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1.  Genetic Analysis of Quantitative Phenotypes in AD and MCI: Imaging, Cognition and Biomarkers 
Brain imaging and behavior  2014;8(2):183-207.
The Genetics Core of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer’s disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g. APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g. FRMD6) that were later replicated on different data sets. Several other genes (e.g. APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.
doi:10.1007/s11682-013-9262-z
PMCID: PMC3976843  PMID: 24092460
Alzheimer’s disease; genetic association study; quantitative traits; neuroimaging; biomarker; cognition
2.  Longitudinal Modeling of Cognitive Aging and the TOMM40 Effect 
Background
TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21–29 T residues) poly-T variants within intron 6 of TOMM40 while APOE e3 can be associated with either with a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer’s disease (AD) onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.
Methods
An APOE e4 enriched cohort of 639 cognitively normal individuals age 21–97 years of known TOMM40 genotype underwent longitudinal neuropsychological testing every two years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross sectional and longitudinal effects of age on the auditory verbal learning test long term memory score (AVLT) by APOE, TOMM40, and the interaction between the two.
Results
There were significant effects overall for both TOMM40 (p=0.04 linear effect, p=0.03 quadratic effect) and APOE (p=0.06 linear effect, p=0.008 quadratic effect) with no significant interaction (p=0.63). These differences were age-dependent: there was a significant TOMM40 effect prior to age 60 (p=0.009) characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect; and a significant APOE effect after age 60 (p=0.006) characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.
Conclusion
Both TOMM40 and APOE significantly influence age-related memory performance, but appear to do so independently of each other.
doi:10.1016/j.jalz.2011.11.006
PMCID: PMC3483561  PMID: 23102119
TOMM40; APOE; preclinical Alzheimer’s disease; cognitive aging; age-related memory loss; mitochondria; very long term memory; test-retest effects
3.  Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers 
Brain Imaging and Behavior  2013;8:183-207.
The Genetics Core of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer’s disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.
Electronic supplementary material
The online version of this article (doi:10.1007/s11682-013-9262-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11682-013-9262-z
PMCID: PMC3976843  PMID: 24092460
Alzheimer’s disease; Genetic association study; Quantitative traits; Neuroimaging; Biomarker; Cognition
4.  A coding variant in CR1 interacts with APOE-ɛ4 to influence cognitive decline 
Human Molecular Genetics  2012;21(10):2377-2388.
Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D′ = 1, r2= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ɛ4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q.
doi:10.1093/hmg/dds054
PMCID: PMC3335317  PMID: 22343410
5.  Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(1):11-22.
IMPORTANCE
Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies.
OBJECTIVE
To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD.
DESIGN, SETTING, AND PARTICIPANTS
Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.
MAIN OUTCOMES AND MEASURES
Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age.
RESULTS
Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.
CONCLUSIONS AND RELEVANCE
While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.
doi:10.1001/jamaneurol.2013.4544
PMCID: PMC4056558  PMID: 24276092
6.  Analysis of Copy Number Variation in Alzheimer’s Disease in a Cohort of Clinically Characterized and Neuropathologically Verified Individuals 
PLoS ONE  2012;7(12):e50640.
Copy number variations (CNVs) are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap genes affecting their function and have been shown to be associated with disease. We previously investigated the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment using Alzheimer’s Disease Neuroimaging Initiative (ADNI) and National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study participants, and identified a number of genes overlapped by CNV calls. To confirm the findings and identify other potential candidate regions, we analyzed array data from a unique cohort of 1617 Caucasian participants (1022 AD cases and 595 controls) who were clinically characterized and whose diagnosis was neuropathologically verified. All DNA samples were extracted from brain tissue. CNV calls were generated and subjected to quality control (QC). 728 cases and 438 controls who passed all QC measures were included in case/control association analyses including candidate gene and genome-wide approaches. Rates of deletions and duplications did not significantly differ between cases and controls. Case-control association identified a number of previously reported regions (CHRFAM7A, RELN and DOPEY2) as well as a new gene (HLA-DRA). Meta-analysis of CHRFAM7A indicated a significant association of the gene with AD and/or MCI risk (P = 0.006, odds ratio = 3.986 (95% confidence interval 1.490–10.667)). A novel APP gene duplication was observed in one case sample. Further investigation of the identified genes in independent and larger samples is warranted.
doi:10.1371/journal.pone.0050640
PMCID: PMC3515604  PMID: 23227193
7.  Are Sema5a mutant mice a good model of autism? A behavioral analysis of sensory systems, emotionality and cognition 
Behavioural brain research  2011;225(1):142-150.
