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1.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
Importance
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
Objectives
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Results
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
doi:10.1001/jamaneurol.2014.1491
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
2.  TREM2 Variants in Alzheimer's Disease 
The New England journal of medicine  2012;368(2):117-127.
BACKGROUND
Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.
METHODS
We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.
RESULTS
We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.
CONCLUSIONS
Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.)
doi:10.1056/NEJMoa1211851
PMCID: PMC3631573  PMID: 23150934
3.  Rare coding variants in Phospholipase D3 (PLD3) confer risk for Alzheimer's disease 
Nature  2013;505(7484):550-554.
Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1,2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low frequency coding variants with large effects on LOAD risk, we performed whole exome-sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large case-control datasets. A rare variant in PLD3 (phospholipase-D family, member 3, rs145999145; V232M) segregated with disease status in two independent families and doubled risk for AD in seven independent case-control series (V232M meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354 cases and controls of European-descent). Gene-based burden analyses in 4,387 cases and controls of European-descent and 302 African American cases and controls, with complete sequence data for PLD3, indicate that several variants in this gene increase risk for AD in both populations (EA: OR= 2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92; p=1.40×10-3). PLD3 is highly expressed in brain regions vulnerable to AD pathology, including hippocampus and cortex, and is expressed at lower levels in neurons from AD brains compared to control brains (p=8.10×10-10). Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may be used to identify rare variants with large effects on risk for disease or other complex traits.
doi:10.1038/nature12825
PMCID: PMC4050701  PMID: 24336208
4.  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
5.  GWAS of cerebrospinal fluid tau levels identifies novel risk variants for Alzheimer’s disease 
Neuron  2013;78(2):256-268.
Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau) and Aβ42 are established biomarkers for Alzheimer’s Disease (AD), and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n=1,269), identifying three novel genome-wide significant loci for CSF tau and ptau: rs9877502 (P=4.89×10−9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (P=1.07×10−8 and P=3.22×10−9 for tau and ptau respectively), located at 9p24.2 within GLIS3 and rs6922617 (P = 3.58×10−8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent datasets rs9877502 showed a strong association with risk for AD, tangle pathology and global cognitive decline (P=2.67×10−4, 0.039, 4.86×10−5 respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
doi:10.1016/j.neuron.2013.02.026
PMCID: PMC3664945  PMID: 23562540
6.  Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease 
Human Molecular Genetics  2012;21(20):4558-4571.
The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10−4) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ42 levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ42 levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ42 levels was independent of the APOE ɛ4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ɛ4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10−13). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ɛ4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10−6. Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10−9).
doi:10.1093/hmg/dds296
PMCID: PMC3459471  PMID: 22821396
7.  Performances on the CogState and Standard Neuropsychological Batteries Among HIV Patients Without Dementia 
AIDS and behavior  2011;15(8):1902-1909.
HIV-associated neurocognitive disorders (HAND) remain prevalent but challenging to diagnose particularly among non-demented individuals. To determine whether a brief computerized battery correlates with formal neurocognitive testing, we identified 46 HIV-infected persons who had undergone both formal neurocognitive testing and a brief computerized battery. Simple detection tests correlated best with formal neuropsychological testing. By multivariable regression model, 53% of the variance in the composite Global Deficit Score was accounted for by elements from the brief computerized tool (p<0.01). These data confirm previous correlation data with the computerized battery, yet illustrate remaining challenges for neurocognitive screening.
doi:10.1007/s10461-011-0033-9
PMCID: PMC3594991  PMID: 21877204
8.  No consistent evidence for association between mtDNA variants and Alzheimer disease 
Hudson, G. | Sims, R. | Harold, D. | Chapman, J. | Hollingworth, P. | Gerrish, A. | Russo, G. | Hamshere, M. | Moskvina, V. | Jones, N. | Thomas, C. | Stretton, A. | Holmans, P.A. | O'Donovan, M.C. | Owen, M.J. | Williams, J. | Chinnery, P.F. | Harold, Denise | Abraham, Richard | Hollingworth, Paul | Sims, Rebecca | Gerrish, Amy | Chapman, Jade | Russo, Giancarlo | Hamshere, Marian | Pahwa, Jaspreet Singh | Moskvina, Valentina | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle | Passmore, Peter | Craig, David | McGuinness, Bernadette | Todd, Stephen | Johnston, Janet | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Heun, Reiner | Kölsch, Heike | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison | Kauwe, John S.K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Holmans, Peter | O'Donovan, Michael | Owen, Michael J. | Williams, Julie
Neurology  2012;78(14):1038-1042.
