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1.  Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer’s disease brains 
Background
Genetic analyses showed that the triggering receptor expressed in myeloid cells 2 (TREM2) p.R47H variant increases the risk for Alzheimer’s disease (AD). The question of whether the p.R47H mutation affects expression or function of the receptor remains unanswered. To address this question we quantified mRNA and analyzed protein profiles of WT and p.R47H TREM2 in human brains.
Methods
Quantitative real-time PCR (qPCR) was performed using 2 sets of primers one that detects all TREM2 mRNA isoforms and one specific for the alternative spliced isoform (TREM2alt) that encodes for the extracellular domain (soluble TREM2). Because in the brain TREM2 is expressed primarily in microglial cells, we also assessed the levels of IBA1 to control for microglial variability across samples. For TREM2 protein quantitation and N-glycosylation processing, RIPA brain extracts were analyzed by Western blot before and after EndoH and PNGaseF treatments.
Results
We identified statistically significant increased levels of TREM2 transcripts in the temporal cortex of AD subjects when compared with controls; TREM2alt was likewise higher in AD cases, but was not significant after adjustment for covariates. Quantitative analysis of TREM2 protein confirmed qPCR results that showed higher levels in AD than in control brains. Among AD subjects, we observed a trend towards higher mRNA and protein TREM2 levels in carriers of the p.R47H risk allele. Analysis of individual TREM2 species found no difference in the relative amounts of mature and immature species, and carboxyl terminal fragments between non carriers and p.R47H samples. Furthermore, TREM2 species from either non carriers or p.R47H brains were equally susceptible to EndoH and PNGaseF treatments.
Conclusions
Our results suggest that TREM2 expression is increased in AD. Furthermore, we provide evidence indicating that p.R47H mutation does not affect the levels of TREM2 either directly by altering expression or indirectly by affecting processing of the protein. Our data support previous findings that suggest that p.R47H variant affects TREM2 function by altering binding properties of the receptor rather than expression.
doi:10.1186/s13024-016-0137-9
PMCID: PMC5124229  PMID: 27887626
AD; TREM2; R47H; Microglia
2.  Evaluating pathogenic dementia variants in posterior cortical atrophy 
Neurobiology of aging  2015;37:38-44.
Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to “posterior Alzheimer’s disease (AD)” pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n=67) or posterior AD neuropathology (n=57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~4,300 European-American population controls from the NHLBI Exome Sequencing Project (ESP). We identified two rare variants not previously reported in PCA, TREM2 Arg47His and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report two rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.
doi:10.1016/j.neurobiolaging.2015.09.023
PMCID: PMC4688220  PMID: 26507310
PCA; posterior Alzheimer’s disease; dementia; APOE; TREM2; PSEN2; NeuroX
3.  Human whole genome genotype and transcriptome data for Alzheimer’s and other neurodegenerative diseases 
Scientific Data  2016;3:160089.
Previous genome-wide association studies (GWAS), conducted by our group and others, have identified loci that harbor risk variants for neurodegenerative diseases, including Alzheimer's disease (AD). Human disease variants are enriched for polymorphisms that affect gene expression, including some that are known to associate with expression changes in the brain. Postulating that many variants confer risk to neurodegenerative disease via transcriptional regulatory mechanisms, we have analyzed gene expression levels in the brain tissue of subjects with AD and related diseases. Herein, we describe our collective datasets comprised of GWAS data from 2,099 subjects; microarray gene expression data from 773 brain samples, 186 of which also have RNAseq; and an independent cohort of 556 brain samples with RNAseq. We expect that these datasets, which are available to all qualified researchers, will enable investigators to explore and identify transcriptional mechanisms contributing to neurodegenerative diseases.
doi:10.1038/sdata.2016.89
PMCID: PMC5058336  PMID: 27727239
Neurodegeneration; Genetics of the nervous system; Genome-wide association studies; RNA sequencing
4.  ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology 
The Journal of Neuroscience  2016;36(13):3848-3859.
