10032, USA

    Richard Mayeux

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Contributions

GT, ISM, CK contributed to the conception and design of the study. GT, SS, RM, BV, IJV, AM, YA, DRD, JH, FR, EM contributed to the acquisition and analysis of data. GT, SS, ISM, CK contributed to drafting the text or preparing the figures.

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Correspondence to Giuseppe Tosto.

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CK has executive role in Neuron-D GmbH, which had no academic or financial relationship to the design and execution of this project. Supplementary Information is available at MP’s website.

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Kizil, C., Sariya, S., Kim, Y.A. et al. Admixture Mapping of Alzheimer’s disease in Caribbean Hispanics identifies a new locus on 22q13.1. Mol Psychiatry 27, 2813–2820 (2022). https://doi.org/10.1038/s41380-022-01526-6

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