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Original Investigation
July 24, 2017

Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport

Author Affiliations
  • 1John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
  • 2The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York
  • 3The Gertrude H. Sergievsky Center, Columbia University, New York, New York
  • 4Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York
  • 5Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 6Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 7Department of Medicine (Biomedical Genetics), Schools of Medicine and Public Health, Boston University, Boston, Massachusetts
  • 8Department of Neurology, Schools of Medicine and Public Health, Boston University, Boston, Massachusetts
  • 9Department of Ophthalmology, Schools of Medicine and Public Health, Boston University, Boston, Massachusetts
  • 10Department of Epidemiology, Schools of Medicine and Public Health, Boston University, Boston, Massachusetts
  • 11Department of Biostatistics, Schools of Medicine and Public Health, Boston University, Boston, Massachusetts
  • 12Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio
  • 13Department of Epidemiology, College of Physicians and Surgeons, Columbia University, New York, New York
  • 14Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
JAMA Neurol. Published online July 24, 2017. doi:10.1001/jamaneurol.2017.1518
Key Points

Question  Are there additional rare variants that contribute to the risk of early-onset Alzheimer disease?

Findings  This case-control study of whole-exome sequencing of 93 patients within early-onset Alzheimer disease cases followed by testing of candidate risk variants found an association between several endolysosomal-related variants and genes with early-onset and late-onset Alzheimer disease. These included suggestive evidence of association for variants in the genes RIN3 and RUFY1, a significant association with a variant in TCIRG1, and a significant gene-based association with PSD2.

Meaning  This study highlights the involvement of additional endolysosomal genes in the risk of both early- and late-onset Alzheimer disease.

Abstract

Importance  Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD.

Objective  To search for rare variants contributing to the risk for EOAD.

Design, Setting, and Participants  In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer’s Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016.

Main Outcomes and Measures  Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test–optimal gene tests, respectively.

Results  Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10−6; Bonferroni-corrected P value [BP] = 1.3 × 10−3) and LOAD (P = 6.22 × 10−6; BP = 4.1 × 10−3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10−4; BP = 5.0 × 10−3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129).

Conclusions and Relevance  The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport—a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2.

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