TY - JOUR T1 - Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. JF - PLoS One Y1 - 2014 A1 - Escott-Price, Valentina A1 - Bellenguez, Céline A1 - Wang, Li-San A1 - Choi, Seung-Hoan A1 - Harold, Denise A1 - Jones, Lesley A1 - Holmans, Peter A1 - Gerrish, Amy A1 - Vedernikov, Alexey A1 - Richards, Alexander A1 - DeStefano, Anita L A1 - Lambert, Jean-Charles A1 - Ibrahim-Verbaas, Carla A A1 - Naj, Adam C A1 - Sims, Rebecca A1 - Jun, Gyungah A1 - Bis, Joshua C A1 - Beecham, Gary W A1 - Grenier-Boley, Benjamin A1 - Russo, Giancarlo A1 - Thornton-Wells, Tricia A A1 - Denning, Nicola A1 - Smith, Albert V A1 - Chouraki, Vincent A1 - Thomas, Charlene A1 - Ikram, M Arfan A1 - Zelenika, Diana A1 - Vardarajan, Badri N A1 - Kamatani, Yoichiro A1 - Lin, Chiao-Feng A1 - Schmidt, Helena A1 - Kunkle, Brian A1 - Dunstan, Melanie L A1 - Vronskaya, Maria A1 - Johnson, Andrew D A1 - Ruiz, Agustin A1 - Bihoreau, Marie-Thérèse A1 - Reitz, Christiane A1 - Pasquier, Florence A1 - Hollingworth, Paul A1 - Hanon, Olivier A1 - Fitzpatrick, Annette L A1 - Buxbaum, Joseph D A1 - Campion, Dominique A1 - Crane, Paul K A1 - Baldwin, Clinton A1 - Becker, Tim A1 - Gudnason, Vilmundur A1 - Cruchaga, Carlos A1 - Craig, David A1 - Amin, Najaf A1 - Berr, Claudine A1 - Lopez, Oscar L A1 - De Jager, Philip L A1 - Deramecourt, Vincent A1 - Johnston, Janet A A1 - Evans, Denis A1 - Lovestone, Simon A1 - Letenneur, Luc A1 - Hernandez, Isabel A1 - Rubinsztein, David C A1 - Eiriksdottir, Gudny A1 - Sleegers, Kristel A1 - Goate, Alison M A1 - Fiévet, Nathalie A1 - Huentelman, Matthew J A1 - Gill, Michael A1 - Brown, Kristelle A1 - Kamboh, M Ilyas A1 - Keller, Lina A1 - Barberger-Gateau, Pascale A1 - McGuinness, Bernadette A1 - Larson, Eric B A1 - Myers, Amanda J A1 - Dufouil, Carole A1 - Todd, Stephen A1 - Wallon, David A1 - Love, Seth A1 - Rogaeva, Ekaterina A1 - Gallacher, John A1 - George-Hyslop, Peter St A1 - Clarimon, Jordi A1 - Lleo, Alberto A1 - Bayer, Anthony A1 - Tsuang, Debby W A1 - Yu, Lei A1 - Tsolaki, Magda A1 - Bossù, Paola A1 - Spalletta, Gianfranco A1 - Proitsi, Petra A1 - Collinge, John A1 - Sorbi, Sandro A1 - Garcia, Florentino Sanchez A1 - Fox, Nick C A1 - Hardy, John A1 - Naranjo, Maria Candida Deniz A1 - Bosco, Paolo A1 - Clarke, Robert A1 - Brayne, Carol A1 - Galimberti, Daniela A1 - Scarpini, Elio A1 - Bonuccelli, Ubaldo A1 - Mancuso, Michelangelo A1 - Siciliano, Gabriele A1 - Moebus, Susanne A1 - Mecocci, Patrizia A1 - Zompo, Maria Del A1 - Maier, Wolfgang A1 - Hampel, Harald A1 - Pilotto, Alberto A1 - Frank-García, Ana A1 - Panza, Francesco A1 - Solfrizzi, Vincenzo A1 - Caffarra, Paolo A1 - Nacmias, Benedetta A1 - Perry, William A1 - Mayhaus, Manuel A1 - Lannfelt, Lars A1 - Hakonarson, Hakon A1 - Pichler, Sabrina A1 - Carrasquillo, Minerva M A1 - Ingelsson, Martin A1 - Beekly, Duane A1 - Alvarez, Victoria A1 - Zou, Fanggeng A1 - Valladares, Otto A1 - Younkin, Steven G A1 - Coto, Eliecer A1 - Hamilton-Nelson, Kara L A1 - Gu, Wei A1 - Razquin, Cristina A1 - Pastor, Pau A1 - Mateo, Ignacio A1 - Owen, Michael J A1 - Faber, Kelley M A1 - Jonsson, Palmi V A1 - Combarros, Onofre A1 - O'Donovan, Michael C A1 - Cantwell, Laura B A1 - Soininen, Hilkka A1 - Blacker, Deborah A1 - Mead, Simon A1 - Mosley, Thomas H A1 - Bennett, David A A1 - Harris, Tamara B A1 - Fratiglioni, Laura A1 - Holmes, Clive A1 - de Bruijn, Renee F A G A1 - Passmore, Peter A1 - Montine, Thomas J A1 - Bettens, Karolien A1 - Rotter, Jerome I A1 - Brice, Alexis A1 - Morgan, Kevin A1 - Foroud, Tatiana M A1 - Kukull, Walter A A1 - Hannequin, Didier A1 - Powell, John F A1 - Nalls, Michael A A1 - Ritchie, Karen A1 - Lunetta, Kathryn L A1 - Kauwe, John S K A1 - Boerwinkle, Eric A1 - Riemenschneider, Matthias A1 - Boada, Merce A1 - Hiltunen, Mikko A1 - Martin, Eden R A1 - Schmidt, Reinhold A1 - Rujescu, Dan A1 - Dartigues, Jean-François A1 - Mayeux, Richard A1 - Tzourio, Christophe A1 - Hofman, Albert A1 - Nöthen, Markus M A1 - Graff, Caroline A1 - Psaty, Bruce M A1 - Haines, Jonathan L A1 - Lathrop, Mark A1 - Pericak-Vance, Margaret A A1 - Launer, Lenore J A1 - Van Broeckhoven, Christine A1 - Farrer, Lindsay A A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Seshadri, Sudha A1 - Schellenberg, Gerard D A1 - Amouyel, Philippe A1 - Williams, Julie KW - Alzheimer Disease KW - Carrier Proteins KW - Case-Control Studies KW - Genome-Wide Association Study KW - Heat-Shock Proteins KW - Humans KW - Polymorphism, Single Nucleotide KW - Receptors, Antigen, B-Cell AB -

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.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract ER - TY - JOUR T1 - Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. JF - Stroke Y1 - 2014 A1 - Malik, Rainer A1 - Bevan, Steve A1 - Nalls, Michael A A1 - Holliday, Elizabeth G A1 - Devan, William J A1 - Cheng, Yu-Ching A1 - Ibrahim-Verbaas, Carla A A1 - Verhaaren, Benjamin F J A1 - Bis, Joshua C A1 - Joon, Aron Y A1 - de Stefano, Anita L A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Ikram, M Arfan A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Sharma, Pankaj A1 - Mitchell, Braxton D A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Levi, Christopher A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Dichgans, Martin KW - Adult KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Blood Pressure KW - Brain Ischemia KW - Case-Control Studies KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Multilocus Sequence Typing KW - Polymorphism, Single Nucleotide KW - Population KW - Prospective Studies KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract ER - TY - JOUR T1 - Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. JF - Stroke Y1 - 2014 A1 - Ibrahim-Verbaas, Carla A A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Choi, Seung Hoan A1 - Psaty, Bruce M A1 - Meigs, James B A1 - Rao, Madhu A1 - Nalls, Mike A1 - Fontes, João D A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Ehret, Georg B A1 - Fox, Caroline S A1 - Malik, Rainer A1 - Dichgans, Martin A1 - Schmidt, Helena A1 - Lahti, Jari A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Folsom, Aaron R A1 - Boerwinkle, Eric A1 - Rosamond, Wayne D A1 - Shahar, Eyal A1 - Gottesman, Rebecca F A1 - Koudstaal, Peter J A1 - Amin, Najaf A1 - Wieberdink, Renske G A1 - Dehghan, Abbas A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - DeStefano, Anita L A1 - Debette, Stephanie A1 - Xue, Luting A1 - Beiser, Alexa A1 - Wolf, Philip A A1 - DeCarli, Charles A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Area Under Curve KW - Case-Control Studies KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - ROC Curve KW - Sex Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract ER - TY - JOUR T1 - Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. JF - Circ Cardiovasc Genet Y1 - 2015 A1 - Verhaaren, Benjamin F J A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Smith, Jennifer A A1 - Ikram, M Kamran A1 - Adams, Hieab H A1 - Beecham, Ashley H A1 - Rajan, Kumar B A1 - Lopez, Lorna M A1 - Barral, Sandra A1 - van Buchem, Mark A A1 - van der Grond, Jeroen A1 - Smith, Albert V