Semaphorin 5A (Sema5A) expression is reduced in the brain of individuals with autism, thus mice with reduced Sema5A levels may serve as a model of this neurodevelopmental disorder. We tested male and female Sema5a knockout mice (B6.129P2SEMA5A/J) and C57BL/6J controls for emotionality, visual ability, prepulse inhibition, motor learning and cognition. Overall, there were only two genotype differences in emotionality: Sema5a mutant mice had more stretch-attend postures in the elevated plus-maze and more defecations in the open field. All mice could see, but Sema5a mice had better visual ability than C57BL/6J mice. There were no genotype differences in sensory-motor gating. Sema5a mice showed higher levels of activity in the elevated plus-maze and light/dark transition box, and there were sex by genotype differences in the Rotarod, suggesting a sex difference in balance and coordination differentially affected by Sema5a. There were no genotype effects on cognition: Sema5a mice did not differ from C57BL/6J in the Morris water maze, set-shifting or cued and contextual fear conditioning. In the social recognition test, all mice preferred social stimuli, but there was no preference for social novelty, thus the Sema5A mice do not have a deficit in social behavior. Overall, there were a number of sex differences, with females showing greater activity and males performing better in tests of spatial learning and memory, but no deficits in the behavior of Sema5A mice. We conclude that the Sema5a mice do not meet the behavioral criteria for a mouse model of autism.
doi:10.1016/j.bbr.2011.07.008
PMCID: PMC3170441  PMID: 21777623
semaphorin 5A; autism; mouse; cognition; anxiety
8.  Induction of Pluripotent Stem Cells from Autopsy Donor-Derived Somatic Cells 
Neuroscience letters  2011;502(3):219-224.
Human induced pluripotent stem cells (iPSCs) have become an intriguing approach for neurological disease modeling, because neural lineage-specific cell types that retain the donors' complex genetics can be established in vitro. The statistical power of these iPSC-based models, however, is dependent on accurate diagnoses of the somatic cell donors; unfortunately, many neurodegenerative diseases are commonly misdiagnosed in live human subjects. Postmortem histopathological examination of a donor's brain, combined with premortem clinical criteria, is often the most robust approach to correctly classify an individual as a disease-specific case or unaffected control. In this study, we describe iPSCs generated from a skin biopsy collected postmortem during the rapid autopsy of a 75-year-old male, whole body donor, defined as an unaffected neurological control by both clinical and histopathological criteria. These iPSCs were established in a feeder-free system by lentiviral transduction of the Yamanaka factors, Oct3/4, Sox2, Klf4, and c-Myc. Selected iPSC clones expressed both nuclear and surface antigens recognized as pluripotency markers of human embryonic stem cells (hESCs) and were able to differentiate in vitro into neurons and glia. Statistical analysis also demonstrated that fibroblast proliferation was significantly affected by biopsy site, but not donor age (within an elderly cohort). These results provide evidence that autopsy donor-derived fibroblasts can be successfully reprogrammed into iPSCs, and may provide an advantageous approach for generating iPSC-based neurological disease models.
doi:10.1016/j.neulet.2011.07.048
PMCID: PMC3195418  PMID: 21839145
induced pluripotent stem cells; genetic disease models; diagnostics; neurodegenerative diseases; postmortem; autopsy; neural differentiation
9.  Genome-wide association between DNA methylation and alternative splicing in an invertebrate 
BMC Genomics  2012;13:480.
Background
Gene bodies are the most evolutionarily conserved targets of DNA methylation in eukaryotes. However, the regulatory functions of gene body DNA methylation remain largely unknown. DNA methylation in insects appears to be primarily confined to exons. Two recent studies in Apis mellifera (honeybee) and Nasonia vitripennis (jewel wasp) analyzed transcription and DNA methylation data for one gene in each species to demonstrate that exon-specific DNA methylation may be associated with alternative splicing events. In this study we investigated the relationship between DNA methylation, alternative splicing, and cross-species gene conservation on a genome-wide scale using genome-wide transcription and DNA methylation data.