In Alzheimer's disease (AD), the accumulation and deposition of amyloid-β (Aβ) peptides in the brain is a central event. Aβ is cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase mainly in neurons. Although mutations in APP, PS1, or PS2 cause early-onset familial AD, ABCA7 encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which its loss-of-function variants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7−/−) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit. In vivo microdialysis studies indicated that the clearance rate of Aβ was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Aβ by increasing the levels of β-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). In the brains of APP/PS1;Abca7−/− mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis.
SIGNIFICANCE STATEMENT Gene variants in ABCA7 encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-β (Aβ) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aβ deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aβ production by increasing the levels of β-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aβ clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.
doi:10.1523/JNEUROSCI.3757-15.2016
PMCID: PMC4812140  PMID: 27030769
ABCA7; APP; BACE1; cognitive function; lipid homeostasis; neuron
5.  Replication of BIN1 association with Alzheimer’s disease and evaluation of genetic interactions 
The most recent late-onset Alzheimer’s disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p=6.5×10−9). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, sex and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR=1.17, p=1.1×10−4) comparable to that previously reported (OR=1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p=0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p=3.8×10−20). We also tested for epistatic interaction between these variants and APOEε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1; rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further.
doi:10.3233/JAD-2011-101932
PMCID: PMC3489170  PMID: 21321396
Alzheimer Disease; Late Onset; Heterogeneity; Meta-Analysis; Case-Control Studies
6.  Convergent genetic and expression data implicate immunity in Alzheimer's disease 
Jones, Lesley | Lambert, Jean-Charles | Wang, Li-San | Choi, Seung-Hoan | Harold, Denise | Vedernikov, Alexey | Escott-Price, Valentina | Stone, Timothy | Richards, Alexander | Bellenguez, Céline | Ibrahim-Verbaas, Carla A | Naj, Adam C | Sims, Rebecca | Gerrish, Amy | 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 | Schmidt, Helena | Kunkle, Brian | Dunstan, Melanie L | Ruiz, Agustin | Bihoreau, Marie-Thérèse | Reitz, Christiane | Pasquier, Florence | Hollingworth, Paul | Hanon, Olivier | Fitzpatrick, Annette L | Buxbaum, Joseph D | Campion, Dominique | Crane, Paul K | 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 | Letteneur, Luc | Kornhuber, Johanes | Tárraga, Lluís | Rubinsztein, David C | Eiriksdottir, Gudny | Sleegers, Kristel | Goate, Alison M | Fiévet, Nathalie | Huentelman, Matthew J | Gill, Michael | Emilsson, Valur | 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 | Kehoe, Pat | Rogaeva, Ekaterina | Gallacher, John | George-Hyslop, Peter St | Clarimon, Jordi | Lleὀ, Alberti | Bayer, Anthony | Tsuang, Debby W | Yu, Lei | Tsolaki, Magda | Bossù, Paola | Spalletta, Gianfranco | Proitsi, Petra | Collinge, John | Sorbi, Sandro | Garcia, Florentino Sanchez | Fox, Nick | Hardy, John | Naranjo, Maria Candida Deniz | Razquin, Cristina | Bosco, Paola | Clarke, Robert | Brayne, Carol | Galimberti, Daniela | Mancuso, Michelangelo | Moebus, Susanne | Mecocci, Patrizia | del Zompo, Maria | Maier, Wolfgang | Hampel, Harald | Pilotto, Alberto | Bullido, Maria | Panza, Francesco | Caffarra, Paolo | Nacmias, Benedetta | Gilbert, John R | Mayhaus, Manuel | Jessen, Frank | Dichgans, Martin | Lannfelt, Lars | Hakonarson, Hakon | Pichler, Sabrina | Carrasquillo, Minerva M | Ingelsson, Martin | Beekly, Duane | Alavarez, Victoria | Zou, Fanggeng | Valladares, Otto | Younkin, Steven G | Coto, Eliecer | Hamilton-Nelson, Kara L | 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 FAG | 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 SK | Boerwinkle, Eric | Riemenschneider, Matthias | Boada, Mercè | Hiltunen, Mikko | Martin, Eden R | Pastor, Pau | 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 | Farrer, Lindsay A | van Duijn, Cornelia M | Van Broekhoven, Christine | Ramirez, Alfredo | Schellenberg, Gerard D | Seshadri, Sudha | Amouyel, Philippe | Williams, Julie | Holmans, Peter A
Background
Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis.
