Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene

• Published in: Neurobiology of aging Vol. 81; pp. 213 - 221
• Main Authors: Yao, Xiaohui, Risacher, Shannon L., Nho, Kwangsik, Saykin, Andrew J., Wang, Ze, Shen, Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - cerebrospinal fluid; Cerebral blood flow; Cerebrovascular Circulation - genetics; Endophenotypes; Female; Genetics; Humans; INPP5D; Male; Neuroimaging; Neurovascular; Parietal Lobe - blood supply; Peptide Fragments - cerebrospinal fluid; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - genetics; Polymorphism, Single Nucleotide; tau Proteins - cerebrospinal fluid; Neurovascular; Genetics; Cerebral blood flow; Alzheimer's disease; INPP5D
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2019.06.003

The vascular hypothesis of Alzheimer's disease (AD) has proposed the involvement of brain hypoperfusion in AD pathogenesis, where cognitive decline and dysfunction result from dwindling cerebral blood flow (CBF). Based on the vascular hypothesis of Alzheimer's disease, we focused on exploring how genetic factors influence AD pathogenesis via the cerebrovascular system. To investigate the role of CBF endophenotypes in AD pathogenesis, we performed a targeted genetic analysis of 258 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort to examine associations between 4033 single-nucleotide polymorphisms of 24 AD genes and CBF measures in 4 brain regions. A novel association with CBF measure in the left angular gyrus was identified in an INPP5D single-nucleotide polymorphism (i.e., rs61068452; p = 1.48E-7; corrected p = 2.39E-3). The gene-based analysis discovered both INPP5D and CD2AP associated with the left angular gyrus CBF. Further analyses on nonoverlapping samples revealed that rs61068452-G was associated with lower CSF t-tau/Aβ1–42 ratio. Our findings suggest a protective role of rs61068452-G in an AD-relevant cerebrovascular endophenotype, which has the potential to provide novel insights for better mechanistic understanding of AD. •We performed a targeted genetic study of CBF phenotypes captured by arterial spin labeling (ASL) perfusion magnetic resonance imaging (pMRI).•We discovered a novel locus in INPP5D (rs61068452) significantly associated with the CBF measure in the L-AG.•The identified genetic variation was also associated with several AD biomarkers.•This work is among the first genetic association studies of CBF in AD, and our finding has the potential to help understand AD molecular mechanism.