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author:("goat, Alison")
1.  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
2.  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
3.  Functional Characterization Improves Associations between Rare Non-Synonymous Variants in CHRNB4 and Smoking Behavior 
PLoS ONE  2014;9(5):e96753.
Smoking is the leading cause of preventable death worldwide. Accordingly, effort has been devoted to determining the genetic variants that contribute to smoking risk. Genome-wide association studies have identified several variants in nicotinic acetylcholine receptor genes that contribute to nicotine dependence risk. We previously undertook pooled sequencing of the coding regions and flanking sequence of the CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 genes and found that rare missense variants at conserved residues in CHRNB4 are associated with reduced risk of nicotine dependence among African Americans. We identified 10 low frequency (<5%) non-synonymous variants in CHRNB4 and investigated functional effects by co-expression with normal α3 or α4 subunits in human embryonic kidney cells. Voltage-clamp was used to obtain acetylcholine and nicotine concentration–response curves and qRT-PCR, western blots and cell-surface ELISAs were performed to assess expression levels. These results were used to functionally weight genetic variants in a gene-based association test. We find that there is a highly significant correlation between carrier status weighted by either acetylcholine EC50 (β = −0.67, r2 = 0.017, P = 2×10−4) or by response to low nicotine (β = −0.29, r2 = 0.02, P = 6×10−5) when variants are expressed with the α3 subunit. In contrast, there is no significant association when carrier status is unweighted (β = −0.04, r2 = 0.0009, P = 0.54). These results highlight the value of functional analysis of variants and the advantages to integrating such data into genetic studies. They also suggest that an increased sensitivity to low concentrations of nicotine is protective from the risk of developing nicotine dependence.
doi:10.1371/journal.pone.0096753
PMCID: PMC4013067  PMID: 24804708
4.  Parkinson Disease is not associated with C9ORF72 repeat expansions 
Neurobiology of aging  2012;34(5):1519.e1-1519.e2.
Hexanucleotide expansions in the C9ORF72 gene are frequently found in patients with amyotrophic lateral sclerosis and/or frontotemporal dementia, some of whom exhibit concurrent extrapyramidal symptoms. To determine if repeat expansions are a cause of Parkinson Disease (PD), we used repeat-primed PCR to investigate the frequency of C9ORF72 repeat expansions in cohort of 478 patients with PD and 662 control subjects. While 3 control subjects were found to be expansion carriers, no expansions were found among patients, suggesting that C9ORF72 expansions are not a common cause of PD.
doi:10.1016/j.neurobiolaging.2012.10.001
PMCID: PMC3566343  PMID: 23116878
Parkinson Disease; genetics; C9ORF72; hexanucleotide repeat
5.  A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53 
Molecular psychiatry  2012;18(11):10.1038/mp.2012.143.
Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with symptom count were also associated with the dichotomous phenotype, DSM-IV alcohol dependence. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol (p=4.5×10−8, inflation corrected p=9.4×10−7). Results with DSM-IV alcohol dependence in the regions of interest support our findings with symptom count, though the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: non-overlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian twin-family study of alcohol use disorders (OZALC). Nominal association of C15orf53 with symptom count was observed in SAGE. The variant that showed strongest association with symptom count, rs12912251 and its highly correlated variants (D′=1, r2≥ 0.95), has previously been associated with risk for bipolar disorder.
doi:10.1038/mp.2012.143
PMCID: PMC3752321  PMID: 23089632
DSM-IV alcohol dependence symptoms; Family-based GWAS; C15orf53; Quantitative traits
6.  Age-Specific Incidence Rates for Dementia and Alzheimer Disease in NIA-LOAD/NCRAD and EFIGA Families 
JAMA neurology  2014;71(3):315-323.
IMPORTANCE
Late-onset Alzheimer disease (LOAD), defined as onset of symptoms after age 65 years, is the most common form of dementia. Few reports investigate incidence rates in large family-based studies in which the participants were selected for family history of LOAD.
