A specialized reference panel with structural variants integration for improving genotype imputation in Alzheimer disease and related dementias
Po-Liang Cheng,
Hui Wang,
Beth A. Dombroski,
John J. Farrell,
Iris Horng,
Tingting Chung,
Giuseppe Tosto,
Brian W. Kunkle,
William S. Bush,
Badri Vardarajan,
Gerard D. Schellenberg,
Wan-Ping Lee
Affiliations
Po-Liang Cheng
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Hui Wang
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Beth A. Dombroski
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
John J. Farrell
Biomedical Genetics, Department of Medicine, Boston University Medical School, Boston, MA, USA
Iris Horng
Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Tingting Chung
Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Giuseppe Tosto
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY 10032, USA
Brian W. Kunkle
John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; John T. Macdonald Department of Human Genetics, University of Miami, Miami, FL, USA
William S. Bush
Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA; Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
Badri Vardarajan
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY 10032, USA
Gerard D. Schellenberg
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Wan-Ping Lee
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corresponding author
Summary: We developed an imputation panel for Alzheimer disease (AD) and related dementias (ADRD) using 15,958 whole-genome sequencing (WGS) samples from the Alzheimer Disease Sequencing Project. Recognizing the importance of associations between structural variants (SVs) and AD and their underrepresentation in existing public reference panels, our panel uniquely integrates single-nucleotide variants (SNVs), short insertions or deletions (indels), and SVs. This panel enhances the imputation of rare variants underlying disease susceptibility onto genotype array data, offering a cost-effective alternative to WGS while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominally significantly associated with AD that are absent in the TOPMed-r2 panel and identified one genome-wide significant (p < 5 × 10−8) and three suggestive significant (p < 1 × 10−5) AD-associated SVs. These findings provide the other insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.
