Large‐scale sequencing studies expand the known genetic architecture of Alzheimer's disease

Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring

The Alzheimer's Disease Sequencing Project¹  Joshua C. Bis²  Anita L. DeStefano³  Lindsay Farrer³  Alison Goate⁴  Edoardo A. Marcora⁴  Alan E. Renton⁴  Jonathan L. Haines⁵  William S. Bush⁵  Sudha Seshadri⁶  Eric Boerwinkle⁷  Diane Xue⁸  Ellen Wijsman⁸  Elizabeth E. Blue⁸  Gerard Schellenberg⁹  Richard Mayeux^1,10  Margaret Pericak‐Vance^1,11  Brian W. Kunkle^1,11 

[1] ;Cardiovascular Health Research Unit Department of Medicine University of Washington Seattle Washington USA;Department of Biostatistics Boston University Boston Massachusetts USA;Department of Genetics and Genomic Sciences Nash Family Department of Neuroscience and Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York New York USA;Department of Population and Quantitative Health Sciences and Department of Genetics and Genome Sciences Case Western Reserve University Cleveland Ohio USA;Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases and Department of Neurology University of Texas Health Science Center San Antonio Texas USA;Human Genome Sequencing Center Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA;Institute for Public Health Genetics University of Washington Seattle Washington USA;Penn Neurodegeneration Genomics Center Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia Pennsylvania USA;Taub Institute for Research on Alzheimer's Disease and the Aging Brain Gertrude H. Sergievsky Center Department of Neurology Department of Psychiatry and Epidemiology Columbia University New York New York USA;The John P. Hussman Institute for Human Genomics University of Miami Miami Florida USA;

关键词: Alzheimer's disease;    genetic architecture;    genome;    networks;    pathways;   

DOI  :  10.1002/dad2.12255

来源: DOAJ

【 摘 要 】

Abstract Introduction Genes implicated by genome‐wide association studies and family‐based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project (ADSP) may bridge this gap and highlight shared biological mechanisms. Methods We performed structured literature review of genes prioritized by ADSP studies, genes underlying familial dementias, and genes nominated by genome‐wide association studies. Gene set enrichment analyses of each list identified enriched pathways. Results The genes prioritized by the ADSP, familial dementia studies, and genome‐wide association studies minimally overlapped. Each gene set identified dozens of enriched pathways, several of which were shared (e.g., regulation of amyloid beta clearance). Discussion Alternative study designs provide unique insights into AD genetics. Shared pathways enriched by different genes highlight their relevance to AD pathogenesis, while the patterns of pathway enrichment unique to each gene set provide additional targets for functional studies.

【 授权许可】

Unknown