Results
We generated RNA deep sequencing data (RNA-seq) to measure genome-wide mRNA expression at the exon- and gene-level. We produced a de novo transcriptome from this RNA-seq data and computationally predicted splice variants for the honeybee genome. We found that exons that are included in transcription are higher methylated than exons that are skipped during transcription. We detected enrichment for alternative splicing among methylated genes compared to unmethylated genes using fisher’s exact test. We performed a statistical analysis to reveal that the presence of DNA methylation or alternative splicing are both factors associated with a longer gene length and a greater number of exons in genes. In concordance with this observation, a conservation analysis using BLAST revealed that each of these factors is also associated with higher cross-species gene conservation.
Conclusions
This study constitutes the first genome-wide analysis exhibiting a positive relationship between exon-level DNA methylation and mRNA expression in the honeybee. Our finding that methylated genes are enriched for alternative splicing suggests that, in invertebrates, exon-level DNA methylation may play a role in the construction of splice variants by positively influencing exon inclusion during transcription. The results from our cross-species homology analysis suggest that DNA methylation and alternative splicing are genetic mechanisms whose utilization could contribute to a longer gene length and a slower rate of gene evolution.
doi:10.1186/1471-2164-13-480
PMCID: PMC3526459  PMID: 22978521
10.  Voxelwise gene-wide association study (vGeneWAS): multivariate gene-based association testing in 731 elderly subjects 
Neuroimage  2011;56(4):1875-1891.
Imaging traits provide a powerful and biologically relevant substrate to examine the influence of genetics on the brain. Interest in genome-wide, brain-wide search for influential genetic variants is growing, but has mainly focused on univariate, SNP-based association tests. Moving to gene-based multivariate statistics, we can test the combined effect of multiple genetic variants in a single test statistic. Multivariate models can reduce the number of statistical tests in gene-wide or genome-wide scans and may discover gene effects undetectable with SNP-based methods. Here we present a gene-based method for associating the joint effect of single nucleotide polymorphisms (SNPs) in 18,044 genes across 31,662 voxels of the whole brain in 731 elderly subjects (mean age: 75.56 ± 6.82SD years; 430 males) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Structural MRI scans were analyzed using tensor-based morphometry (TBM) to compute 3D maps of regional brain volume differences compared to an average template image based on healthy elderly subjects. Using the voxel-level volume difference values as the phenotype, we selected the most significantly associated gene (out of 18,044) at each voxel across the brain. No genes identified were significant after correction for multiple comparisons, but several known candidates were re-identified, as were other genes highly relevant to brain function. GAB2, which has been previously associated with late-onset AD, was identified as the top gene in this study, suggesting the validity of the approach. This multivariate, gene-based voxelwise association study offers a novel framework to detect genetic influences on the brain.
doi:10.1016/j.neuroimage.2011.03.077
PMCID: PMC3366726  PMID: 21497199
principal components regression; voxelwise; multivariate; gene-based; GWAS; GAB2 (max. 6 keywords)
11.  Tonic Premarin dose-dependently enhances memory, affects neurotrophin protein levels and alters gene expression in middle-aged rats 
Neurobiology of aging  2009;32(4):680-697.
Premarin™ is the most commonly prescribed estrogenic component of hormone therapy, given since 1942. The current study is the first examining cognitive effects of tonic Premarin treatment in an animal model. Middle-aged ovariectomized (Ovx) rats received vehicle or one of three doses of Premarin (12, 24 or 36 μg daily). Rats were tested on a spatial working and reference memory maze battery. Both Medium- and High- dose Premarin enhanced memory retention, while Low-dose Premarin impaired learning and memory retention. Correlations with serum hormone levels showed that as the ratio of estrone:17β-estradiol increased, animals tended to show better working memory performance. Taken together with the dissociation of dose-specific estrogenic profiles, results suggest that higher levels of estrone, in the presence of 17β-estradiol concentrations higher than that of Ovx levels, may be beneficial for memory. Moreover, Premarin exerted dose and brain-region specific effects on BDNF and NGF protein levels, with most marked changes in cingulate and perirhinal cortices. Hippocampal gene expression profiling demonstrated significant Premarin-induced transcriptional changes in genes linked to plasticity and cognition. These findings indicate that Premarin can impact memory and the brain, and that dosing should be recognized as a clinically relevant factor possibly affecting the direction and efficacy of cognitive outcome.
doi:10.1016/j.neurobiolaging.2009.09.005
PMCID: PMC3016463  PMID: 19883953
Premarin; estrogen; hormone replacement; working memory; spatial memory; neurotrophins; gene expression
12.  A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies 
The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise FST statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, FST was smallest for the comparison with the Russians (FST=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.
doi:10.1038/ejhg.2010.179
PMCID: PMC3062008  PMID: 21150888
Saami; genetic association studies; population structure; population isolates
13.  IDENTIFICATION OF GENETIC VARIANTS USING BARCODED MULTIPLEXED SEQUENCING 
Nature methods  2008;5(10):887-893.
