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

Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)213-221
Number of pages9
JournalNeurobiology of Aging
Volume81
DOIs
StatePublished - Sep 1 2019

Fingerprint

Cerebrovascular Circulation
Alzheimer Disease
Phenotype
Genes
Endophenotypes
Parietal Lobe
Single Nucleotide Polymorphism
Blood Vessels
Brain
Neuroimaging

Keywords

  • Alzheimer's disease
  • Cerebral blood flow
  • Genetics
  • INPP5D
  • Neurovascular

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene. / Alzheimer's Disease Neuroimaging Initiative.

In: Neurobiology of Aging, Vol. 81, 01.09.2019, p. 213-221.

Research output: Contribution to journalArticle

Alzheimer's Disease Neuroimaging Initiative. / Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene. In: Neurobiology of Aging. 2019 ; Vol. 81. pp. 213-221.
@article{9a86cbf8ab744cd49e9bcb40e0357fa5,
title = "Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene",
abstract = "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.",
keywords = "Alzheimer's disease, Cerebral blood flow, Genetics, INPP5D, Neurovascular",
author = "{Alzheimer's Disease Neuroimaging Initiative} and Xiaohui Yao and Risacher, {Shannon L.} and Kwangsik Nho and Andrew Saykin and Ze Wang and Li Shen",
year = "2019",
month = "9",
day = "1",
doi = "10.1016/j.neurobiolaging.2019.06.003",
language = "English (US)",
volume = "81",
pages = "213--221",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene

AU - Alzheimer's Disease Neuroimaging Initiative

AU - Yao, Xiaohui

AU - Risacher, Shannon L.

AU - Nho, Kwangsik

AU - Saykin, Andrew

AU - Wang, Ze

AU - Shen, Li

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Cerebral blood flow

KW - Genetics

KW - INPP5D

KW - Neurovascular

UR - http://www.scopus.com/inward/record.url?scp=85068833198&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068833198&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2019.06.003

DO - 10.1016/j.neurobiolaging.2019.06.003

M3 - Article

C2 - 31319229

AN - SCOPUS:85068833198

VL - 81

SP - 213

EP - 221

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -