Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease

Kwangsik Nho, Sungeun Kim, Emrin Horgusluoglu, Shannon L. Risacher, Li Shen, Dokyoon Kim, Seunggeun Lee, Tatiana Foroud, Leslie M. Shaw, John Q. Trojanowski, Paul S. Aisen, Ronald C. Petersen, Clifford R. Jack, Michael W. Weiner, Robert C. Green, Arthur W. Toga, Andrew Saykin

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer’s disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Methods: Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE’s vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results: A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10−3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Conclusions: Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.

Original languageEnglish (US)
Article number29
JournalBMC Medical Genomics
Volume10
DOIs
StatePublished - May 24 2017

Fingerprint

Neuroimaging
Cerebrospinal Fluid
Alzheimer Disease
Biomarkers
Genes
Endophenotypes
Genotype
Frontal Lobe
Temporal Lobe
Amyloid
Chromosomes, Human, Pair 19
Entorhinal Cortex
Parietal Lobe
Brain
Gene Frequency
Alleles
Genome
DNA

Keywords

  • ADNI
  • CSF
  • Near APOE
  • Neuroimaging
  • Rare variants
  • Whole genome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease. / Nho, Kwangsik; Kim, Sungeun; Horgusluoglu, Emrin; Risacher, Shannon L.; Shen, Li; Kim, Dokyoon; Lee, Seunggeun; Foroud, Tatiana; Shaw, Leslie M.; Trojanowski, John Q.; Aisen, Paul S.; Petersen, Ronald C.; Jack, Clifford R.; Weiner, Michael W.; Green, Robert C.; Toga, Arthur W.; Saykin, Andrew.

In: BMC Medical Genomics, Vol. 10, 29, 24.05.2017.

Research output: Contribution to journalArticle

Nho, K, Kim, S, Horgusluoglu, E, Risacher, SL, Shen, L, Kim, D, Lee, S, Foroud, T, Shaw, LM, Trojanowski, JQ, Aisen, PS, Petersen, RC, Jack, CR, Weiner, MW, Green, RC, Toga, AW & Saykin, A 2017, 'Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease', BMC Medical Genomics, vol. 10, 29. https://doi.org/10.1186/s12920-017-0267-0
Nho, Kwangsik ; Kim, Sungeun ; Horgusluoglu, Emrin ; Risacher, Shannon L. ; Shen, Li ; Kim, Dokyoon ; Lee, Seunggeun ; Foroud, Tatiana ; Shaw, Leslie M. ; Trojanowski, John Q. ; Aisen, Paul S. ; Petersen, Ronald C. ; Jack, Clifford R. ; Weiner, Michael W. ; Green, Robert C. ; Toga, Arthur W. ; Saykin, Andrew. / Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease. In: BMC Medical Genomics. 2017 ; Vol. 10.
@article{ab5ea1317c884354a9e376e005f8e507,
title = "Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease",
abstract = "Background: The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer’s disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Methods: Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE’s vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results: A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10−3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Conclusions: Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.",
keywords = "ADNI, CSF, Near APOE, Neuroimaging, Rare variants, Whole genome sequencing",
author = "Kwangsik Nho and Sungeun Kim and Emrin Horgusluoglu and Risacher, {Shannon L.} and Li Shen and Dokyoon Kim and Seunggeun Lee and Tatiana Foroud and Shaw, {Leslie M.} and Trojanowski, {John Q.} and Aisen, {Paul S.} and Petersen, {Ronald C.} and Jack, {Clifford R.} and Weiner, {Michael W.} and Green, {Robert C.} and Toga, {Arthur W.} and Andrew Saykin",
year = "2017",
month = "5",
day = "24",
doi = "10.1186/s12920-017-0267-0",
language = "English (US)",
volume = "10",
journal = "BMC Medical Genomics",
issn = "1755-8794",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer’s disease

AU - Nho, Kwangsik

AU - Kim, Sungeun

AU - Horgusluoglu, Emrin

AU - Risacher, Shannon L.

AU - Shen, Li

AU - Kim, Dokyoon

AU - Lee, Seunggeun

AU - Foroud, Tatiana

AU - Shaw, Leslie M.

AU - Trojanowski, John Q.

AU - Aisen, Paul S.

AU - Petersen, Ronald C.

AU - Jack, Clifford R.

AU - Weiner, Michael W.

AU - Green, Robert C.

AU - Toga, Arthur W.

AU - Saykin, Andrew

PY - 2017/5/24

Y1 - 2017/5/24

N2 - Background: The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer’s disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Methods: Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE’s vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results: A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10−3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Conclusions: Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.

AB - Background: The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer’s disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Methods: Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE’s vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). Results: A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ1-42 (p < 1.0 × 10−3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Conclusions: Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.

KW - ADNI

KW - CSF

KW - Near APOE

KW - Neuroimaging

KW - Rare variants

KW - Whole genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85019547754&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019547754&partnerID=8YFLogxK

U2 - 10.1186/s12920-017-0267-0

DO - 10.1186/s12920-017-0267-0

M3 - Article

VL - 10

JO - BMC Medical Genomics

JF - BMC Medical Genomics

SN - 1755-8794

M1 - 29

ER -