OBJECTIVE
To determine the incidence rates of dementia and LOAD in unaffected members in the National Institute on Aging Genetics Initiative for Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease (NIA-LOAD/NCRAD) and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) family studies.
DESIGN, SETTING, AND PARTICIPANTS
Families with 2 or more affected siblings who had a clinical or pathological diagnosis of LOAD were recruited as a part of the NIA-LOAD/NCRAD Family Study. A cohort of Caribbean Hispanics with familial LOAD was recruited in a different study at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain in New York and from clinics in the Dominican Republic as part of the EFIGA study.
MAIN OUTCOMES AND MEASURES
Age-specific incidence rates of LOAD were estimated in the unaffected family members in the NIA-LOAD/NCRAD and EFIGA data sets. We restricted analyses to families with follow-up and complete phenotype information, including 396 NIA-LOAD/NCRAD and 242 EFIGA families. Among the 943 at-risk family members in the NIA-LOAD/NCRAD families, 126 (13.4%) developed dementia, of whom 109 (86.5%) met criteria for LOAD. Among 683 at-risk family members in the EFIGA families, 174 (25.5%) developed dementia during the study period, of whom 145 (83.3%) had LOAD.
RESULTS
The annual incidence rates of dementia and LOAD in the NIA-LOAD/NCRAD families per person-year were 0.03 and 0.03, respectively, in participants aged 65 to 74 years; 0.07 and 0.06, respectively, in those aged 75 to 84 years; and 0.08 and 0.07, respectively, in those 85 years or older. Incidence rates in the EFIGA families were slightly higher, at 0.03 and 0.02, 0.06 and 0.05, 0.10 and 0.08, and 0.10 and 0.07, respectively, in the same age groups. Contrasting these results with the population-based estimates, the incidence was increased by 3-fold for NIA-LOAD/NCRAD families (standardized incidence ratio, 3.44) and 2-fold among the EFIGA compared with the NIA-LOAD/NCRAD families (1.71).
CONCLUSIONS AND RELEVANCE
The incidence rates for familial dementia and LOAD in the NIA-LOAD/NCRAD and EFIGA families are significantly higher than population-based estimates. The incidence rates in all groups increase with age. The higher incidence of LOAD can be explained by segregation of Alzheimer disease–related genes in these families or shared environmental risks.
doi:10.1001/jamaneurol.2013.5570
PMCID: PMC4000602  PMID: 24425039
7.  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
8.  A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease 
Holmans, Peter | Moskvina, Valentina | Jones, Lesley | Sharma, Manu | Vedernikov, Alexey | Buchel, Finja | Sadd, Mohamad | Bras, Jose M. | Bettella, Francesco | Nicolaou, Nayia | Simón-Sánchez, Javier | Mittag, Florian | Gibbs, J. Raphael | Schulte, Claudia | Durr, Alexandra | Guerreiro, Rita | Hernandez, Dena | Brice, Alexis | Stefánsson, Hreinn | Majamaa, Kari | Gasser, Thomas | Heutink, Peter | Wood, Nicholas W. | Martinez, Maria | Singleton, Andrew B. | Nalls, Michael A. | Hardy, John | Morris, Huw R. | Williams, Nigel M. | Arepalli, Sampath | Barker, Roger | Barrett, Jeffrey | Ben-Shlomo, Yoav | Berendse, Henk W. | Berg, Daniela | Bhatia, Kailash | de Bie, Rob M.A. | Biffi, Alessandro | Bloem, Bas | Brice, Alexis | Bochdanovits, Zoltan | Bonin, Michael | Bras, Jose M. | Brockmann, Kathrin | Brooks, Janet | Burn, David J. | Charlesworth, Gavin | Chen, Honglei | Chinnery, Patrick F. | Chong, Sean | Clarke, Carl E. | Cookson, Mark R. | Cooper, Jonathan M. | Corvol, Jen-Christophe | Counsell, Carl | Damier, Philippe | Dartigues, Jean Francois | Deloukas, Panagiotis | Deuschl, Günther | Dexter, David T. | van Dijk, Karin D. | Dillman, Allissa | Durif, Frank | Durr, Alexandra | Edkins, Sarah | Evans, Jonathan R. | Foltynie, Thomas | Gao, Jianjun | Gardner, Michelle | Gasser, Thomas | Gibbs, J. Raphael | Goate, Alison | Gray, Emma | Guerreiro, Rita | Gústafsson, Ómar | Hardy, John | Harris, Clare | Hernandez, Dena G. | Heutink, Peter | van Hilten, Jacobus J. | Hofman, Albert | Hollenbeck, Albert | Holmans, Peter | Holton, Janice | Hu, Michele | Huber, Heiko | Hudson, Gavin | Hunt, Sarah E. | Huttenlocher, Johanna | Illig, Thomas | Langford, Cordelia | Lees, Andrew | Lesage, Suzanne | Lichtner, Peter | Limousin, Patricia | Lopez, Grisel | Lorenz, Delia | Martinez, Maria | McNeill, Alisdair | Moorby, Catriona | Moore, Matthew | Morris, Huw | Morrison, Karen E. | Moskvina, Valentina | Mudanohwo, Ese | Nalls, Michael A. | Pearson, Justin | Perlmutter, Joel S. | Pétursson, Hjörvar | Plagnol, Vincent | Pollak, Pierre | Post, Bart | Potter, Simon | Ravina, Bernard | Revesz, Tamas | Riess, Olaf | Rivadeneira, Fernando | Rizzu, Patrizia | Ryten, Mina | Saad, Mohamad | Sawcer, Stephen | Schapira, Anthony | Scheffer, Hans | Sharma, Manu | Shaw, Karen | Sheerin, Una-Marie | Shoulson, Ira | Schulte, Claudia | Sidransky, Ellen | Simón-Sánchez, Javier | Singleton, Andrew B. | Smith, Colin | Stefánsson, Hreinn | Stefánsson, Kári | Steinberg, Stacy | Stockton, Joanna D. | Sveinbjornsdottir, Sigurlaug | Talbot, Kevin | Tanner, Carlie M. | Tashakkori-Ghanbaria, Avazeh | Tison, François | Trabzuni, Daniah | Traynor, Bryan J. | Uitterlinden, André G. | Velseboer, Daan | Vidailhet, Marie | Walker, Robert | van de Warrenburg, Bart | Wickremaratchi, Mirdhu | Williams, Nigel | Williams-Gray, Caroline H. | Winder-Rhodes, Sophie | Wood, Nicholas
Human Molecular Genetics  2012;22(5):1039-1049.
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people >60 and 3–4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10−16) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the ‘regulation of leucocyte/lymphocyte activity’ and also ‘cytokine-mediated signalling’ as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
doi:10.1093/hmg/dds492
PMCID: PMC3561909  PMID: 23223016
9.  A compensatory effect upon splicing results in normal function of the CYP2A6*14 allele 
Pharmacogenetics and genomics  2013;23(3):107-116.
A synonymous variant in the first exon of CYP2A6, rs1137115 (51G > A), defines the common reference allele CYP2A6*1A, and is associated with lower mRNA expression and slower in-vivo nicotine metabolism. Another common allele, CYP2A6*14, differs from CYP2A6*1A by a single variant, rs28399435 (86G > A, S29N). However, CYP2A6*14 shows in-vivo activity comparable with that of full-function alleles, and significantly higher than CYP2A6*1A. rs1137115A is predicted to create an exonic splicing suppressor site overlapping an exonic splicing enhancer (ESE) site in the first exon of CYP2A6, whereas rs28399435A is predicted to strengthen another adjacent ESE, potentially compensating for rs1137115A. Using an allelic expression assay to assess cDNAs produced from rs1137115 heterozygous liver biopsy samples, lower expression of the CYP2A6*1A allele is confirmed while CYP2A6*14 expression is found to be indistinguishable from that of rs1137115G alleles. Quantitative PCR assays to determine the relative abundance of spliced and unspliced or partially spliced CYP2A6 mRNAs in liver biopsy samples show that *1A/*1A homozygotes have a significantly lower ratio, due to both a reduction in spliced forms and an increase in unspliced or partially spliced CYP2A6. These results show the importance of common genetic variants that effect exonic splicing suppressor and ESEs to explain human variation regarding clinically-relevant phenotypes.
doi:10.1097/FPC.0b013e32835caf7d
PMCID: PMC3919506  PMID: 23292114
CYP2A6; exonic splice enhancer; exonic splice suppressor; nicotine metabolism; splicing
10.  Calcium phosphatase calcineurin influences tau metabolism 
Neurobiology of aging  2012;34(2):10.1016/j.neurobiolaging.2012.05.003.
Alzheimer’s disease (AD) is characterized by neuronal loss and the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. Cerebrospinal fluid (CSF) levels of β-amyloid and tau/ptau181 are also associated with AD. We have previously demonstrated that a single nucleotide polymorphism in calcineurin is associated with CSF ptau181 levels and AD progression. In this study, we demonstrate that calcineurin protein levels are inversely correlated with dementia severity and Braak tangle stage in AD brains, and calcineurin activity is globally reduced in AD brains. We then sought to model the observed changes in CSF tau by measuring extracellular tau in cultured cells. SH-SY5Y cells treated with calcineurin inhibitors produced reduced calcineurin activity and a corresponding increase in extracellular ptau181. These findings are consistent with our observations in AD patients, who have elevated CSF ptau181 and reduced calcineurin activity in brain extracts. Thus, we have identified a gene that contributes to AD pathology and has functional consequences on tau metabolism in cultured cells.
doi:10.1016/j.neurobiolaging.2012.05.003
PMCID: PMC3879081  PMID: 22676853
Calcineurin; tau; Alzheimer’s disease; phosphorylation
11.  Pupil Response Biomarkers Distinguish Amyloid Precursor Protein Mutation Carriers from Non-Carriers 
Current Alzheimer research  2013;10(8):790-796.
Context
Alzheimer’s disease (AD) is usually only diagnosed many years after pathology begins. Earlier detection would allow emerging interventions to have a greater chance to preserve healthy brain function. A rare form of Alzheimer’s disease, caused by autosomal-dominant mutations, affects carriers with 100% certainty and at a younger age specific to their mutation. Studying families with these mutations allows a unique investigation of the temporal sequence of biomarker changes in Alzheimer’s disease.
Objective
To determine whether the pupil flash response (PFR), previously reported to be altered in sporadic Alzheimer’s disease, is different in pre-symptomatic mutation carriers.
Design
Researchers blinded to participant mutation status collected pupil response data from cognitively normal participants in the Dominantly Inherited Alzheimer's Network (DIAN) Study during 2010–2011.
Setting
The pupil response was examined at the McCusker Alzheimer’s Research Foundation in Perth, Western Australia.
Participants
Participants were from a single family harboring an Amyloid-Beta Precursor Protein genetic mutation (APPGlu693Gln). Six carriers and six non-carriers were available for pupil testing (age 43.0±8.3 years old, 2 males and 10 females, 4 with hypertension).
Main Outcome Measure
Pupil response parameter comparison between mutation carriers and non-carriers.
Results
75% recovery time was longer in mutation carriers (p<0.0003, ROC AUC 1.000, Sensitivity 100%, Specificity 100%) and percentage recovery 3.5 seconds after stimulus was less in mutation carriers (p<0.006, ROC AUC 1.000, Sensitivity 100%, Specificity 100%).
Conclusions
PFR changes occur pre-symptomatically in autosomal dominant AD mutation carriers, supporting further investigation of PFR for early detection of AD.
PMCID: PMC3879087  PMID: 23919771
Alzheimer’s; autosomal; amyloid; eye; pupil
12.  C9ORF72 hexanucleotide repeat expansions in clinical Alzheimer’s disease 
JAMA neurology  2013;70(6):736-741.
Objective
Hexanucleotide repeat expansions in C9ORF72 underlie a significant fraction of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study investigates the frequency of C9ORF72 repeat expansions in clinically diagnosed late-onset Alzheimer’s disease (AD).
Design, setting and patients
This case-control study genotyped the C9ORF72 repeat expansion in 872 unrelated familial AD cases and 888 controls recruited as part of the NIA-LOAD cohort, a multi-site collaboration studying 1000 families with two or more individuals clinically diagnosed with late-onset-AD.
Main Outcome Measure
We determined the presence or absence of the C9ORF72 repeat expansion by repeat-primed PCR, the length of the longest non-expanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers.
Results
Three families showed large C9ORF72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the NIA-LOAD series, the C9ORF72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions.
Interpretation
C9ORF72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and highlight the necessity of screening “FTD genes” in clinical AD cases with strong family history.
doi:10.1001/2013.jamaneurol.537
PMCID: PMC3681841  PMID: 23588422
13.  Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry 
PLoS ONE  2013;8(11):e80204.
Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.
doi:10.1371/journal.pone.0080204
PMCID: PMC3841173  PMID: 24303001
14.  Increased in vivo Amyloid-β42 production, exchange, and irreversible loss in Presenilin Mutations Carriers 
Science translational medicine  2013;5(189):10.1126/scitranslmed.3005615.
Alzheimer’s disease is hypothesized to be caused by an over-production or reduced clearance of amyloid-beta (Aβ) peptide. Autosomal Dominant Alzheimer’s Disease (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related non-carriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer, Pittsburgh compound B (PiB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to non-carriers and this was independent of fibrillar amyloid deposits quantified by PET PiB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with pre-existing unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with presenilin mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.
doi:10.1126/scitranslmed.3005615
PMCID: PMC3838868  PMID: 23761040
15.  CYP2B6 Non-Coding Variation Associated with Smoking Cessation Is Also Associated with Differences in Allelic Expression, Splicing, and Nicotine Metabolism Independent of Common Amino-Acid Changes 
PLoS ONE  2013;8(11):e79700.
The Cytochrome P450 2B6 (CYP2B6) enzyme makes a small contribution to hepatic nicotine metabolism relative to CYP2A6, but CYP2B6 is the primary enzyme responsible for metabolism of the smoking cessation drug bupropion. Using CYP2A6 genotype as a covariate, we find that a non-coding polymorphism in CYP2B6 previously associated with smoking cessation (rs8109525) is also significantly associated with nicotine metabolism. The association is independent of the well-studied non-synonymous variants rs3211371, rs3745274, and rs2279343 (CYP2B6*5 and *6). Expression studies demonstrate that rs8109525 is also associated with differences in CYP2B6 mRNA expression in liver biopsy samples. Splicing assays demonstrate that specific splice forms of CYP2B6 are associated with haplotypes defined by variants including rs3745274 and rs8109525. These results indicate differences in mRNA expression and splicing as potential molecular mechanisms by which non-coding variation in CYP2B6 may affect enzymatic activity leading to differences in metabolism and smoking cessation.
doi:10.1371/journal.pone.0079700
PMCID: PMC3829832  PMID: 24260284
16.  A Systematic SNP Screen to Fine-Map Alcohol Dependence Genes on Chromosome 7 Identifies Association with a Novel Susceptibility Gene ACN9 
Biological psychiatry  2007;63(11):10.1016/j.biopsych.2007.11.005.