Methods
The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.
Results
ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05).
Conclusions
The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics.
doi:10.1016/j.jalz.2014.05.1757
PMCID: PMC4672734  PMID: 25533204
Alzheimer's disease; dementia; neurodegeneration; immune response; endocytosis; cholesterol metabolism; uniquitination; pathway analysis; ALIGATOR; Weighted gene coexpression network analysis
8.  A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN 
Jun, Gyungah | Ibrahim-Verbaas, Carla A. | Vronskaya, Maria | Lambert, Jean-Charles | Chung, Jaeyoon | Naj, Adam C. | Kunkle, Brian W. | Wang, Li-San | Bis, Joshua C. | Bellenguez, Céline | Harold, Denise | Lunetta, Kathryn L. | Destefano, Anita L. | Grenier-Boley, Benjamin | Sims, Rebecca | Beecham, Gary W. | Smith, Albert V. | Chouraki, Vincent | Hamilton-Nelson, Kara L. | Ikram, M. Arfan | Fievet, Nathalie | Denning, Nicola | Martin, Eden R. | Schmidt, Helena | Kamatani, Yochiro | Dunstan, Melanie L | Valladares, Otto | Laza, Agustin Ruiz | Zelenika, Diana | Ramirez, Alfredo | Foroud, Tatiana M. | Choi, Seung-Hoan | Boland, Anne | Becker, Tim | Kukull, Walter A. | van der Lee, Sven J. | Pasquier, Florence | Cruchaga, Carlos | Beekly, Duane | Fitzpatrick, Annette L. | Hanon, Oliver | Gill, Michael | Barber, Robert | Gudnason, Vilmundur | Campion, Dominique | Love, Seth | Bennett, David A. | Amin, Najaf | Berr, Claudine | Tsolaki, Magda | Buxbaum, Joseph D. | Lopez, Oscar L. | Deramecourt, Vincent | Fox, Nick C | Cantwell, Laura B. | Tárraga, Lluis | Dufouil, Carole | Hardy, John | Crane, Paul K. | Eiriksdottir, Gudny | Hannequin, Didier | Clarke, Robert | Evans, Denis | Mosley, Thomas H. | Letenneur, Luc | Brayne, Carol | Maier, Wolfgang | De Jager, Philip | Emilsson, Valur | Dartigues, Jean-François | Hampel, Harald | Kamboh, M. Ilyas | de Bruijn, Renee F.A.G. | Tzourio, Christophe | Pastor, Pau | Larson, Eric B. | Rotter, Jerome I. | O’Donovan, Michael C | Montine, Thomas J. | Nalls, Michael A. | Mead, Simon | Reiman, Eric M. | Jonsson, Palmi V. | Holmes, Clive | St George-Hyslop, Peter H. | Boada, Mercè | Passmore, Peter | Wendland, Jens R. | Schmidt, Reinhold | Morgan, Kevin | Winslow, Ashley R. | Powell, John F | Carasquillo, Minerva | Younkin, Steven G. | Jakobsdóttir, Jóhanna | Kauwe, John SK | Wilhelmsen, Kirk C. | Rujescu, Dan | Nöthen, Markus M | Hofman, Albert | Jones, Lesley | Haines, Jonathan L. | Psaty, Bruce M. | Van Broeckhoven, Christine | Holmans, Peter | Launer, Lenore J. | Mayeux, Richard | Lathrop, Mark | Goate, Alison M. | Escott-Price, Valentina | Seshadri, Sudha | Pericak-Vance, Margaret A. | Amouyel, Philippe | Williams, Julie | van Duijn, Cornelia M. | Schellenberg, Gerard D. | Farrer, Lindsay A.