We developed a generalized framework for multiplexed resequencing of targeted regions of the human genome on the Illumina Genome Analyzer using degenerate indexed DNA sequence barcodes ligated to fragmented DNA prior to sequencing. Using this method, the DNA of multiple HapMap individuals was simultaneously sequenced at several ENCODE (ENCyclopedia of DNA Elements) regions. We then evaluated the use of Bayes factors for discovering and genotyping polymorphisms from aligned sequenced reads. If we required that predicted polymorphisms be either previously identified by dbSNP or be visually evident upon reinspection of archived ENCODE traces, we observed a false-positive rate of 11.3% using strict thresholds (Ks>1,000) for predicting variants and 69.6% for lax thresholds (Ks>10). Conversely, false-negative rates ranged from 10.8% to 90.8%, with those at stricter cut-offs occurring at lower coverage (< 10 aligned reads). These results suggest that >90% of genetic variants are discoverable using multiplexed sequencing provided sufficient coverage at the polymorphic base.
doi:10.1038/nmeth.1251
PMCID: PMC3171277  PMID: 18794863
14.  Amyloid pathway-based candidate gene analysis of [11C]PiB-PET in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort 
Brain Imaging and Behavior  2011;6(1):1-15.
Amyloid imaging with [11 C]Pittsburgh Compound-B (PiB) provides in vivo data on plaque deposition in those with, or at risk for, Alzheimer’s disease (AD). We performed a gene-based association analysis of 15 quality-controlled amyloid-pathway associated candidate genes in 103 Alzheimer’s Disease Neuroimaging Initiative participants. The mean normalized PiB uptake value across four brain regions known to have amyloid deposition in AD was used as a quantitative phenotype. The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake. Further investigation at whole-brain voxel-wise level indicated that non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers. DHCR24 has been previously shown to confer resistance against beta-amyloid and oxidative stress-induced apoptosis, thus our findings support a neuroprotective role. Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets.
doi:10.1007/s11682-011-9136-1
PMCID: PMC3256261  PMID: 21901424
Alzheimer’s disease; ADNI; Pathway-based gene analysis; PiB-PET; Endophenotype; Voxel-based analysis
15.  Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE ε4 Allele, the Major Late-Onset Alzheimer's Susceptibility Gene 
In vivoPET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology.
doi:10.3233/JAD-2010-100129
PMCID: PMC3124564  PMID: 20847408
Alzheimer's etiology; bioenergetics; biomarkers; cytochrome c oxidase; differential vulnerability; neocortex
16.  Genomic Copy Number Analysis in Alzheimer's Disease and Mild Cognitive Impairment: An ADNI Study 
Copy number variants (CNVs) are DNA sequence alterations, resulting in gains (duplications) and losses (deletions) of genomic segments. They often overlap genes and may play important roles in disease. Only one published study has examined CNVs in late-onset Alzheimer's disease (AD), and none have examined mild cognitive impairment (MCI). CNV calls were generated in 288 AD, 183 MCI, and 184 healthy control (HC) non-Hispanic Caucasian Alzheimer's Disease Neuroimaging Initiative participants. After quality control, 222 AD, 136 MCI, and 143 HC participants were entered into case/control association analyses, including candidate gene and whole genome approaches. Although no excess CNV burden was observed in cases (AD and/or MCI) relative to controls (HC), gene-based analyses revealed CNVs overlapping the candidate gene CHRFAM7A, as well as CSMD1, SLC35F2, HNRNPCL1, NRXN1, and ERBB4 regions, only in cases. Replication in larger samples is important, after which regions detected here may be promising targets for resequencing.
doi:10.4061/2011/729478
PMCID: PMC3109875  PMID: 21660214
17.  A genome-wide association study for age-related hearing impairment in the Saami 
This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55 × 10−7), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.