Background
Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. Using a sample of 262 densely affected families, a peak lod score for alcohol dependence of 2.9 was observed at D7S1799 (Wang et al., 2004, Hum Mol Genet). The lod score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14; Dunn et al., 2005, BMC Genetics). To follow-up on this linkage region, we systematically screened SNPs across a 2 LOD support interval surrounding the alcohol dependence peak.
Methods
SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. 1340 across the 18Mb region, genotyped by the Center for Inherited Disease Research (CIDR), were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families. Results: Eight SNPs showed association with alcohol dependence at p<0.01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence.
Conclusions
These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate.
doi:10.1016/j.biopsych.2007.11.005
PMCID: PMC3823371  PMID: 18163977
genetics; association; linkage disequilibrium; alcohol dependence; ACN9
17.  CHRNB3 is more strongly associated with FTCD-based nicotine dependence than cigarettes per day: phenotype definition changes GWAS results 
Addiction (Abingdon, England)  2012;107(11):2019-2028.
Aims
Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerström Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence.
Design
Genome-wide association study
Setting
Community sample
Participants
A total of 3,365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2,267 were European Americans,999 were African Americans.
Measurements
Nicotine dependence defined by FTCD score ≥4, CPD
Findings
The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 (OR=0.65, p=2.4×10−8). This association was further strengthened in a meta-analysis with a previously published dataset (combined p=6.7 ×10−16, total n=4,200).When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (β=−0.08, p=0.0007).
Conclusions
Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence (FTCD) show different associations with polymorphisms in genetic loci.
doi:10.1111/j.1360-0443.2012.03922.x
PMCID: PMC3427406  PMID: 22524403
18.  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
19.  Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network 
Clinical investigation  2012;2(10):975-984.
The Dominantly Inherited Alzheimer Network (DIAN) is a collaborative effort of international Alzheimer disease (AD) centers that are conducting a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). DIAN collects comprehensive information and tissue in accordance with standard protocols from asymptomatic and symptomatic ADAD mutation carriers and their non-carrier family members to determine the pathochronology of clinical, cognitive, neuroimaging, and fluid biomarkers of AD. This article describes the structure, implementation, and underlying principles of DIAN, as well as the demographic features of the initial DIAN cohort.
doi:10.4155/cli.12.93
PMCID: PMC3489185  PMID: 23139856
Alzheimer disease; autosomal dominant; biomarkers of Alzheimer disease; PSEN1; PSEN2; APP; amyloid-beta; preclinical Alzheimer disease
20.  Characterizing the Role of Brain Derived Neurotrophic Factor Genetic Variation in Alzheimer’s Disease Neurodegeneration 
PLoS ONE  2013;8(9):e76001.
There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF), may impact aging and Alzheimer’s Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs) impact Alzheimer’s Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer’s Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154) who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met), rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459). We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108). No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850). We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD-related brain neurodegeneration.
doi:10.1371/journal.pone.0076001
PMCID: PMC3784423  PMID: 24086677
21.  The Genetics of Substance Dependence 
A large segment of the population suffers from addiction to alcohol, smoking, or illicit drugs. Not only do substance abuse and addiction pose a threat to health, but the consequences of addiction also impose a social and economic burden on families, communities, and nations. Genome-wide linkage and association studies have been used for addiction research with varying degrees of success. The most well-established genetic factors associated with alcohol dependence are in the genes encoding alcohol dehydrogenase (ADH), which oxidizes alcohol to acetaldehyde, and aldehyde dehydrogenase (ALDH2), which oxidizes acetaldehyde to acetate. Recently emerging genetic studies have linked variants in the genes encoding the α3, α5, and β4 nicotinic acetylcholine receptor subunits to smoking risk. However, the influence of these well-established genetic variants accounts for only a small portion of the heritability of alcohol and nicotine addiction, and it is likely that there are both common and rare risk variants yet to be identified. Newly developed DNA sequencing technologies could potentially advance the detection of rare variants with a larger impact on addiction risk.
doi:10.1146/annurev-genom-090711-163844
PMCID: PMC3474605  PMID: 22703173
addiction; alcoholism; smoking; nicotinic acetylcholine receptors; alcohol metabolizing genes
22.  Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence 
Background
Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between DSM-IV alcohol dependence and all common copy number variations (CNV) with good reliability in the Study of Addiction: Genetics and Environment (SAGE).