Objective:
Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.
Methods:
We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.
Results:
In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.
Conclusion:
The current evidence linking common mtDNA variations with AD is not compelling.
doi:10.1212/WNL.0b013e31824e8f1d
PMCID: PMC3317529  PMID: 22442439
9.  Association and Expression analyses with SNPs in TOMM40 in Alzheimer’s Disease 
Archives of neurology  2011;68(8):1013-1019.
Objectives
Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer’s disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all of the association signal is derived from APOE or if there is an independent signal from a nearby gene. In this study we attempted to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset.
Design
We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data and in brain tissue.
Results
We failed to replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk for LOAD among APOE 33 homozygotes but in the opposite direction to the previously reported association (the very-long allele was underrepresented in cases compared to controls in our study (allele frequency: 0.41 vs. 0.48 respectively; p=0.004)). We found no association between rs10524523 and CSF tau or Aβ42 levels or TOMM40 or APOE gene expression.
Conclusions
Although we were not able to replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we did observe that the polyT polymorphism is associated with risk for LOAD among APOE 33 homozygotes in a large case-control series, but in the opposite direction to the previous report. Additional studies in very large samples will be needed to confirm this association.
doi:10.1001/archneurol.2011.155
PMCID: PMC3204798  PMID: 21825236
10.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes 
Harold, Denise | Abraham, Richard | Hollingworth, Paul | Sims, Rebecca | Gerrish, Amy | Hamshere, Marian | Singh Pahwa, Jaspreet | Moskvina, Valentina | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle | Passmore, Peter | Craig, David | McGuinness, Bernadette | Todd, Stephen | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison | Kauwe, John S.K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Sleegers, Kristel | Bettens, Karolien | Engelborghs, Sebastiaan | De Deyn, Peter | van Broeckhoven, Christine | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Al-Chalabi, Ammar | Shaw, Christopher E. | Tsolaki, Magda | Singleton, Andrew | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Carrasquillo, Minerva M. | Pankratz, V. Shane | Younkin, Steven G. | Holmans, Peter | O'Donovan, Michael | Owen, Michael J. | Williams, Julie
Nature genetics  2009;41(10):1088-1093.
We undertook a two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the APOE locus (most significant SNP: rs2075650, p= 1.8×10−157) and observed genome-wide significant association with SNPs at two novel loci: rs11136000 in the CLU or APOJ gene (p= 1.4×10−9) and rs3851179, a SNP 5′ to the PICALM gene (p= 1.9×10−8). Both novel associations were supported in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with AD in the combined dataset (rs11136000: p= 8.5×10−10, odds ratio= 0.86; rs3851179: p= 1.3×10−9, odds ratio= 0.86). We also observed more variants associated at p< 1×10−5 than expected by chance (p=7.5×10−6), including polymorphisms at the BIN1, DAB1 and CR1 loci.
doi:10.1038/ng.440
PMCID: PMC2845877  PMID: 19734902
11.  Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer's disease 
Mutations in the progranulin gene (GRN) are causative for Frontotemporal Lobar Degeneration with ubiquitin-immunoreactive neuronal inclusions (FTLD-U). However, additional studies have demonstrated that these variants could be associated with Alzheimer's disease (AD). The influence of GRN genetic variability on susceptibility to AD and on expression levels in a series of neuropathologically-confirmed AD patients as well as in Peripheral Mononuclear Cells (PBMC) and in cells isolated from cerebrospinal fluid (CSF) was investigated. An association study of rs9897526 and rs5848 was carried out in an Italian population and in a replication population of European American patients and controls.
None of the variants tested act as unequivocal susceptibility factor in both populations although a tendency to an increased frequency of rs5848T allele was observed in the Italian group of AD patients. Furthermore, rs9897526 anticipated the onset of the disease in the Italian population. GRN expression in the parietal lobe of AD cases showed a 0.76-fold decrease compared with controls (1.31±0.07 versus 1.73±0.12, P=0.0025). Patients carrying the rs5848 TT genotype had the lowest GRN expression levels (0.96±0.12, P=0.014). Despite no significant differences were found in the relative PBMC and CSF GRN expression in patients compared to controls, stratifying patients according to the presence of rs5848 T allele, a 0.57-fold decrease in GRN mRNA levels over C carriers was found in PBMC (1.22±0.23 versus 0.70±0.12, P=0.04). Similarly to data obtained in brain samples, patients carrying the TT genotype showed the lowest GRN mRNA levels (TT= 0.46±0.14, CC=1.22±0.23; P=0.013). These data argue against a direct role of GRN as a susceptibility factor for sporadic AD but support a role of GRN as a disease-modifying gene, possibly contributing to the failure of neuronal survival.
