Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer’s Disease Neuropathology and Genetics

Diana J. Zajac, James Simpson, Eric Zhang, Ishita Parikh, Steven Estus

Research output: Contribution to journalArticlepeer-review


The single nucleotide polymorphisms rs35349669 and rs10933431 within Inositol Polyphosphate-5-Phosphatase D (INPP5D) are strongly associated with Alzheimer’s Disease risk. To better understand INPP5D expression in the brain, we investigated INPP5D isoform expression as a function of rs35349669 and rs10933431, as well as Alzheimer’s disease neuropathology, by qPCR and isoform-specific primers. In addition, INPP5D allelic expression imbalance was evaluated relative to rs1141328 within exon 1. Expression of INPP5D isoforms associated with transcription start sites in exon 1 and intron 14 was increased in individuals with high Alzheimer’s disease neuropathology. In addition, a novel variant with 47bp lacking from exon 12 increased expression in Alzheimer’s Disease brains, accounting for 13% of total INPP5D expression, and was found to undergo nonsense-mediated decay. Although inter-individual variation obscured a possible polymorphism effect on INPP5D isoform expression as measured by qPCR, rs35349669 was associated with rs1141328 allelic expression imbalance, suggesting that rs35349669 is significantly associated with full-length INPP5D isoform expression. In summary, expression of INPP5D isoforms with start sites in exon 1 and intron 14 are increased in brains with high Alzheimer’s Disease neuropathology, a novel isoform lacking the phosphatase domain was significantly increased with the disease, and the polymorphism rs35349669 correlates with allele-specific full-length INPP5D expression.

Original languageEnglish
Article number763
Issue number3
StatePublished - Mar 2023

Bibliographical note

Funding Information:
The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 15 January 2023.

Funding Information:
This research was funded by NIH, grant numbers RF1AG059717 (SE), R21AG068370 (SE) and GM118292-03 (DZ). The University of Kentucky Alzheimer’s disease center is supported by 5P30AG028383.

Publisher Copyright:
© 2023 by the authors.


  • Alzheimer’s disease
  • INPP5D
  • SHIP1
  • allelic expression imbalance
  • genetics
  • microglia
  • next-generation sequencing
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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