Elsevier

Neurobiology of Aging

Volume 39, March 2016, Pages 82-89
Neurobiology of Aging

Regular article
Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy

https://doi.org/10.1016/j.neurobiolaging.2015.10.037Get rights and content

Abstract

The precise physiologic function of many of the recently discovered Alzheimer's disease risk variants remains unknown. The downstream effects of genetic variants remain largely unexplored. We studied the relationship between the top 10 non-APOE genes with cortical and hippocampal atrophy as markers of neurodegeneration using 1.5T magnetic resonance imaging, 1-million single nucleotide polymorphism Illumina Human Omni-Quad array and Illumina Human BeadChip peripheral blood expression array data on 50 cognitively normal and 98 mild cognitive impairment subjects. After explicit matching of cortical and hippocampal morphology, we computed in 3D, the cortical thickness and hippocampal radial distance measures for each participant. Associations between the top 10 non-APOE genome-wide hits and neurodegeneration were explored using linear regression. Map-wise statistical significance was determined with permutations using threshold of p < 0.01. MS4A6A rs610932 and ABCA7 rs3764650 demonstrated significant associations with cortical and hippocampal atrophy. Exploratory MS4A6A and ABCA7 peripheral blood expression analyses revealed a similar pattern of associations with cortical neurodegeneration. To our knowledge, this is the first report of the effect of ABCA7 and MS4A6A on neurodegeneration.

Introduction

Alzheimer's disease (AD) is the leading cause of dementia and the sixth overall cause of death in the United States (Alzheimer's_Association, 2014). The prevalence of AD and other types of dementia in the elderly is steadily on the rise largely due to increased longevity (Alzheimer's_Association, 2014). Sporadic AD is 70% heritable (Wingo et al., 2012). The genetics of AD has been a topic of intense research. This has, in recent years, led to the discovery and validation of many genetic variants that influence AD prevalence. Using multiple data sets and genome-wide association approaches the following 9 genes have been ranked, alongside the apolipoprotein E4 (APOE4) gene, as the top 10 AD risk genes—ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, and PICALM (Harold et al., 2009, Hollingworth et al., 2011, Lambert et al., 2009, Seshadri et al., 2010).

The genome-wide association studies approach uses exploratory design to find single nucleotide polymorphisms (SNPs) that are significantly associated with disease presence in the population studied (Harold et al., 2009, Hollingworth et al., 2011, Lambert et al., 2009, Seshadri et al., 2010). The observed effect is then attributed to the gene these SNPs are in or near. This exploratory approach has revealed many new risk variants that have been successfully replicated; yet, for many of these genes, the precise mechanism through which they exert their disease effect remains unknown. One commonly used approach to uncover the AD pathologic process these genetic variants contribute to is to study their association with well-established disease characteristics. The effects of the top 10 AD risk genes on several disease-associated biomarkers have been previously explored. Using this approach, APOE4 has been associated with hippocampal, amygdalar, entorhinal, parahippocampal, and temporopolar atrophy (Biffi et al., 2010) as well as with brain amyloid levels across the stages of AD (Fleisher et al., 2011) and in cognitively normal subjects (Reiman et al., 2009). Of the remaining genes, PICALM rs3851179, CR1 rs1408077, and BIN1 rs7561528 showed an effect on entorhinal atrophy (Biffi et al., 2010). Of these 3 variants, PICALM rs3851179 was also associated with hippocampal atrophy (Biffi et al., 2010). An association with amyloid deposition has been described for ABCA7 rs3764650 (Shulman et al., 2013), ABCA7 rs3752246 (Hughes et al., 2014), BIN1 rs744373 (Hohman et al., 2013), CR1 rs6701713 (Shulman et al., 2013), CR1 rs3818361 (Thambisetty et al., 2013), CR1 rs6656401, and CLU rs3818361 (Hohman et al., 2013). CD2AP rs9349407 has been associated with postmortem neuritic plaque burden in the advanced stages of the disease (Shulman et al., 2013), but interestingly not with PiB binding in nondemented elderly (Hughes et al., 2014).

The present study was designed to further enrich the gene-biomarker association literature. We investigated the association between the top 10 non-APOE AD risk genes as listed on AlzGene (http://www.alzgene.org) with the 2 most established structural AD biomarkers to date—cortical and hippocampal atrophy. We also explored the associations between the peripheral blood expression of the 2 significant genes and neurodegeneration.