doi:10.3233/JAD-2009-1170
PMCID: PMC2842455  PMID: 19625741
Alzheimer's Disease (AD); Progranulin (GRN); Single Nucleotide Polymorphism (SNP); Cerebrospinal Fluid (CSF); Peripheral Mononuclear Cells (PBMC)
12.  Molecular Characterization of Novel Progranulin (GRN) Mutations in Frontotemporal Dementia 
Human mutation  2008;29(4):512-521.
Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6–2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.
doi:10.1002/humu.20681
PMCID: PMC2756561  PMID: 18183624
Frontotemporal dementia; FTD; granulin; progranulin; GRN; PGRN
13.  Association Studies between Common Variants in Prolyl isomerase Pin1 and the Risk for Late-Onset Alzheimer's Disease 
Neuroscience letters  2007;419(1):15-17.
Alzheimer's disease (AD) pathology is associated with two proteins, the microtubule-binding protein tau and the amyloid-precursor protein (APP). When tau becomes hyperphosphorylated, it forms neuritic aggregates, called neurofibrillary tangles. APP is cleaved by several enzymes to generate Aβ peptides, which are - depending on their length - more or less amyloidogenic and form senile plaques. Pin1, a peptidyl-propyl cis/trans-isomerase, seems to be involved in both pathologies. Pin1 may facilitate dephosphorylation of tau by PP2A phosphatase, while cellular overexpression of Pin1 causes a reduction in the amyloidogenic processing of APP, making this enzyme an interesting target for pharmaceutical intervention. The gene encoding Pin1 maps to 19p13.2, a region previously linked to LOAD. Therefore Pin1 is an excellent positional and functional candidate for LOAD. In this study, we investigated whether common SNPs in Pin1 can influence the risk for developing late-Onset Alzheimer's disease (LOAD). No association was observed with any of six polymorphisms or their resulting haplotypes. A meta-analysis of two promoter SNPs, which combined the data from this study with two previous ones, did not show any association either suggesting that common SNPs in Pin1 do not increase the risk for LOAD.
doi:10.1016/j.neulet.2007.03.071
PMCID: PMC1952685  PMID: 17482359
Pin1; late-onset Alzheimer's disease; genotyping
14.  A Versatile Omnibus Test for Detecting Mean and Variance Heterogeneity 
Genetic epidemiology  2014;38(1):51-59.
Recent research has revealed loci that display variance heterogeneity through various means such as biological disruption, linkage disequilibrium (LD), gene-by-gene (GxG), or gene-by-environment (GxE) interaction. We propose a versatile likelihood ratio test that allows joint testing for mean and variance heterogeneity (LRTMV) or either effect alone (LRTM or LRTV) in the presence of covariates. Using extensive simulations for our method and others we found that all parametric tests were sensitive to non-normality regardless of any trait transformations. Coupling our test with the parametric bootstrap solves this issue. Using simulations and empirical data from a known mean-only functional variant we demonstrate how linkage disequilibrium (LD) can produce variance-heterogeneity loci (vQTL) in a predictable fashion based on differential allele frequencies, high D’ and relatively low r2 values. We propose that a joint test for mean and variance heterogeneity is more powerful than a variance only test for detecting vQTL. This takes advantage of loci that also have mean effects without sacrificing much power to detect variance only effects. We discuss using vQTL as an approach to detect gene-by-gene interactions and also how vQTL are related to relationship loci (rQTL) and how both can create prior hypothesis for each other and reveal the relationships between traits and possibly between components of a composite trait.
PMCID: PMC4019404  PMID: 24482837
Linkage Disequilibrium; vQTL; rQTL; GxG; GxE; GWAS
15.  Assessment of TREM2 R47H association with Alzheimer’s disease in a population-based sample: The Cache County Study 
Neurobiology of aging  2013;34(12):2889.e11-2889.e13.
