Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data

Yanbing Wang; Chloé Sarnowski; Honghuang Lin; Achilleas N Pitsillides; Nancy L Heard-Costa; Seung Hoan Choi; Dongyu Wang; Joshua C Bis; Elizabeth E Blue; Alzheimer's Disease Neuroimaging Initiative (ADNI); Eric Boerwinkle; Philip L De Jager; Myriam Fornage; Ellen M Wijsman; Sudha Seshadri; Josée Dupuis; Gina M Peloso; Anita L DeStefano; Alzheimer's Disease Sequencing Project (ADSP)

doi:10.1002/alz.13705

Key variants via the Alzheimer's Disease Sequencing Project whole genome sequence data

Alzheimers Dement. 2024 Mar 21. doi: 10.1002/alz.13705. Online ahead of print.

Authors

Yanbing Wang¹, Chloé Sarnowski^{1

2}, Honghuang Lin³, Achilleas N Pitsillides¹, Nancy L Heard-Costa^{1

4}, Seung Hoan Choi¹, Dongyu Wang¹, Joshua C Bis⁵, Elizabeth E Blue^{6

7}; Alzheimer's Disease Neuroimaging Initiative (ADNI); Eric Boerwinkle², Philip L De Jager^{8

9}, Myriam Fornage^{2

10}, Ellen M Wijsman¹¹, Sudha Seshadri^{4

12

13}, Josée Dupuis^{1

14}, Gina M Peloso¹, Anita L DeStefano^{1

4}; Alzheimer's Disease Sequencing Project (ADSP)

Affiliations

¹ Department of Biostatistics, Boston University, School of Public Health, Boston, Massachusetts, USA.
² Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
³ Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
⁴ The Framingham Heart Study, Framingham, Massachusetts, USA.
⁵ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
⁶ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA.
⁷ Brotman Baty Institute, Seattle, Washington, USA.
⁸ Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
⁹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA.
¹⁰ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹¹ Division of Medical Genetics and Department Biostatistics Statistical Genetics Lab, University of Washington, Hans Rosling Center for Population Health, Seattle, Washington, USA.
¹² Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
¹³ Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
¹⁴ Department of Epidemiology, Biostatistics and Occupational Health, School of Population and Global Health, McGill University, Montreal, Quebec, Canada.

PMID: 38511601
DOI: 10.1002/alz.13705

Abstract

Introduction: Genome-wide association studies (GWAS) have identified loci associated with Alzheimer's disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci.

Methods: We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases = 2184, N controls = 2383) and targeted analyses in subpopulations using WGS data from the Alzheimer's Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants.

Results: Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses.

Discussion: This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.

Keywords: Alzheimer's disease; association analyses; diverse populations; genome‐wide association study; single nucleotide variations; whole genome sequencing.

Abstract

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