doi:10.1038/ejhg.2009.234
PMCID: PMC2987344  PMID: 20068591
Saami; isolated population; mixed model; genome-wide association study; age-related hearing impairment; presbycusis
18.  Genome-wide SNP analysis reveals no gain in power for association studies of common variants in the Finnish Saami 
The Saami from Fennoscandia are believed to represent an ancient, genetically isolated population with no evidence of population expansion. Theoretical work has indicated that under this demographic scenario, extensive linkage disequilibrium (LD) is generated by genetic drift. Therefore, it has been suggested that the Saami would be particularly suited for genetic association studies, offering a substantial power advantage and allowing more economic study designs. However, no study has yet assessed this claim. As part of a GWAS for a complex trait, we evaluated the relative power for association studies of common variants in the Finnish Saami. LD patterns in the Saami were very similar to those in the non-African HapMap reference panels. Haplotype diversity was reduced and, on average, levels of LD were higher in the Saami as compared with those in the HapMap panels. However, using a ‘hidden' SNP approach we show that this does not translate into a power gain in association studies. Contrary to earlier claims, we show that for a given set of common SNPs, genomic coverage attained in the Saami is similar to that in the non-African HapMap panels. Nevertheless, the reduced haplotype diversity could potentially facilitate gene identification, especially if multiple rare variants play a role in disease etiology. Our results further indicate that the HapMap is a useful resource for genetic studies in the Saami.
doi:10.1038/ejhg.2009.210
PMCID: PMC2987317  PMID: 19935831
Saami; genome-wide association studies; linkage disequilibrium; population isolates
19.  Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort 
NeuroImage  2010;53(3):1051-1063.
A genome-wide, whole brain approach to investigate genetic effects on neuroimaging phenotypes for identifying quantitative trait loci is described. The Alzheimer's Disease Neuroimaging Initiative 1.5 T MRI and genetic dataset was investigated using voxel-based morphometry (VBM) and FreeSurfer parcellation followed by genome-wide association studies (GWAS). One hundred forty-two measures of grey matter (GM) density, volume, and cortical thickness were extracted from baseline scans. GWAS, using PLINK, were performed on each phenotype using quality-controlled genotype and scan data including 530,992 of 620,903 single nucleotide polymorphisms (SNPs) and 733 of 818 participants (175 AD, 354 amnestic mild cognitive impairment, MCI, and 204 healthy controls, HC). Hierarchical clustering and heat maps were used to analyze the GWAS results and associations are reported at two significance thresholds (p<10−7 and p<10−6). As expected, SNPs in the APOE and TOMM40 genes were confirmed as markers strongly associated with multiple brain regions. Other top SNPs were proximal to the EPHA4, TP63 and NXPH1 genes. Detailed image analyses of rs6463843 (flanking NXPH1) revealed reduced global and regional GM density across diagnostic groups in TT relative to GG homozygotes. Interaction analysis indicated that AD patients homozygous for the T allele showed differential vulnerability to right hippocampal GM density loss. NXPH1 codes for a protein implicated in promotion of adhesion between dendrites and axons, a key factor in synaptic integrity, the loss of which is a hallmark of AD. A genome-wide, whole brain search strategy has the potential to reveal novel candidate genes and loci warranting further investigation and replication.
doi:10.1016/j.neuroimage.2010.01.042
PMCID: PMC2892122  PMID: 20100581
20.  Voxelwise genome-wide association study (vGWAS) 
NeuroImage  2010;53(3):1160-1174.
The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age±s.d.: 75.52±6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure.
doi:10.1016/j.neuroimage.2010.02.032
PMCID: PMC2900429  PMID: 20171287
21.  Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene 
Hereditary hearing loss is a very heterogeneous trait, with 46 gene identifications for nonsyndromic hearing loss. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive nonsyndromic hearing loss, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the hearing loss of 35delG homozygous patients is mild-to-profound. We hypothesize that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based whole-genome association study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed SNPs according to their p-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant p-values were genotyped in a second independent set of 297 samples for replication. The significant p-values were replicated in nine SNPs, with combined p-values between 3×10−3 and 1×10−4. This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of the greatest importance to confirm these results.
doi:10.1038/ejhg.2008.201
PMCID: PMC2883287  PMID: 18985073
Hereditary hearing loss; connexin 26; 35delG; association study; modifier gene
22.  Genome-Wide Analysis Reveals Novel Genes Influencing Temporal Lobe Structure with Relevance to Neurodegeneration in Alzheimer’s Disease 
NeuroImage  2010;51(2):542-554.