Methods
All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), as a part of three contributing studies. 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVpartition, PennCNV and QuantiSNP and only CNVs identified by all three software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory.
Results
CNVs in 6q14.1 (P= 1.04 × 10−6) and 5q13.2 (P= 3.37 × 10−4) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2 there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation, and language delay. The CNV in 5q13.2 was validated whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution.
Conclusion
This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.
doi:10.1111/j.1530-0277.2012.01758.x
PMCID: PMC3436997  PMID: 22702843
Copy Number Variations; Alcohol dependence; CNV Accuracy
23.  The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers 
PLoS Genetics  2013;9(8):e1003685.
The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2×10−4) and ptau (p = 1.8×10−3) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7–24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9–13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4–4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.
Author Summary
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 5.3 million people in the US. AD-causing mutations have been identified in APP, PSEN1 and PSEN2 genes. Heterozygous carriers of APOE-ε4 allele exhibit a 3-fold increased risk for developing AD, while homozygous carriers show a 10-fold greater risk than non-carriers. Here, we sequenced individuals with extreme levels of well-established AD cerebrospinal fluid (CSF) biomarkers in order to identify variants in APOE, APP, PSEN1, PSEN2, GRN and MAPT genes associated with AD risk. This approach allowed us to identify known pathogenic variants, additional AD risk genetic factors and identify a low frequency variant in PSEN1, p.E318G (rs17125721-G) that increases risk for AD in a gene-gene interaction with APOE. These findings were replicated in three large (>4,000 individuals) and independent datasets. This finding is particularly important because we demonstrated that a currently considered non-pathogenic variant is associated with higher levels of neuronal degeneration, and with Aβ deposition, more Aβ plaques and faster cognitive decline in an APOE-ε4-dependent fashion. APOE-ε4 heterozygous individuals who carry this variant are at similar AD risk as APOE-ε4 homozygous individuals.
doi:10.1371/journal.pgen.1003685
PMCID: PMC3750021  PMID: 23990795
25.  Characterization of N-Terminal Processing of Group VIA Phospholipase A2 and of Potential Cleavage Sites of Amyloid Precursor Protein Constructs by Automated Identification of Signature Peptides in LC/MS/MS Analyses of Proteolytic Digests 
Dysregulation of proteolytic processing of the amyloid precursor protein (APP) contributes to the pathogenesis of Alzheimer’s Disease, and the Group VIA phospholipase A2 (iPLA2β) is the dominant PLA2 enzyme in the central nervous system and is subject to regulatory proteolytic processing. We have identified novel N-terminal variants of iPLA2β and previously unrecognized proteolysis sites in APP constructs with a C-terminal 6-myc tag by automated identification of signature peptides in LC/MS/MS analyses of proteolytic digests. We have developed a Signature-Discovery (SD) program to characterize protein isoforms by identifying signature peptides that arise from proteolytic processing in vivo. This program analyzes MS/MS data from LC analyses of proteolytic digests of protein mixtures that can include incompletely resolved components in biological samples. This reduces requirements for purification and thereby minimizes artifactual modifications during sample processing. A new algorithm to generate the theoretical signature peptide set and to calculate similarity scores between predicted and observed mass spectra has been tested and optimized with model proteins. The program has been applied to the identification of variants of proteins of biological interest, including APP cleavage products and iPLA2β, and such applications demonstrate the utility of this approach.
doi:10.1016/j.jasms.2004.08.012
PMCID: PMC3732747  PMID: 15589755

Results 1-25 (108)