Molecular psychiatry  2015;21(1):108-117.
APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4− subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10−7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
doi:10.1038/mp.2015.23
PMCID: PMC4573764  PMID: 25778476
9.  Shared genetic contribution to ischemic stroke and Alzheimer's disease 
Traylor, Matthew | Adib‐Samii, Poneh | Harold, Denise | Dichgans, Martin | Williams, Julie | Lewis, Cathryn M. | Markus, Hugh S. | Fornage, Myriam | Holliday, Elizabeth G | Sharma, Pankaj | Bis, Joshua C | Psaty, Bruce M | Seshadri, Sudha | Nalls, Mike A | Devan, William J | Boncoraglio, Giorgio | Malik, Rainer | Mitchell, Braxton D | Kittner, Steven J | Ikram, M Arfan | Clarke, Robert | Rosand, Jonathan | Meschia, James F | Sudlow, Cathie | Rothwell, Peter M | Levi, Christopher | Bevan, Steve | Kilarski, Laura L | Walters, Matthew | Thijs, Vincent | Slowik, Agnieszka | Lindgren, Arne | de Bakker, Paul I W | 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‐Thçrèse | 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 | Fiçvet, 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 | Del Zompo, Maria | 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
Annals of Neurology  2016;79(5):739-747.
Objective
Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases.
Methods
Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred.
Results
We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response.
Interpretation
Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–747
doi:10.1002/ana.24621
PMCID: PMC4864940  PMID: 26913989
10.  Network-driven plasma proteomics expose molecular changes in the Alzheimer’s brain 
Background
Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.
Results
To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.
Conclusions
We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer’s disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-016-0095-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13024-016-0095-2
PMCID: PMC4845325  PMID: 27112350
11.  Late-Onset Alzheimer Risk Variants in Memory Decline, Incident Mild Cognitive Impairment and Alzheimer Disease 
Neurobiology of aging  2014;36(1):60-67.
Background
Genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) identified risk variants. We assessed the association of nine variants with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD).
Methods
Older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville, were assessed for associations of genetic variants with memory decline (n=2,262) using linear mixed models and for incident MCI/LOAD (n=2,674) with Cox proportional hazards models. Each variant was tested both individually and collectively using a single weighted risk score.
Results
APOE-ε4 was significantly associated with worse memory at baseline (β=-0.88, p=2.78E-03) and increased rate of 5-year decline (β=-1.43, p=3.71E-06) with highly significant overall effect on memory (p=3.88E-09). CLU-locus risk allele rs11136000-G was associated with worse memory at baseline (β=-0.51, p=0.012), but not with increased rate of decline. CLU allele was also associated with incident MCI/LOAD (hazard ratio=HR=1.14, p=0.049) in sensitivity analysis. MS4A6A-locus risk allele rs610932-C was associated with increased incident MCI/LOAD in primary analysis (HR=1.17, p=0.016) and had suggestive association with lower baseline memory (β=-0.35, p=0.08). PICALM-locus risk allele rs3851179-G had nominally significant HR in both primary and sensitivity analysis, but with a protective estimate. LOAD risk alleles ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in the subset of subjects with a final diagnosis of MCI/LOAD. Risk scores excluding APOE were not significant, whereas APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD.
Conclusions
The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Given the significant associations observed with APOE-ε4, discovery of the biologically functional variants at these loci may uncover stronger effects on memory and incident disease.
doi:10.1016/j.neurobiolaging.2014.07.042
PMCID: PMC4268433  PMID: 25189118
Alzheimer's disease; memory; mild cognitive impairment; genetic risk; association; cognitive decline
12.  Late-onset Alzheimer disease risk variants mark brain regulatory loci 
Neurology: Genetics  2015;1(2):e15.
Objective:
To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation.
