Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease
Introduction
The quest to identify genes that influence brain integrity or degeneration has been greatly accelerated by large-scale scanning and genotyping of subjects with Alzheimer's disease (AD) and those at risk with amnestic mild cognitive impairment (MCI). Here we developed a high-resolution mapping approach to associate 546,314 genomic markers with regional volumetric differences in the brain MRI scans of 742 subjects. The resulting study is the largest brain mapping to date that has used genome-wide scans, which we applied to create point-by-point maps of genetic association. We found that lower temporal lobe volumes were most associated with a common variant in the glutamate receptor gene, GRIN2B. In addition, this risk allele was statistically over-represented in AD and MCI vs. elderly control subjects.
Structural brain degeneration is a characteristic of AD and MCI (Du et al., 2001, Apostolova et al., 2007, Thompson et al., 2007), a condition with 5-fold increased risk for subsequent development of AD (Petersen et al., 1999, Petersen, 2000). In AD, the hippocampus and entorhinal cortex of the temporal lobes are typically the first structures to degenerate (Braak and Braak, 1991, Thompson et al., 2003). Temporal lobe volume differences are detectable on structural brain MRI through delineation of the hippocampus (Morra et al., 2009) or by tensor-based morphometry (Hua et al., 2008), which plots the 3D profile of volume loss or gain relative to a template. Lower temporal lobe volume is a well known biological marker and risk factor for AD and MCI (Hua et al., 2008), and reflects both cellular atrophy (shrinkage) and overt neuronal loss (Brun and Englund, 1981). In young healthy adults, twin studies attribute ∼ 50% of the temporal lobe volume variation (Brun et al., 2008) and 40–69% of hippocampal volume variation (Peper et al., 2007) to genetic influences.
Late-onset AD is genetically complex; most likely, many genes with small effects contribute to the overall disease phenotype (Tanzi, 1999, Waring and Rosenberg, 2008). Several genetic variants are known to increase the risk for late-onset AD including those in the CLU and PICALM genes (Harold et al., 2009, Lambert et al., 2009) and most notably the ε4 allele of the APOE gene (Farrer et al., 1997); however, the ε4 allele is found in only around 38% of those with AD (relative to 14% of healthy subjects), and these genetic variants do not account for the full genetic risk for late-onset AD (Farrer et al., 1997, Bertram et al., 2007). Risk alleles for AD have been verified by comparing allele frequencies of common polymorphisms between AD patients and healthy controls (Bertram et al., 2007). Here, instead of first comparing the incidence of genetic polymorphisms between diagnostic categories, we ask a distinct but related question: which common genetic polymorphisms influence brain structure in pathological aging? Progressive temporal lobe and hippocampal atrophy may mediate the link between genes and behavioral deficits, so any genes associated with structural degeneration may be a more powerful way to identify mechanisms of disease onset and cognitive decline. In addition, the gene products identified may become future therapeutic targets.
Prior genome-wide analysis using quantitative traits relevant to disease or brain function has been successful, and will likely help in better understanding the etiology of these processes. Genetic variants in the KIBRA gene were identified using association to memory performance (Papassotiropoulos et al., 2006) and other genetic variants worthy of further study were implicated through studying activation during fMRI tasks of working memory (Potkin et al., 2009a).
In a large-scale genetic analysis of 742 subjects, we set out to identify common genetic polymorphisms that influence brain structure in the elderly. By enforcing a genome-wide statistical threshold to avoid false positives, and incorporating prior knowledge of genetic mechanisms in biochemical pathways relevant to aging and AD, we identified 2 regions on the genome that are strongly associated with temporal lobe structure. The structure-modifying genetic variants were further assessed by comparing allele frequencies between AD patients and healthy controls, a common method to validate a candidate risk gene (Bertram et al., 2007). The function of the most strongly associated gene, already known from prior studies of glutamate receptors, is highly relevant to learning and memory, and relates to current therapeutic strategies for AD (i.e., memantine drug treatment) (Parsons et al., 2007).
