Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project

Wan-Ping Lee; Seung Hoan Choi; Margaret G Shea; Po-Liang Cheng; Beth A Dombroski; Achilleas N Pitsillides; Nancy L Heard-Costa; Hui Wang; Katia Bulekova; Amanda B Kuzma; Yuk Yee Leung; John J Farrell; Honghuang Lin; Brian W Kunkle; Adam Naj; Elizabeth E Blue; Frederick Nusetor; Dongyu Wang; Eric Boerwinkle; William S Bush; Xiaoling Zhang; Philip L De Jager; Josée Dupuis; Lindsay A Farrer; Myriam Fornage; Eden Martin; Margaret Pericak-Vance; Sudha Seshadri; Ellen M Wijsman; Li-San Wang; Alzheimer's Disease Sequencing Project; Gerard D Schellenberg; Anita L Destefano; Jonathan L Haines; Gina M Peloso

doi:10.1002/alz.14283

Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project

Alzheimers Dement. 2024 Oct 20. doi: 10.1002/alz.14283. Online ahead of print.

Authors

Wan-Ping Lee^{1

2}, Seung Hoan Choi³, Margaret G Shea⁴, Po-Liang Cheng^{1

2}, Beth A Dombroski¹, Achilleas N Pitsillides³, Nancy L Heard-Costa^{5

6}, Hui Wang^{1

2}, Katia Bulekova⁷, Amanda B Kuzma^{1

2}, Yuk Yee Leung^{1

2}, John J Farrell⁸, Honghuang Lin⁹, Brian W Kunkle^{10

11}, Adam Naj¹², Elizabeth E Blue^{13

14}, Frederick Nusetor³, Dongyu Wang³, Eric Boerwinkle^{15

16}, William S Bush^{17

18}, Xiaoling Zhang^{3

8}, Philip L De Jager¹⁹, Josée Dupuis^{3

20}, Lindsay A Farrer^{3

5

6

8

21

22}, Myriam Fornage^{23

24}, Eden Martin^{10

11

25}, Margaret Pericak-Vance^{10

11

25}, Sudha Seshadri²⁶, Ellen M Wijsman^{13

27

28}, Li-San Wang^{1

2}; Alzheimer's Disease Sequencing Project; Gerard D Schellenberg^{1

2}, Anita L Destefano^{3

5}, Jonathan L Haines^{17

18}, Gina M Peloso³

Affiliations

¹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
⁴ Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, Massachusetts, USA.
⁵ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
⁶ Framingham Heart Study, Framingham, Massachusetts, USA.
⁷ Research Computing Services, Information Services & Technology, Boston University, Boston, Massachusetts, USA.
⁸ Biomedical Genetics, Department of Medicine, Boston University Medical School, Boston, Massachusetts, USA.
⁹ Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
¹⁰ John P. Hussman Institute for Human Genomics, Miami, Florida, USA.
¹¹ John T. Macdonald Department of Human Genetics, Miami, Florida, USA.
¹² Department of Biostatistics, Epidemiology, and Informatics, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹³ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, Washington, USA.
¹⁴ Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA.
¹⁵ Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹⁶ Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
¹⁷ Cleveland Institute for Computational Biology, Cleveland, Ohio, USA.
¹⁸ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
¹⁹ Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York, USA.
²⁰ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada.
²¹ Department of Ophthalmology, Department of Medicine, Boston University Medical School, Boston, Massachusetts, USA.
²² Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.
²³ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁴ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁵ University of Miami Miller School of Medicine, Miami, Florida, USA.
²⁶ Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, Texas, USA.
²⁷ Department of Biostatistics, University of Washington, Seattle, Washington, USA.
²⁸ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

PMID: 39428839
DOI: 10.1002/alz.14283

Abstract

Introduction: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous.

Methods: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data.

Results: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10^-8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10^-9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10^-8).

Discussion: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD.

Highlights: We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD. We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE.

Keywords: Alzheimer's disease; genetics; rare genetic variants; whole genome sequencing.

Grants and funding

AG/NIA NIH HHS/United States