Methods:
Expression levels from the cerebellum (CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation assay (WG-DASL) for ∼400 autopsied patients (∼200 with AD and ∼200 with non-AD pathologies). We tested 12 significant LOAD genome-wide association study (GWAS) index single nucleotide polymorphisms (SNPs) for cis association with levels of 34 genes within ±100 kb. We also evaluated brain levels of 14 LOAD GWAS candidate genes for association with 1,899 cis-SNPs. Significant associations were validated in a subset of TCX samples using next-generation RNA sequencing (RNAseq).
Results:
We identified strong associations of brain CR1, HLA-DRB1, and PILRB levels with LOAD GWAS index SNPs. We also detected other strong cis-SNPs for LOAD candidate genes MEF2C, ZCWPW1, and SLC24A4. MEF2C and SLC24A4, but not ZCWPW1 cis-SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1, HLA-DRB1, ZCWPW1, and SLC24A4.
Conclusions:
Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these variants for their brain regulatory effects.
doi:10.1212/NXG.0000000000000012
PMCID: PMC4807909  PMID: 27066552
13.  Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy 
Nature communications  2015;6:7247.
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here we conduct a GWAS in CBD cases (n = 152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P = 1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P = 3.41 × 10−8), and 2p22 at SOS1 (rs963731; P = 1.76 × 10−7). Testing for association of CBD with top PSP GWAS SNPs identified associations at MOBP (3p22; rs1768208; P = 2.07 × 10−7) and MAPT H1c (17q21; rs242557; P = 7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT, at 3p22 MOBP (myelin-associated oligodendrocytic protein).
doi:10.1038/ncomms8247
PMCID: PMC4469997  PMID: 26077951
14.  Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy 
Nature Communications  2015;6:7247.
Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 (MAPT) and 3p12 (MOBP), and a novel susceptibility locus at 8p12.
doi:10.1038/ncomms8247
PMCID: PMC4469997  PMID: 26077951
15.  Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer’s Disease 
Epidemiological studies suggest that individuals with greater education or more cognitively demanding occupations have diminished risk of developing dementia. We wanted to test whether this effect could be recapitulated in rodents using environmental enrichment, a paradigm well documented to attenuate behavioral deficits induced by various pathological insults. Here, we demonstrate that learning and memory deficits observed in a transgenic mouse model of Alzheimer’s disease can be ameliorated by enrichment. Female transgenic mice overexpressing amyloid precursor protein and/or presenilin-1 and nontransgenic controls were placed into enriched or standard cages at 2 months of age and tested for cognitive behavior after 6 months of differential housing. Enrichment significantly improved performance of all genotypes in the radial water maze and in the classic and repeated-reversal versions of the Morris water maze. However, enrichment did not benefit all genotypes equally. Mice overproducing amyloid-β (Aβ), particularly those with amyloid deposits, showed weaker memory for the platform location in the classic Morris water maze and learned new platform positions in the repeated-reversals task less quickly than their nontransgenic cagemates. Nonetheless, enrichment normalized the performance of Aβ-overproducing mice to the level of standard-housed nontransgenic mice. Moreover, this functional preservation occurred despite increased neuritic plaque burden in the hippocampus of double-transgenic animals and elevated steady-state Aβ levels, because both endogenous and transgene-derived Aβ are increased in enriched animals. These results demonstrate that the generation of Aβ in vivo and its impact on the function of the nervous system can be strongly modulated by environmental factors.
doi:10.1523/JNEUROSCI.5080-04.2005
PMCID: PMC4440804  PMID: 15917461
Alzheimer’s disease; transgenic mouse; amyloid precursor protein; Aβ; environmental enrichment; cognitive behavior
16.  Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice* 
The Journal of biological chemistry  2007;282(31):22707-22720.