Recent studies have identified the R47H variant in TREM2 as an Alzheimer’s disease (AD) risk factor with estimated odds ratio ranging from 2.9–5.1. The Cache County Memory Study is a large, population-based sample designed for the study of memory and aging. We genotyped rs75932628 (R47H) in 2974 samples (427 cases and 2540 controls) from the Cache County study using a custom Taqman Assay. We observed 7 heterozygous cases and 12 heterozygous controls with an odds ratio of 3.5 (95% confidence interval, 1.3–8.8; p = 0.0076). The minor allele frequency and population attributable fraction for R47H were 0.0029 and 0.004, respectively. This study replicates the association between R47H and AD risk in a large, population-based sample and estimates the population frequency and attributable risk of this rare variant.
doi:10.1016/j.neurobiolaging.2013.06.004
PMCID: PMC3779500  PMID: 23855982
Alzheimer’s disease; human; TREM2; rare variant; R47H
16.  Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation 
PLoS Genetics  2014;10(10):e1004758.
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10−10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.
Author Summary
The use of quantitative endophenotypes from cerebrospinal fluid has led to the identification of several genetic variants that alter risk or rate of progression of Alzheimer's disease. Here we have analyzed the levels of 58 disease-related proteins in the cerebrospinal fluid for association with millions of variants across the human genome. We have identified significant, replicable associations with 5 analytes, Angiotensin-converting enzyme, Chemokine (C-C motif) ligand 2, Chemokine (C-C motif) ligand 4, Interleukin 6 receptor and Matrix metalloproteinase-3. Our results suggest that these variants play a regulatory role in the respective protein levels and are relevant to the inflammatory and amyloid processing pathways. Variants in associated with ACE and those associated with MMP3 levels also show association with risk for Alzheimer's disease in the expected directions. These associations are consistent in cerebrospinal fluid and plasma and in samples with only cognitively normal individuals suggesting that they are relevant in the regulation of these protein levels beyond the context of Alzheimer's disease.
doi:10.1371/journal.pgen.1004758
PMCID: PMC4207667  PMID: 25340798
17.  The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer’s Disease 
Gerrish, Amy | Russo, Giancarlo | Richards, Alexander | Moskvina, Valentina | Ivanov, Dobril | Harold, Denise | Sims, Rebecca | Abraham, Richard | Hollingworth, Paul | Chapman, Jade | Hamshere, Marian | Pahwa, Jaspreet Singh | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad R. | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K. | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle S. | Passmore, Peter A. | Craig, David | McGuinness, Bernadette | Todd, Stephen | Johnston, Janet A. | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Kölsch, Heike | Heun, Reinhard | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison M. | Kauwe, John S. K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Davies, Gail | Harris, Sarah E. | Starr, John M. | Deary, Ian J. | Al-Chalabi, Ammar | Shaw, Christopher E. | Tsolaki, Magda | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Carrasquillo, Minerva M | Pankratz, V Shane | Younkin, Steven G. | Jones, Lesley | Holmans, Peter A. | O’Donovan, Michael C. | Owen, Michael J. | Williams, Julie
Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer’s disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson’s disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
doi:10.3233/JAD-2011-110824
PMCID: PMC4118466  PMID: 22027014
Alzheimer’s disease; amyloid-β protein precursor; genetics; human; MAPT protein; PSEN1 protein; PSEN2 protein
18.  Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels 
Introduction
MAPT encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Genetic association of MAPT variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of MAPT haplotypes may account for this.
Methods
We examined the association of MAPT haplotypes with LOAD risk in more than 20,000 subjects (n-cases = 9,814, n-controls = 11,550) from Mayo Clinic (n-cases = 2,052, n-controls = 3,406) and the Alzheimer’s Disease Genetics Consortium (ADGC, n-cases = 7,762, n-controls = 8,144). We also assessed associations with brain MAPT gene expression levels measured in the cerebellum (n = 197) and temporal cortex (n = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag MAPT haplotypes with frequencies greater than 1% were evaluated.
Results
H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes. MAPT SNPs and haplotypes also associated with brain MAPT levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain MAPT levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03).