In a genome-wide association study of structural brain degeneration, we mapped the 3D profile of temporal lobe volume differences in 742 brain MRI scans of Alzheimer’s disease patients, mildly impaired, and healthy elderly subjects. After searching 546,314 genomic markers, 2 single nucleotide polymorphisms (SNPs) were associated with bilateral temporal lobe volume (P < 5×10−7). One SNP, rs10845840, is located in the GRIN2B gene which encodes the N-Methyl-D-Aspartate (NMDA) glutamate receptor NR2B subunit. This protein - involved in learning and memory, and excitotoxic cell death - has age-dependent prevalence in the synapse and is already a therapeutic target in Alzheimer’s disease. Risk alleles for lower temporal lobe volume at this SNP were significantly over-represented in AD and MCI subjects versus controls (odds ratio = 1.273; P = 0.039) and were associated with the mini-mental state exam (MMSE; t = −2.114; P = 0.035) demonstrating a negative effect on global cognitive function. Voxelwise maps of genetic association of this SNP with regional brain volumes, revealed intense temporal lobe effects (FDR correction at q = 0.05; critical P = 0.0257). This study uses large-scale brain mapping for gene discovery with implications for Alzheimer’s disease.
doi:10.1016/j.neuroimage.2010.02.068
PMCID: PMC2856746  PMID: 20197096
23.  Alzheimer’s Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans 
The role of the Alzheimer’s Disease Neuroimaging Initiative Genetics Core is to facilitate the investigation of genetic influences on disease onset and trajectory as reflected in structural, functional, and molecular imaging changes; fluid biomarkers; and cognitive status. Major goals include (1) blood sample processing, genotyping, and dissemination, (2) genome-wide association studies (GWAS) of longitudinal phenotypic data, and (3) providing a central resource, point of contact and planning group for genetics within Alzheimer’s Disease Neuroimaging Initiative. Genome-wide array data have been publicly released and updated, and several neuroimaging GWAS have recently been reported examining baseline magnetic resonance imaging measures as quantitative phenotypes. Other preliminary investigations include copy number variation in mild cognitive impairment and Alzheimer’s disease and GWAS of baseline cerebrospinal fluid biomarkers and longitudinal changes on magnetic resonance imaging. Blood collection for RNA studies is a new direction. Genetic studies of longitudinal phenotypes hold promise for elucidating disease mechanisms and risk, development of therapeutic strategies, and refining selection criteria for clinical trials.
doi:10.1016/j.jalz.2010.03.013
PMCID: PMC2868595  PMID: 20451875
Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s disease; Mild cognitive impairment (MCI); Genome-wide association studies (GWAS); Copy number variation (CNV); Magnetic resonance imaging (MRI); Cerebrospinal fluid (CSF)
24.  Initial Assessment of the Pathogenic Mechanisms of the recently identified Alzheimer Risk Loci 
Annals of human genetics  2013;77(2):85-105.
SUMMARY
Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer’s disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology.
Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer’s disease.
doi:10.1111/ahg.12000
PMCID: PMC3578142  PMID: 23360175
Alzheimer’s disease; genetic risk; GWAS
25.  GRM7 variants confer susceptibility to age-related hearing impairment 
Human Molecular Genetics  2008;18(4):785-796.
Age-related hearing impairment (ARHI), or presbycusis, is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. Here we describe the results of the first whole genome association study for ARHI. The study was performed using 846 cases and 846 controls selected from 3434 individuals collected by eight centers in six European countries. DNA pools for cases and controls were allelotyped on the Affymetrix 500K GeneChip® for each center separately. The 252 top-ranked single nucleotide polymorphisms (SNPs) identified in a non-Finnish European sample group (1332 samples) and the 177 top-ranked SNPs from a Finnish sample group (360 samples) were confirmed using individual genotyping. Subsequently, the 23 most interesting SNPs were individually genotyped in an independent European replication group (138 samples). This resulted in the identification of a highly significant and replicated SNP located in GRM7, the gene encoding metabotropic glutamate receptor type 7. Also in the Finnish sample group, two GRM7 SNPs were significant, albeit in a different region of the gene. As the Finnish are genetically distinct from the rest of the European population, this may be due to allelic heterogeneity. We performed histochemical studies in human and mouse and showed that mGluR7 is expressed in hair cells and in spiral ganglion cells of the inner ear. Together these data indicate that common alleles of GRM7 contribute to an individual's risk of developing ARHI, possibly through a mechanism of altered susceptibility to glutamate excitotoxicity.
doi:10.1093/hmg/ddn402
PMCID: PMC2638831  PMID: 19047183

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