The amino acid sequence of amyloid precursor protein (APP) is highly conserved, and age-related Aβ aggregates have been described in a variety of vertebrate animals, with the notable exception of mice and rats. Three amino acid substitutions distinguish mouse and human Aβ that might contribute to their differing properties in vivo. To examine the amyloidogenic potential of mouse Aβ, we studied several lines of transgenic mice overexpressing wild-type mouse amyloid precursor protein (moAPP) either alone or in conjunction with mutant PS1 (PS1dE9). Neither overexpression of moAPP alone nor co-expression with PS1dE9 caused mice to develop Alzheimer-type amyloid pathology by 24 months of age. We further tested whether mouse Aβ could accelerate the deposition of human Aβ by crossing the moAPP transgenic mice to a bigenic line expressing human APPswe with PS1dE9. The triple transgenic animals (moAPP × APPswe/PS1dE9) produced 20% more Aβ but formed amyloid deposits no faster and to no greater extent than APPswe/PS1dE9 siblings. Instead, the additional mouse Aβ increased the detergent solubility of accumulated amyloid and exacerbated amyloid deposition in the vasculature. These findings suggest that, although mouse Aβ does not influence the rate of amyloid formation, the incorporation of Aβ peptides with differing sequences alters the solubility and localization of the resulting aggregates.
doi:10.1074/jbc.M611050200
PMCID: PMC4435736  PMID: 17556372
17.  Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD 
Neurology  2014;82(16):1455-1462.
Objective:
To investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of “posterior AD” neuropathology.
Methods:
We assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies.
Results:
There was highly significant association with APOE ε4 and increased risk of PCA (p = 0.0003, odds ratio [OR] = 3.17) and posterior AD (p = 1.11 × 10−17, OR = 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p = 0.019, OR = 0.60) and rs744373 near BIN1 (p = 0.025, OR = 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p = 0.0003, OR = 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk.
Conclusions:
We identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies.
doi:10.1212/WNL.0000000000000335
PMCID: PMC4001196  PMID: 24670887
18.  Genome-wide association analysis of age-at-onset in Alzheimer’s disease 
Molecular psychiatry  2011;17(12):1340-1346.
The risk of Alzheimer’s disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta analysis on 3 samples comprising a total of 2,222 AD cases. A total of ~2.5 million directly genotyped or imputed SNPs were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the APOE region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.
doi:10.1038/mp.2011.135
PMCID: PMC3262952  PMID: 22005931
Genome-wide association study; age-at-onset; Alzheimer’s disease; single-nucleotide polymorphisms; meta analysis
19.  Evaluation of Memory Endophenotypes for Association with CLU, CR1 and PICALM variants in African-American and Caucasian Subjects 
Background
Genetic variants at the CLU, CR1 and PICALM loci associate with risk for late-onset Alzheimer’s disease (LOAD) in genome-wide association studies (GWAS). In this study, our aim was to determine whether the LOAD risk variants at these three loci influence memory endophenotypes in African-American and Caucasian subjects.
Methods
We pursued an association study between single nucleotide polymorphism (SNP) genotypes at the CLU, CR1 and PICALM loci and memory endophenotypes. We assessed African-American subjects (AA: 44 with LOAD, 224 controls) recruited at Mayo Clinic Florida and Caucasians recruited at Mayo Clinic Minnesota (RS: 372 with LOAD, 1,690 controls) and Florida (JS: 60 with LOAD, 529 controls). SNPs at the LOAD risk loci CLU (rs11136000), CR1 (rs6656401, rs3818361) and PICALM (rs3851179) were genotyped and tested for association with Logical Memory immediate recall (LMIR), delayed recall (LMDR) and percent retention (LMPR) and Visual Reproduction (VRIR, VRDR, VRPR) scores from Wechsler Memory Scale-Revised, using multivariable linear regression analysis, adjusting for age-at-exam, sex, education and APOE ε4 dosage.
Results
We identified nominally significant or suggestive associations between the LOAD risky CR1 variants and worse LMIR scores in the African-Americans (p=0.068 - 0.046, β= −2.7 to −1.2). The LOAD protective CLU variant is associated with better logical memory endophenotypes in the Caucasian subjects (p=0.099-0.027, β= 0.31 to 0.93). The CR1 associations persisted when the control subjects from the African-American series were assessed separately. The CLU associations appeared to be driven by one of the Caucasian series (RS) and were also observed when the control subset from RS was analyzed.
