Association of Common and Rare Variants with Alzheimer's Disease in over 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; 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; Gerard D Schellenberg; Anita L Destefano; Jonathan L Haines; Gina M Peloso

doi:10.1101/2023.09.01.23294953

Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project

medRxiv [Preprint]. 2023 Sep 2:2023.09.01.23294953. doi: 10.1101/2023.09.01.23294953.

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, Adam Naj¹⁰, Elizabeth E Blue^{11

12}, Frederick Nusetor³, Dongyu Wang³, Eric Boerwinkle¹³, William S Bush^{14

15}, Xiaoling Zhang^{3

8}, Philip L De Jager¹⁶, Josée Dupuis^{3

17}, Lindsay A Farrer^{3

5

6

8

18

19}, Myriam Fornage^{20

21}, Eden Martin^{22

23

24}, Margaret Pericak-Vance^{22

23

24}, Sudha Seshadri²⁵, Ellen M Wijsman^{11

26

27}, Li-San Wang^{1

2}, Gerard D Schellenberg^{1

2}, Anita L Destefano^{3

5}, Jonathan L Haines^{14

15}, Gina M Peloso³

Affiliations

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

Abstract

Alzheimer's Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near APOE, BIN1, and LINC00320 significantly associated with AD (p < 5×10^-8). Population-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5×10^-5) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4×10^-6), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2×10^-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.

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Abstract

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