Section snippets

Subjects

All subjects were assessed to meet the inclusion and/or exclusion criteria set by the UCLA Imaging and Genetic Biomarkers for AD (ImaGene) study. ImaGene has prospectively enrolled and follows 50 cognitively normal (NC) and 98 mild cognitive impairment (MCI) subjects. ImaGene subjects were identified and recruited from 2 sources: (1) referring UCLA and outside neurologists and (2) our Alzheimer's Disease Research Center (ADRC) ongoing longitudinal database study. The latter group consists of

Results

Only 2 of the 9 risk-associated variants—MS4A6A rs610932 and ABCA7 rs3764650—showed significant associations with cortical and hippocampal atrophy in the ImaGene sample. The baseline demographic characteristics of our sample grouped by MS4A6A rs610932 and ABCA7 rs3764650 carrier status are listed in Table 1. We found no significant differences in age, sex, education, baseline diagnosis, and APOE4 genotype between risk allele carriers and noncarriers. MS4A6A rs610932 protective allele A carriers

Discussion

In our study, we found an association between ABCA7 and MS4A6A and their peripheral blood expression levels with cortical and hippocampal atrophy. To our knowledge, these associations have not been previously described.

The associations of ABCA7 and MS4A6A risk variants with AD prevalence were first described in 2011 (Hollingworth et al., 2011) and have since been well replicated (Beecham et al., 2014, Kamboh et al., 2012, Naj et al., 2011, Reitz et al., 2013). ABCA7 is a member of the ABC

Conclusions

In summary, this is to our knowledge the first report of an association of MS4A6A and ABCA7 and their peripheral blood expression levels with neurodegeneration in the normal and mildly impaired cognitive spectrum. Our work further extends the growing literature on the effects of these 2 genes on the brain and suggests that peripheral blood genetic markers might prove useful in clinical screening and disease monitoring.

Disclosure statement

The authors have no conflicts of interest to disclose.

Acknowledgements

This work has been generously supported by NIA studies R01 AG040770, K02 AG048240, P50 AG16570, P30 AG010133 and the Easton Consortium for Alzheimer's Drug Discovery and Biomarker Development.

References (67)

  • D.W. Shattuck et al.

    Magnetic resonance image tissue classification using a partial volume model

    Neuroimage

    (2001)
  • M. Thambisetty et al.

    Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype

    Biol. Psychiatry

    (2013)
  • P.M. Thompson et al.

    Mapping hippocampal and ventricular change in Alzheimer disease

    Neuroimage

    (2004)
  • J.B. Vasquez et al.

    ABCA7 expression is associated with Alzheimer's disease polymorphism and disease status

    Neurosci. Lett.

    (2013)
  • 2014 Alzheimer’s disease facts and figures

    Alzheimers Dement.

    (2014)
  • L.G. Apostolova et al.

    3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer's disease

    Brain

    (2006)
  • L.G. Apostolova et al.

    Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps

    Arch. Neurol.

    (2006)
  • L.G. Apostolova et al.

    3D mapping of mini-mental state examination performance in clinical and preclinical Alzheimer disease

    Alzheimer Dis. Assoc. Disord.

    (2006)
  • L.G. Apostolova et al.

    Three-dimensional gray matter atrophy mapping in mild cognitive impairment and mild Alzheimer disease

    Arch. Neurol.

    (2007)
  • L.G. Apostolova et al.

    3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI

    Hum. Brain Mapp.

    (2010)
  • G.W. Beecham et al.

    Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias

    PLoS Genet.

    (2014)
  • A.L. Benton et al.

    Multilingual Apahasia Examination

    (1989)
  • A. Biffi et al.

    Genetic variation and neuroimaging measures in Alzheimer disease

    Arch. Neurol.

    (2010)
  • M. Boccardi et al.

    Delphi definition of the EADC-ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance

    Alzheimers Dement.

    (2014)
  • M. Bocchetta et al.

    Harmonized benchmark labels of the hippocampus on magnetic resonance: the EADC-ADNI project

    Alzheimers Dement.

    (2014)
  • S.L. Chan et al.

    ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro

    J. Neurochem.

    (2008)
  • D.L. Collins et al.

    Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space

    J. Comput. Assist. Tomogr.

    (1994)
  • G. Coppola

    Designing, performing, and interpreting a microarray-based gene expression study

    Methods Mol. Biol.

    (2011)
  • D.C. Delis et al.

    California Verbal Learning Test, Form II

    (1987)
  • H. Duvernoy

    The Human hippocampus. An Atlas of Applied Anatomy

    (1988)
  • A.S. Fleisher et al.

    Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease

    Arch. Neurol.

    (2011)
  • R.S.J. Frackowiak et al.

    Human Brain Function

    (2007)
  • G.B. Frisoni et al.

    The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity

    Alzheimers Dement.

    (2014)
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