Conclusion
These results suggest for the first time that LOAD risk variants at CR1 may influence memory endophenotypes in African-Americans. Additionally, CLU LOAD protective variant may confer enhanced memory in Caucasians. Although these results would not remain significant after stringent corrections for multiple testing, they need to be considered in the context of the LOAD associations, with which they have biological consistency. They also provide estimates for effect sizes on memory endophenotypes that could guide future studies. The detection of memory effects for these variants in clinically normal subjects, implies that these LOAD risk loci might modify memory prior to clinical diagnosis of AD.
doi:10.1016/j.jalz.2013.01.016
PMCID: PMC3815516  PMID: 23643458
20.  Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus 
Neurobiology of aging  2012;33(8):1848.e1-1848.13.
Nicastrin (NCSTN) is a component of the γ-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn−/−) cells and clonal NCSTN-BAC+/Ncstn−/− cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued γ-secretase activity and amyloid beta (Aβ) production in NCSTN-BAC+/Ncstn−/− lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.
doi:10.1016/j.neurobiolaging.2012.02.005
PMCID: PMC3683320  PMID: 22405046
Nicastrin; Haplotype variation; Functional genomics; Alzheimer's disease; γ-Secretase complex
21.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
doi:10.1371/journal.pgen.1004606
PMCID: PMC4154667  PMID: 25188341
22.  Correction: Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease 
Jones, Lesley | Holmans, Peter A. | Hamshere, Marian L. | Harold, Denise | Moskvina, Valentina | Ivanov, Dobril | Pocklington, Andrew | Abraham, Richard | Hollingworth, Paul | Sims, Rebecca | Gerrish, Amy | Pahwa, Jaspreet Singh | Jones, Nicola | 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 | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Peters, Oliver | 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, Panos | Al-Chalabi, Ammar | Shaw, Christopher E. | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H.-Erich | Rüther, Eckhard | Carrasquillo, Minerva M. | Pankratz, V. Shane | Younkin, Steven G. | Hardy, John | O'Donovan, Michael C. | Owen, Michael J. | Williams, Julie
PLoS ONE  2011;6(2):10.1371/annotation/a0bb886d-d345-4a20-a82e-adce9b047798.
doi:10.1371/annotation/a0bb886d-d345-4a20-a82e-adce9b047798
PMCID: PMC3039022
23.  Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease 
Neurology  2010;74(6):480-486.
Background:
Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels.
Methods:
We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD. Using the genotypes from our LOAD genome-wide association study for the cis-single nucleotide polymorphisms (SNPs) (n = 619) of these 12 LOAD candidate genes, we tested for associations with expression levels as endophenotypes. The strongest expression cis-SNP was tested for AD association in 7 independent case-control series (2,280 AD and 2,396 controls).
Results:
We identified 3 SNPs that associated significantly with IDE (insulin degrading enzyme) expression levels. A single copy of the minor allele for each significant SNP was associated with ∼twofold higher IDE expression levels. The most significant SNP, rs7910977, is 4.2 kb beyond the 3′ end of IDE. The association observed with this SNP was significant even at the genome-wide level (p = 2.7 × 10−8). Furthermore, the minor allele of rs7910977 associated significantly (p = 0.0046) with reduced LOAD risk (OR = 0.81 with a 95% CI of 0.70-0.94), as expected biologically from its association with elevated IDE expression.
Conclusions:
These results provide strong evidence that IDE is a late-onset Alzheimer disease (LOAD) gene with variants that modify risk of LOAD by influencing IDE expression. They also suggest that the use of expression levels as endophenotypes in genome-wide association studies may provide a powerful approach for the identification of disease susceptibility alleles.
GLOSSARY
= Alzheimer disease;
= confidence interval;
= genome-wide association study;
= late-onset Alzheimer disease;
= messenger RNA;
= odds ratio;
= single nucleotide polymorphism.
doi:10.1212/WNL.0b013e3181d07654
PMCID: PMC2830916  PMID: 20142614
24.  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
25.  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

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