Section snippets
Sample
Neuroimaging and genetic data were acquired from 818 subjects as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large five-year study launched in 2004 by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Food and Drug Administration (FDA), private pharmaceutical companies, and non-profit organizations, as a $60 million, public–private partnership. The goal of the ADNI study is to determine biological markers of
Population stratification
Population stratification is a known problem in genetic association analyses, which can produce false-positive or false-negative results (McCarthy et al., 2008). When multiple subpopulations are present in the data (population stratification), spurious associations (or lack of associations) can result from allele frequency differences between populations rather than associations with the phenotype (Lander and Schork, 1994). Self-declared Caucasian (non-Hispanic) subjects represented the vast
Discussion
We have identified here two common polymorphisms that are associated with temporal lobe volume with genome-wide support in a large cohort of elderly subjects, assessed with brain imaging and genome-wide scanning. We also identified several potential candidate genes associated with both temporal lobe and hippocampal volume. We identified one SNP within an intergenic region on chromosome 15 which is strongly associated with temporal lobe volume. The most strongly associated polymorphism was
Acknowledgments
Data used in preparing this article were obtained from the Alzheimer's Disease Neuroimaging Initiative database (www.loni.ucla.edu/ADNI). Consequently, many ADNI investigators contributed to the design and implementation of ADNI or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators is available at www.loni.ucla.edu/ADNI/Collaboration/ADNI_Citation.shtml. This work was primarily funded by the ADNI (Principal Investigator:
Glossary
- TBM
- tensor-based morphometry
- MDT
- minimal deformation template
- AD
- Alzheimer's disease
- MCI
- mild cognitive impairment
- ADNI
- Alzheimer's Disease Neuroimaging Initiative
- SNP
- single nucleotide polymorphisms
- NMDA receptor
- N-methyl-d-aspartate glutamate receptor
- LD
- linkage disequilibrium
- OR
- odds ratio
- FDR
- false discovery rate
- EST
- expressed sequence tag
References (67)
- et al.
The power of genomic control
Am. J. Hum. Genet.
(2000) - et al.
A decision-theoretic generalization of on-line learning and an application to boosting
J. Comput. Sys. Sci.
(1997) - et al.
Thresholding of statistical maps in functional neuroimaging using the false discovery rate
Neuroimage
(2002) - et al.
Tensor-based morphometry as a neuroimaging biomarker for Alzheimer's disease: an MRI study of 676 AD, MCI, and normal subjects
Neuroimage
(2008) - et al.
A non-organic and non-enzymatic extraction method gives higher yields of genomic DNA from whole-blood samples than do nine other methods tested
J. Biochem. Biophys. Methods
(1992) - et al.
Validation of a fully automated 3D hippocampal segmentation method using subjects with Alzheimer's disease mild cognitive impairment, and elderly controls
Neuroimage
(2008) - et al.
The application of serial MRI analysis techniques to the study of cerebral atrophy in late-onset dementia
Med. Image Anal.
(2004) - et al.
Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse
Neuropharmacology
(2007) - et al.
PLINK: a tool set for whole-genome association and population-based linkage analyses
Am. J. Hum. Genet.
(2007) - et al.
mRNA distribution in adult human brain of GRIN2B, a N-methyl-d-aspartate (NMDA) receptor subunit
Neurosci. Lett.
(1997)
Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity
Neuropharmacology
Allen Institute Human Cortex Study
Three-dimensional gray matter atrophy mapping in mild cognitive impairment and mild Alzheimer disease
Arch. Neurol.
Haploview: analysis and visualization of LD and haplotype maps
Bioinformatics
Controlling the False Discovery Rate — a practical and powerful approach to multiple testing
J. R. Stat. Soc. B Methodol.
Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database
Nat. Genet.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol.
Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading
Histopathology
A tensor-based morphometry study of genetic influences on brain structure using a new fluid registration method
Int. Conf. Med. Image Comput. Comput. Assist. Interv.
Sex differences in brain structure in auditory and cingulate regions
Neuroreport
Endophenotypes in the genetic analyses of mental disorders
Annu. Rev. Clin. Psychol.
Mini-Mental State Examination (MMSE)
Psychopharmacol. Bull.
Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer's disease
J. Neurol. Neurosurg. Psychiatry
Estimation of significance thresholds for genomewide association scans
Genet. Epidemiol.
Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium
JAMA
A second generation human haplotype map of over 3.1 million SNPs
Nature
The clinical use of structural MRI in Alzheimer's disease
Nat. Rev. Neurol.
The endophenotype concept in psychiatry: etymology and strategic intentions
Am. J. Psychiatry
Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease
Nat. Genet.
The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods
J. Magn. Reson. Imaging
The relationship between corpus callosum size and forebrain volume
Cereb. Cortex
Efficient control of population structure in model organism association mapping
Genetics
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Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI investigators include (complete listing available at http://www.loni.ucla.edu/ADNI/Collaboration/ADNI_Manuscript_Citations.pdf).