Conclusions
These results confirm the previously reported MAPT H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain MAPT expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the MAPT region for regulatory variants which confer LOAD risk by influencing its brain gene expression.
doi:10.1186/alzrt268
PMCID: PMC4198935  PMID: 25324900
19.  Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease 
Escott-Price, Valentina | Bellenguez, Céline | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Jones, Lesley | Holmans, Peter | Gerrish, Amy | Vedernikov, Alexey | Richards, Alexander | DeStefano, Anita L. | Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A. | Naj, Adam C. | Sims, Rebecca | Jun, Gyungah | Bis, Joshua C. | Beecham, Gary W. | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A. | Denning, Nicola | Smith, Albert V. | Chouraki, Vincent | Thomas, Charlene | Ikram, M. Arfan | Zelenika, Diana | Vardarajan, Badri N. | Kamatani, Yoichiro | Lin, Chiao-Feng | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L. | Vronskaya, Maria | Johnson, Andrew D. | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L. | Buxbaum, Joseph D. | Campion, Dominique | Crane, Paul K. | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L. | De Jager, Philip L. | Deramecourt, Vincent | Johnston, Janet A. | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Hernández, Isabel | Rubinsztein, David C. | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M. | Fiévet, Nathalie | Huentelman, Matthew J. | Gill, Michael | Brown, Kristelle | Kamboh, M. Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B. | Myers, Amanda J. | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W. | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick C. | Hardy, John | Naranjo, Maria Candida Deniz | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Scarpini, Elio | Bonuccelli, Ubaldo | Mancuso, Michelangelo | Siciliano, Gabriele | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Frank-García, Ana | Panza, Francesco | Solfrizzi, Vincenzo | Caffarra, Paolo | Nacmias, Benedetta | Perry, William | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M. | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G. | Coto, Eliecer | Hamilton-Nelson, Kara L. | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J. | Faber, Kelley M. | Jonsson, Palmi V. | Combarros, Onofre | O'Donovan, Michael C. | Cantwell, Laura B. | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H. | Bennett, David A. | Harris, Tamara B. | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F. A. G. | Passmore, Peter | Montine, Thomas J. | Bettens, Karolien | Rotter, Jerome I. | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M. | Kukull, Walter A. | Hannequin, Didier | Powell, John F. | Nalls, Michael A. | Ritchie, Karen | Lunetta, Kathryn L. | Kauwe, John S. K. | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R. | Schmidt, Reinhold | Rujescu, Dan | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M. | Graff, Caroline | Psaty, Bruce M. | Haines, Jonathan L. | Lathrop, Mark | Pericak-Vance, Margaret A. | Launer, Lenore J. | Van Broeckhoven, Christine | Farrer, Lindsay A. | van Duijn, Cornelia M. | Ramirez, Alfredo | Seshadri, Sudha | Schellenberg, Gerard D. | Amouyel, Philippe | Williams, Julie
PLoS ONE  2014;9(6):e94661.
Background
Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal Findings
In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance
The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
doi:10.1371/journal.pone.0094661
PMCID: PMC4055488  PMID: 24922517
20.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 
Lambert, Jean-Charles | Ibrahim-Verbaas, Carla A | Harold, Denise | Naj, Adam C | Sims, Rebecca | Bellenguez, Céline | Jun, Gyungah | DeStefano, Anita L | Bis, Joshua C | Beecham, Gary W | Grenier-Boley, Benjamin | Russo, Giancarlo | Thornton-Wells, Tricia A | Jones, Nicola | Smith, Albert V | Chouraki, Vincent | Thomas, Charlene | Ikram, M Arfan | Zelenika, Diana | Vardarajan, Badri N | Kamatani, Yoichiro | Lin, Chiao-Feng | Gerrish, Amy | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Choi, Seung-Hoan | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Ramirez, Alfredo | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | Baldwin, Clinton | Becker, Tim | Gudnason, Vilmundur | Cruchaga, Carlos | Craig, David | Amin, Najaf | Berr, Claudine | Lopez, Oscar L | De Jager, Philip L | Deramecourt, Vincent | Johnston, Janet A | Evans, Denis | Lovestone, Simon | Letenneur, Luc | Morón, Francisco J | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Brown, Kristelle | Kamboh, M Ilyas | Keller, Lina | Barberger-Gateau, Pascale | McGuinness, Bernadette | Larson, Eric B | Green, Robert | Myers, Amanda J | Dufouil, Carole | Todd, Stephen | Wallon, David | Love, Seth | Rogaeva, Ekaterina | Gallacher, John | St George-Hyslop, Peter | Clarimon, Jordi | Lleo, Alberto | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petroula | Collinge, John | Sorbi, Sandro | Sanchez-Garcia, Florentino | Fox, Nick C | Hardy, John | Deniz Naranjo, Maria Candida | Bosco, Paolo | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Matthews, Fiona | Moebus, Susanne | Mecocci, Patrizia | Zompo, Maria Del | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alvarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | Gu, Wei | Razquin, Cristina | Pastor, Pau | Mateo, Ignacio | Owen, Michael J | Faber, Kelley M | Jonsson, Palmi V | Combarros, Onofre | O’Donovan, Michael C | Cantwell, Laura B | Soininen, Hilkka | Blacker, Deborah | Mead, Simon | Mosley, Thomas H | Bennett, David A | Harris, Tamara B | Fratiglioni, Laura | Holmes, Clive | de Bruijn, Renee F A G | Passmore, Peter | Montine, Thomas J | Bettens, Karolien | Rotter, Jerome I | Brice, Alexis | Morgan, Kevin | Foroud, Tatiana M | Kukull, Walter A | Hannequin, Didier | Powell, John F | Nalls, Michael A | Ritchie, Karen | Lunetta, Kathryn L | Kauwe, John S K | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Schmidt, Reinhold | Rujescu, Dan | Wang, Li-san | Dartigues, Jean-François | Mayeux, Richard | Tzourio, Christophe | Hofman, Albert | Nöthen, Markus M | Graff, Caroline | Psaty, Bruce M | Jones, Lesley | Haines, Jonathan L | Holmans, Peter A | Lathrop, Mark | Pericak-Vance, Margaret A | Launer, Lenore J | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broeckhoven, Christine | Moskvina, Valentina | Seshadri, Sudha | Williams, Julie | Schellenberg, Gerard D | Amouyel, Philippe
Nature genetics  2013;45(12):1452-1458.
Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.
doi:10.1038/ng.2802
PMCID: PMC3896259  PMID: 24162737
21.  Alzheimer’s Disease: Analyzing the Missing Heritability 
PLoS ONE  2013;8(11):e79771.
Alzheimer’s disease (AD) is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to analyze >2 million SNPs for 10,922 individuals from the Alzheimer’s Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer’s Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer’s disease.
doi:10.1371/journal.pone.0079771
PMCID: PMC3820606  PMID: 24244562
22.  Strong Evidence for a Genetic Contribution to Late-Onset Alzheimer’s Disease Mortality: A Population-Based Study 
PLoS ONE  2013;8(10):e77087.
Background
Alzheimer’s disease (AD) is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer’s disease. Here we present the largest genealogy-based analysis of AD to date.
Methods
We assessed the familiality of AD in The Utah Population Database (UPDB), a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF) between AD individuals and randomly selected controls and estimated the Relative Risk (RR) for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.
Results
The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.
Conclusions
These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.
doi:10.1371/journal.pone.0077087
PMCID: PMC3792903  PMID: 24116205
23.  Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers 
Brain Imaging and Behavior  2013;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.
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
24.  Mitochondrial Haplotypes Associated with Biomarkers for Alzheimer’s Disease 
PLoS ONE  2013;8(9):e74158.
Various studies have suggested that the mitochondrial genome plays a role in late-onset Alzheimer’s disease, although results are mixed. We used an endophenotype-based approach to further characterize mitochondrial genetic variation and its relationship to risk markers for Alzheimer’s disease. We analyzed longitudinal data from non-demented, mild cognitive impairment, and late-onset Alzheimer’s disease participants in the Alzheimer’s Disease Neuroimaging Initiative with genetic, brain imaging, and behavioral data. We assessed the relationship of structural MRI and cognitive biomarkers with mitochondrial genome variation using TreeScanning, a haplotype-based approach that concentrates statistical power by analyzing evolutionarily meaningful groups (or clades) of haplotypes together for association with a phenotype. Four clades were associated with three different endophenotypes: whole brain volume, percent change in temporal pole thickness, and left hippocampal atrophy over two years. This is the first study of its kind to identify mitochondrial variation associated with brain imaging endophenotypes of Alzheimer’s disease. Our results provide additional evidence that the mitochondrial genome plays a role in risk for Alzheimer’s disease.
doi:10.1371/journal.pone.0074158
PMCID: PMC3770576  PMID: 24040196
25.  Genetics of Alzheimer's Disease 
BioMed Research International  2013;2013:254954.
Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease.
doi:10.1155/2013/254954
PMCID: PMC3741956  PMID: 23984328

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