Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease 06 Biological Sciences 0604 Genetics

Jason E. Miller, Manu K. Shivakumar, Younghee Lee, Seonggyun Han, Emrin Horgousluoglu, Shannon L. Risacher, Andrew Saykin, Kwangsik Nho, Dokyoon Kim

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that causes problems related to brain function. To some extent it is understood on a molecular level how AD arises, however there are a lack of biomarkers that can be used for early diagnosis. Two popular methods to identify AD-related biomarkers use genetics and neuroimaging. Genes and neuroimaging phenotypes have provided some insights as to the potential for AD biomarkers. While the field of imaging-genomics has identified genetic features associated with structural and functional neuroimaging phenotypes, it remains unclear how variants that affect splicing could be important for understanding the genetic etiology of AD. Methods: In this study, rare variants (minor allele frequency < 0.01) in splicing regulatory element (SRE) loci from whole genome sequencing (WGS) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, were used to identify genes that are associated with global brain cortical glucose metabolism in AD measured by FDG PET-scans. Gene-based associated analyses of rare variants were performed using the program BioBin and the optimal Sequence Kernel Association Test (SKAT-O). Results: The gene, EXOC3L4, was identified as significantly associated with global cortical glucose metabolism (FDR (false discovery rate) corrected p < 0.05) using SRE coding variants only. Three loci that may affect splicing within EXOC3L4 contribute to the association. Conclusion: Based on sequence homology, EXOC3L4 is likely a part of the exocyst complex. Our results suggest the possibility that variants which affect proper splicing of EXOC3L4 via SREs may impact vesicle transport, giving rise to AD related phenotypes. Overall, by utilizing WGS and functional neuroimaging we have identified a gene significantly associated with an AD related endophenotype, potentially through a mechanism that involves splicing.

Original languageEnglish (US)
Article number76
JournalBMC Medical Genomics
Volume11
DOIs
StatePublished - Sep 14 2018

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Biological Science Disciplines
Alzheimer Disease
Glucose
Brain
Neuroimaging
Functional Neuroimaging
Biomarkers
Genes
Phenotype
Genome
Endophenotypes
Transport Vesicles
Sequence Homology
Genomics
Gene Frequency
Neurodegenerative Diseases
Positron-Emission Tomography
Early Diagnosis

Keywords

  • Alternative splicing
  • Alzheimer's disease
  • Imaging genomics
  • Rare variants
  • Whole genome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease 06 Biological Sciences 0604 Genetics. / Miller, Jason E.; Shivakumar, Manu K.; Lee, Younghee; Han, Seonggyun; Horgousluoglu, Emrin; Risacher, Shannon L.; Saykin, Andrew; Nho, Kwangsik; Kim, Dokyoon.

In: BMC Medical Genomics, Vol. 11, 76, 14.09.2018.

Research output: Contribution to journalArticle

Miller, Jason E. ; Shivakumar, Manu K. ; Lee, Younghee ; Han, Seonggyun ; Horgousluoglu, Emrin ; Risacher, Shannon L. ; Saykin, Andrew ; Nho, Kwangsik ; Kim, Dokyoon. / Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease 06 Biological Sciences 0604 Genetics. In: BMC Medical Genomics. 2018 ; Vol. 11.
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abstract = "Background: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that causes problems related to brain function. To some extent it is understood on a molecular level how AD arises, however there are a lack of biomarkers that can be used for early diagnosis. Two popular methods to identify AD-related biomarkers use genetics and neuroimaging. Genes and neuroimaging phenotypes have provided some insights as to the potential for AD biomarkers. While the field of imaging-genomics has identified genetic features associated with structural and functional neuroimaging phenotypes, it remains unclear how variants that affect splicing could be important for understanding the genetic etiology of AD. Methods: In this study, rare variants (minor allele frequency < 0.01) in splicing regulatory element (SRE) loci from whole genome sequencing (WGS) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, were used to identify genes that are associated with global brain cortical glucose metabolism in AD measured by FDG PET-scans. Gene-based associated analyses of rare variants were performed using the program BioBin and the optimal Sequence Kernel Association Test (SKAT-O). Results: The gene, EXOC3L4, was identified as significantly associated with global cortical glucose metabolism (FDR (false discovery rate) corrected p < 0.05) using SRE coding variants only. Three loci that may affect splicing within EXOC3L4 contribute to the association. Conclusion: Based on sequence homology, EXOC3L4 is likely a part of the exocyst complex. Our results suggest the possibility that variants which affect proper splicing of EXOC3L4 via SREs may impact vesicle transport, giving rise to AD related phenotypes. Overall, by utilizing WGS and functional neuroimaging we have identified a gene significantly associated with an AD related endophenotype, potentially through a mechanism that involves splicing.",
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T1 - Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease 06 Biological Sciences 0604 Genetics

AU - Miller, Jason E.

AU - Shivakumar, Manu K.

AU - Lee, Younghee

AU - Han, Seonggyun

AU - Horgousluoglu, Emrin

AU - Risacher, Shannon L.

AU - Saykin, Andrew

AU - Nho, Kwangsik

AU - Kim, Dokyoon

PY - 2018/9/14

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AB - Background: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that causes problems related to brain function. To some extent it is understood on a molecular level how AD arises, however there are a lack of biomarkers that can be used for early diagnosis. Two popular methods to identify AD-related biomarkers use genetics and neuroimaging. Genes and neuroimaging phenotypes have provided some insights as to the potential for AD biomarkers. While the field of imaging-genomics has identified genetic features associated with structural and functional neuroimaging phenotypes, it remains unclear how variants that affect splicing could be important for understanding the genetic etiology of AD. Methods: In this study, rare variants (minor allele frequency < 0.01) in splicing regulatory element (SRE) loci from whole genome sequencing (WGS) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, were used to identify genes that are associated with global brain cortical glucose metabolism in AD measured by FDG PET-scans. Gene-based associated analyses of rare variants were performed using the program BioBin and the optimal Sequence Kernel Association Test (SKAT-O). Results: The gene, EXOC3L4, was identified as significantly associated with global cortical glucose metabolism (FDR (false discovery rate) corrected p < 0.05) using SRE coding variants only. Three loci that may affect splicing within EXOC3L4 contribute to the association. Conclusion: Based on sequence homology, EXOC3L4 is likely a part of the exocyst complex. Our results suggest the possibility that variants which affect proper splicing of EXOC3L4 via SREs may impact vesicle transport, giving rise to AD related phenotypes. Overall, by utilizing WGS and functional neuroimaging we have identified a gene significantly associated with an AD related endophenotype, potentially through a mechanism that involves splicing.

KW - Alternative splicing

KW - Alzheimer's disease

KW - Imaging genomics

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KW - Whole genome sequencing

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