A1 - Hegenscheid, Katrin A1 - Aggarwal, Neelum T A1 - de Andrade, Mariza A1 - Atkinson, Elizabeth J A1 - Beekman, Marian A1 - Beiser, Alexa S A1 - Blanton, Susan H A1 - Boerwinkle, Eric A1 - Brickman, Adam M A1 - Bryan, R Nick A1 - Chauhan, Ganesh A1 - Chen, Christopher P L H A1 - Chouraki, Vincent A1 - de Craen, Anton J M A1 - Crivello, Fabrice A1 - Deary, Ian J A1 - Deelen, Joris A1 - De Jager, Philip L A1 - Dufouil, Carole A1 - Elkind, Mitchell S V A1 - Evans, Denis A A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Guðnason, Vilmundur A1 - Habes, Mohamad A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hilal, Saima A1 - Hofer, Edith A1 - Hofman, Albert A1 - Ibrahim-Verbaas, Carla A A1 - Knopman, David S A1 - Lewis, Cora E A1 - Liao, Jiemin A1 - Liewald, David C M A1 - Luciano, Michelle A1 - van der Lugt, Aad A1 - Martinez, Oliver O A1 - Mayeux, Richard A1 - Mazoyer, Bernard A1 - Nalls, Mike A1 - Nauck, Matthias A1 - Niessen, Wiro J A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - von Sarnowski, Bettina A1 - Schmidt, Helena A1 - Schreiner, Pamela J A1 - Schuur, Maaike A1 - Sidney, Stephen S A1 - Sigurdsson, Sigurdur A1 - Slagboom, P Eline A1 - Stott, David J M A1 - van Swieten, John C A1 - Teumer, Alexander A1 - Töglhofer, Anna Maria A1 - Traylor, Matthew A1 - Trompet, Stella A1 - Turner, Stephen T A1 - Tzourio, Christophe A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vernooij, Meike W A1 - Wang, Jing J A1 - Wong, Tien Y A1 - Wardlaw, Joanna M A1 - Windham, B Gwen A1 - Wittfeld, Katharina A1 - Wolf, Christiane A1 - Wright, Clinton B A1 - Yang, Qiong A1 - Zhao, Wei A1 - Zijdenbos, Alex A1 - Jukema, J Wouter A1 - Sacco, Ralph L A1 - Kardia, Sharon L R A1 - Amouyel, Philippe A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - DeCarli, Charles C A1 - van Duijn, Cornelia M A1 - Schmidt, Reinhold A1 - Launer, Lenore J A1 - Grabe, Hans J A1 - Seshadri, Sudha S A1 - Ikram, M Arfan A1 - Fornage, Myriam KW - Aged KW - Aged, 80 and over KW - Chromosomes, Human KW - Continental Population Groups KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Models, Genetic KW - Stroke KW - White Matter AB -

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract ER - TY - JOUR T1 - Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. JF - PLoS Genet Y1 - 2016 A1 - Jakobsdottir, Johanna A1 - van der Lee, Sven J A1 - Bis, Joshua C A1 - Chouraki, Vincent A1 - Li-Kroeger, David A1 - Yamamoto, Shinya A1 - Grove, Megan L A1 - Naj, Adam A1 - Vronskaya, Maria A1 - Salazar, Jose L A1 - DeStefano, Anita L A1 - Brody, Jennifer A A1 - Smith, Albert V A1 - Amin, Najaf A1 - Sims, Rebecca A1 - Ibrahim-Verbaas, Carla A A1 - Choi, Seung-Hoan A1 - Satizabal, Claudia L A1 - Lopez, Oscar L A1 - Beiser, Alexa A1 - Ikram, M Arfan A1 - Garcia, Melissa E A1 - Hayward, Caroline A1 - Varga, Tibor V A1 - Ripatti, Samuli A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Rolandsson, Olov A1 - Jansson, Jan-Håkon A1 - Porteous, David J A1 - Salomaa, Veikko A1 - Eiriksdottir, Gudny A1 - Rice, Kenneth M A1 - Bellen, Hugo J A1 - Levy, Daniel A1 - Uitterlinden, André G A1 - Emilsson, Valur A1 - Rotter, Jerome I A1 - Aspelund, Thor A1 - O'Donnell, Christopher J A1 - Fitzpatrick, Annette L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Wang, Li-San A1 - Williams, Julie A1 - Schellenberg, Gerard D A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Shulman, Joshua M A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M AB -

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

VL - 12 IS - 10 ER -