. 2024 Dec;20(12):8470-8483.

doi: 10.1002/alz.14283. Epub 2024 Oct 20.

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^{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
PMCID: PMC11667527
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

Wan-Ping Lee et al. Alzheimers Dement. 2024 Dec.

. 2024 Dec;20(12):8470-8483.

doi: 10.1002/alz.14283. Epub 2024 Oct 20.

Authors

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
PMCID: PMC11667527
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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Study overview. Three types of association analyses in four sets of individuals were performed, pooled samples, non‐Hispanic Whites (NHW), African Americans (AA), and Hispanics (HIS). The pooled samples set included all individuals in the NHW, AA, and HIS sets, plus individuals that were not defined to be in one of those subsets.

**FIGURE 2**
Association of *APOE* alleles with AD by subgroup. AA, African American; AD, Alzheimer's disease; *APOE*, apolipoprotein E; CI, confidence interval; HIS, Hispanic; LCL, lower confidence limit; MAF, minor allele frequency; NHW, non‐Hispanic White; OR, odds ratio; PP, pooled population (samples); UCL, upper confidence limit.

**FIGURE 3**
Association of *PSEN1* with AD by subgroup, with and without p.G206A (rs63750082) included. We performed aggregated‐based association testing for variants within *PSEN1* in the pooled sample as well as in each subgroup. We then removed the p.G206A variant (rs63750082) from the aggregation‐based test. We observed that the odds ratio and p value reduced significantly after excluding rs63750082 in the Hispanic subset but the results remained consistent in the NHW and AA subsets. AA, Black or African American; AD, Alzheimer's disease; CI, confidence interval; cMAC, cumulative minor allele counts across the variants contributing to the analysis; N variant, number of variants contributing to the analysis; NHW, non‐Hispanic White.

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Update of

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.
Lee WP, Choi SH, Shea MG, Cheng PL, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, Naj A, Blue EE, Nusetor F, Wang D, Boerwinkle E, Bush WS, Zhang X, De Jager PL, Dupuis J, Farrer LA, Fornage M, Martin E, Pericak-Vance M, Seshadri S, Wijsman EM, Wang LS, Schellenberg GD, Destefano AL, Haines JL, Peloso GM. Lee WP, et al. medRxiv [Preprint]. 2023 Sep 2:2023.09.01.23294953. doi: 10.1101/2023.09.01.23294953. medRxiv. 2023. Update in: Alzheimers Dement. 2024 Dec;20(12):8470-8483. doi: 10.1002/alz.14283. PMID: 37693521 Free PMC article. Updated. Preprint.

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous