TY - JOUR T1 - Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. JF - Neurobiol Aging Y1 - 2015 A1 - Chauhan, Ganesh A1 - Adams, Hieab H H A1 - Bis, Joshua C A1 - Weinstein, Galit A1 - Yu, Lei A1 - Töglhofer, Anna Maria A1 - Smith, Albert Vernon A1 - van der Lee, Sven J A1 - Gottesman, Rebecca F A1 - Thomson, Russell A1 - Wang, Jing A1 - Yang, Qiong A1 - Niessen, Wiro J A1 - Lopez, Oscar L A1 - Becker, James T A1 - Phan, Thanh G A1 - Beare, Richard J A1 - Arfanakis, Konstantinos A1 - Fleischman, Debra A1 - Vernooij, Meike W A1 - Mazoyer, Bernard A1 - Schmidt, Helena A1 - Srikanth, Velandai A1 - Knopman, David S A1 - Jack, Clifford R A1 - Amouyel, Philippe A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Bennett, David A A1 - Schmidt, Reinhold A1 - Longstreth, William T A1 - Mosley, Thomas H A1 - Fornage, Myriam A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Debette, Stephanie KW - Aging KW - Alleles KW - Alzheimer Disease KW - Apolipoproteins E KW - Brain KW - Female KW - Genome-Wide Association Study KW - Hippocampus KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Organ Size KW - Polymorphism, Single Nucleotide KW - Risk KW - Sialic Acid Binding Ig-like Lectin 3 AB -

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

VL - 36 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract ER - TY - JOUR T1 - Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. JF - J Alzheimers Dis Y1 - 2016 A1 - Chouraki, Vincent A1 - Reitz, Christiane A1 - Maury, Fleur A1 - Bis, Joshua C A1 - Bellenguez, Céline A1 - Yu, Lei A1 - Jakobsdottir, Johanna A1 - Mukherjee, Shubhabrata A1 - Adams, Hieab H A1 - Choi, Seung Hoan A1 - Larson, Eric B A1 - Fitzpatrick, Annette A1 - Uitterlinden, André G A1 - De Jager, Philip L A1 - Hofman, Albert A1 - Gudnason, Vilmundur A1 - Vardarajan, Badri A1 - Ibrahim-Verbaas, Carla A1 - van der Lee, Sven J A1 - Lopez, Oscar A1 - Dartigues, Jean-François A1 - Berr, Claudine A1 - Amouyel, Philippe A1 - Bennett, David A A1 - van Duijn, Cornelia A1 - DeStefano, Anita L A1 - Launer, Lenore J A1 - Ikram, M Arfan A1 - Crane, Paul K A1 - Lambert, Jean-Charles A1 - Mayeux, Richard A1 - Seshadri, Sudha AB -

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

VL - 53 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract ER - TY - JOUR T1 - Novel Genetic Loci Associated With Retinal Microvascular Diameter. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Li, Xiaohui A1 - Jakobsdottir, Johanna A1 - Cheng, Ching-Yu A1 - Brody, Jennifer A A1 - Cotch, Mary Frances A1 - McKnight, Barbara A1 - Klein, Ronald A1 - Wang, Jie Jin A1 - Kifley, Annette A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Taylor, Kent D A1 - Klein, Barbara E K A1 - Raffel, Leslie J A1 - Li, Xiang A1 - Ikram, M Arfan A1 - Klaver, Caroline C A1 - van der Lee, Sven J A1 - Mutlu, Unal A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Liu, Chunyu A1 - Kraja, Aldi T A1 - Mitchell, Paul A1 - Gudnason, Vilmundur A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Wong, Tien Y AB -

BACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.

METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).

CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26567291?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 - TY - JOUR T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. JF - Nat Genet Y1 - 2017 A1 - Sims, Rebecca A1 - van der Lee, Sven J A1 - Naj, Adam C A1 - Bellenguez, Céline A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Kunkle, Brian W A1 - Boland, Anne A1 - Raybould, Rachel A1 - Bis, Joshua C A1 - Martin, Eden R A1 - Grenier-Boley, Benjamin A1 - Heilmann-Heimbach, Stefanie A1 - Chouraki, Vincent A1 - Kuzma, Amanda B A1 - Sleegers, Kristel A1 - Vronskaya, Maria A1 - Ruiz, Agustin A1 - Graham, Robert R A1 - Olaso, Robert A1 - Hoffmann, Per A1 - Grove, Megan L A1 - Vardarajan, Badri N A1 - Hiltunen, Mikko A1 - Nöthen, Markus M A1 - White, Charles C A1 - Hamilton-Nelson, Kara L A1 - Epelbaum, Jacques A1 - Maier, Wolfgang A1 - Choi, Seung-Hoan A1 - Beecham, Gary W A1 - Dulary, Cécile A1 - Herms, Stefan A1 - Smith, Albert V A1 - Funk, Cory C A1 - Derbois, Céline A1 - Forstner, Andreas J A1 - Ahmad, Shahzad A1 - Li, Hongdong A1 - Bacq, Delphine A1 - Harold, Denise A1 - Satizabal, Claudia L A1 - Valladares, Otto A1 - Squassina, Alessio A1 - Thomas, Rhodri A1 - Brody, Jennifer A A1 - Qu, Liming A1 - Sánchez-Juan, Pascual A1 - Morgan, Taniesha A1 - Wolters, Frank J A1 - Zhao, Yi A1 - Garcia, Florentino Sanchez A1 - Denning, Nicola A1 - Fornage, Myriam A1 - Malamon, John A1 - Naranjo, Maria Candida Deniz A1 - Majounie, Elisa A1 - Mosley, Thomas H A1 - Dombroski, Beth A1 - Wallon, David A1 - Lupton, Michelle K A1 - Dupuis, Josée A1 - Whitehead, Patrice A1 - Fratiglioni, Laura A1 - Medway, Christopher A1 - Jian, Xueqiu A1 - Mukherjee, Shubhabrata A1 - Keller, Lina A1 - Brown, Kristelle A1 - Lin, Honghuang A1 - Cantwell, Laura B A1 - Panza, Francesco A1 - McGuinness, Bernadette A1 - Moreno-Grau, Sonia A1 - Burgess, Jeremy D A1 - Solfrizzi, Vincenzo A1 - Proitsi, Petra A1 - Adams, Hieab H A1 - Allen, Mariet A1 - Seripa, Davide A1 - Pastor, Pau A1 - Cupples, L Adrienne A1 - Price, Nathan D A1 - Hannequin, Didier A1 - Frank-García, Ana A1 - Levy, Daniel A1 - Chakrabarty, Paramita A1 - Caffarra, Paolo A1 - Giegling, Ina A1 - Beiser, Alexa S A1 - Giedraitis, Vilmantas A1 - Hampel, Harald A1 - Garcia, Melissa E A1 - Wang, Xue A1 - Lannfelt, Lars A1 - Mecocci, Patrizia A1 - Eiriksdottir, Gudny A1 - Crane, Paul K A1 - Pasquier, Florence A1 - Boccardi, Virginia A1 - Henández, Isabel A1 - Barber, Robert C A1 - Scherer, Martin A1 - Tarraga, Lluis A1 - Adams, Perrie M A1 - Leber, Markus A1 - Chen, Yuning A1 - Albert, Marilyn S A1 - Riedel-Heller, Steffi A1 - Emilsson, Valur A1 - Beekly, Duane A1 - Braae, Anne A1 - Schmidt, Reinhold A1 - Blacker, Deborah A1 - Masullo, Carlo A1 - Schmidt, Helena A1 - Doody, Rachelle S A1 - Spalletta, Gianfranco A1 - Jr, W T Longstreth A1 - Fairchild, Thomas J A1 - Bossù, Paola A1 - Lopez, Oscar L A1 - Frosch, Matthew P A1 - Sacchinelli, Eleonora A1 - Ghetti, Bernardino A1 - Yang, Qiong A1 - Huebinger, Ryan M A1 - Jessen, Frank A1 - Li, Shuo A1 - Kamboh, M Ilyas A1 - Morris, John A1 - Sotolongo-Grau, Oscar A1 - Katz, Mindy J A1 - Corcoran, Chris A1 - Dunstan, Melanie A1 - Braddel, Amy A1 - Thomas, Charlene A1 - Meggy, Alun A1 - Marshall, Rachel A1 - Gerrish, Amy A1 - Chapman, Jade A1 - Aguilar, Miquel A1 - Taylor, Sarah A1 - Hill, Matt A1 - Fairén, Mònica Díez A1 - Hodges, Angela A1 - Vellas, Bruno A1 - Soininen, Hilkka A1 - Kloszewska, Iwona A1 - Daniilidou, Makrina A1 - Uphill, James A1 - Patel, Yogen A1 - Hughes, Joseph T A1 - Lord, Jenny A1 - Turton, James A1 - Hartmann, Annette M A1 - Cecchetti, Roberta A1 - Fenoglio, Chiara A1 - Serpente, Maria A1 - Arcaro, Marina A1 - Caltagirone, Carlo A1 - Orfei, Maria Donata A1 - Ciaramella, Antonio A1 - Pichler, Sabrina A1 - Mayhaus, Manuel A1 - Gu, Wei A1 - Lleo, Alberto A1 - Fortea, Juan A1 - Blesa, Rafael A1 - Barber, Imelda S A1 - Brookes, Keeley A1 - Cupidi, Chiara A1 - Maletta, Raffaele Giovanni A1 - Carrell, David A1 - Sorbi, Sandro A1 - Moebus, Susanne A1 - Urbano, Maria A1 - Pilotto, Alberto A1 - Kornhuber, Johannes A1 - Bosco, Paolo A1 - Todd, Stephen A1 - Craig, David A1 - Johnston, Janet A1 - Gill, Michael A1 - Lawlor, Brian A1 - Lynch, Aoibhinn A1 - Fox, Nick C A1 - Hardy, John A1 - Albin, Roger L A1 - Apostolova, Liana G A1 - Arnold, Steven E A1 - Asthana, Sanjay A1 - Atwood, Craig S A1 - Baldwin, Clinton T A1 - Barnes, Lisa L A1 - Barral, Sandra A1 - Beach, Thomas G A1 - Becker, James T A1 - Bigio, Eileen H A1 - Bird, Thomas D A1 - Boeve, Bradley F A1 - Bowen, James D A1 - Boxer, Adam A1 - Burke, James R A1 - Burns, Jeffrey M A1 - Buxbaum, Joseph D A1 - Cairns, Nigel J A1 - Cao, Chuanhai A1 - Carlson, Chris S A1 - Carlsson, Cynthia M A1 - Carney, Regina M A1 - Carrasquillo, Minerva M A1 - Carroll, Steven L A1 - Diaz, Carolina Ceballos A1 - Chui, Helena C A1 - Clark, David G A1 - Cribbs, David H A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Dick, Malcolm A1 - Duara, Ranjan A1 - Evans, Denis A A1 - Faber, Kelley M A1 - Fallon, Kenneth B A1 - Fardo, David W A1 - Farlow, Martin R A1 - Ferris, Steven A1 - Foroud, Tatiana M A1 - Galasko, Douglas R A1 - Gearing, Marla A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Graff-Radford, Neill R A1 - Green, Robert C A1 - Growdon, John H A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Honig, Lawrence S A1 - Huentelman, Matthew J A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Jarvik, Gail P A1 - Abner, Erin A1 - Jin, Lee-Way A1 - Jun, Gyungah A1 - Karydas, Anna A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Kowall, Neil W A1 - Kramer, Joel H A1 - LaFerla, Frank M A1 - Lah, James J A1 - Leverenz, James B A1 - Levey, Allan I A1 - Li, Ge A1 - Lieberman, Andrew P A1 - Lunetta, Kathryn L A1 - Lyketsos, Constantine G A1 - Marson, Daniel C A1 - Martiniuk, Frank A1 - Mash, Deborah C A1 - Masliah, Eliezer A1 - McCormick, Wayne C A1 - McCurry, Susan M A1 - McDavid, Andrew N A1 - McKee, Ann C A1 - Mesulam, Marsel A1 - Miller, Bruce L A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Morris, John C A1 - Murrell, Jill R A1 - Myers, Amanda J A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Pankratz, Vernon S A1 - Parisi, Joseph E A1 - Paulson, Henry L A1 - Perry, William A1 - Peskind, Elaine A1 - Pierce, Aimee A1 - Poon, Wayne W A1 - Potter, Huntington A1 - Quinn, Joseph F A1 - Raj, Ashok A1 - Raskind, Murray A1 - Reisberg, Barry A1 - Reitz, Christiane A1 - Ringman, John M A1 - Roberson, Erik D A1 - Rogaeva, Ekaterina A1 - Rosen, Howard J A1 - Rosenberg, Roger N A1 - Sager, Mark A A1 - Saykin, Andrew J A1 - Schneider, Julie A A1 - Schneider, Lon S A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tanzi, Rudolph E A1 - Thornton-Wells, Tricia A A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Garzia, Fabienne A1 - Golamaully, Feroze A1 - Septier, Gislain A1 - Engelborghs, Sebastien A1 - Vandenberghe, Rik A1 - De Deyn, Peter P A1 - Fernadez, Carmen Muñoz A1 - Benito, Yoland Aladro A1 - Thonberg, Håkan A1 - Forsell, Charlotte A1 - Lilius, Lena A1 - Kinhult-Ståhlbom, Anne A1 - Kilander, Lena A1 - Brundin, RoseMarie A1 - Concari, Letizia A1 - Helisalmi, Seppo A1 - Koivisto, Anne Maria A1 - Haapasalo, Annakaisa A1 - Dermecourt, Vincent A1 - Fiévet, Nathalie A1 - Hanon, Olivier A1 - Dufouil, Carole A1 - Brice, Alexis A1 - Ritchie, Karen A1 - Dubois, Bruno A1 - Himali, Jayanadra J A1 - Keene, C Dirk A1 - Tschanz, JoAnn A1 - Fitzpatrick, Annette L A1 - Kukull, Walter A A1 - Norton, Maria A1 - Aspelund, Thor A1 - Larson, Eric B A1 - Munger, Ron A1 - Rotter, Jerome I A1 - Lipton, Richard B A1 - Bullido, María J A1 - Hofman, Albert A1 - Montine, Thomas J A1 - Coto, Eliecer A1 - Boerwinkle, Eric A1 - Petersen, Ronald C A1 - Alvarez, Victoria A1 - Rivadeneira, Fernando A1 - Reiman, Eric M A1 - Gallo, Maura A1 - O'Donnell, Christopher J A1 - Reisch, Joan S A1 - Bruni, Amalia Cecilia A1 - Royall, Donald R A1 - Dichgans, Martin A1 - Sano, Mary A1 - Galimberti, Daniela A1 - St George-Hyslop, Peter A1 - Scarpini, Elio A1 - Tsuang, Debby W A1 - Mancuso, Michelangelo A1 - Bonuccelli, Ubaldo A1 - Winslow, Ashley R A1 - Daniele, Antonio A1 - Wu, Chuang-Kuo A1 - Peters, Oliver A1 - Nacmias, Benedetta A1 - Riemenschneider, Matthias A1 - Heun, Reinhard A1 - Brayne, Carol A1 - Rubinsztein, David C A1 - Bras, Jose A1 - Guerreiro, Rita A1 - Al-Chalabi, Ammar A1 - Shaw, Christopher E A1 - Collinge, John A1 - Mann, David A1 - Tsolaki, Magda A1 - Clarimon, Jordi A1 - Sussams, Rebecca A1 - Lovestone, Simon A1 - O'Donovan, Michael C A1 - Owen, Michael J A1 - Behrens, Timothy W A1 - Mead, Simon A1 - Goate, Alison M A1 - Uitterlinden, André G A1 - Holmes, Clive A1 - Cruchaga, Carlos A1 - Ingelsson, Martin A1 - Bennett, David A A1 - Powell, John A1 - Golde, Todd E A1 - Graff, Caroline A1 - De Jager, Philip L A1 - Morgan, Kevin A1 - Ertekin-Taner, Nilufer A1 - Combarros, Onofre A1 - Psaty, Bruce M A1 - Passmore, Peter A1 - Younkin, Steven G A1 - Berr, Claudine A1 - Gudnason, Vilmundur A1 - Rujescu, Dan A1 - Dickson, Dennis W A1 - Dartigues, Jean-François A1 - DeStefano, Anita L A1 - Ortega-Cubero, Sara A1 - Hakonarson, Hakon A1 - Campion, Dominique A1 - Boada, Merce A1 - Kauwe, John Keoni A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - Ikram, M Arfan A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Tzourio, Christophe A1 - Launer, Lenore J A1 - Escott-Price, Valentina A1 - Mayeux, Richard A1 - Deleuze, Jean-Francois A1 - Amin, Najaf A1 - Holmans, Peter A A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - van Duijn, Cornelia M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Lambert, Jean-Charles A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Schellenberg, Gerard D KW - Adaptor Proteins, Signal Transducing KW - Alzheimer Disease KW - Amino Acid Sequence KW - Case-Control Studies KW - Exome KW - Gene Expression Profiling KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Immunity, Innate KW - Linkage Disequilibrium KW - Membrane Glycoproteins KW - Microglia KW - Odds Ratio KW - Phospholipase C gamma KW - Polymorphism, Single Nucleotide KW - Protein Interaction Maps KW - Receptors, Immunologic KW - Sequence Homology, Amino Acid AB -

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

VL - 49 IS - 9 ER - TY - JOUR T1 - Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease. JF - Alzheimers Dement (Amst) Y1 - 2018 A1 - Peloso, Gina M A1 - van der Lee, Sven J A1 - DeStefano, Anita L A1 - Seshardi, Sudha AB -

Introduction: There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein () locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.

Methods: Ten single nucleotide polymorphisms within the locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.

Results: Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the locus, we found that HDL-C was not associated with risk of AD ( > .7).

Discussion: Our study does not support the role of HDL-C on risk of AD through HDL-C altered by . This study does not rule out other mechanisms by which HDL-C affects risk of AD.

VL - 10 ER - TY - JOUR T1 - Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. JF - Nat Commun Y1 - 2018 A1 - Vojinovic, Dina A1 - Adams, Hieab H A1 - Jian, Xueqiu A1 - Yang, Qiong A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Teumer, Alexander A1 - Scholz, Markus A1 - Armstrong, Nicola J A1 - Hofer, Edith A1 - Saba, Yasaman A1 - Luciano, Michelle A1 - Bernard, Manon A1 - Trompet, Stella A1 - Yang, Jingyun A1 - Gillespie, Nathan A A1 - van der Lee, Sven J A1 - Neumann, Alexander A1 - Ahmad, Shahzad A1 - Andreassen, Ole A A1 - Ames, David A1 - Amin, Najaf A1 - Arfanakis, Konstantinos A1 - Bastin, Mark E A1 - Becker, Diane M A1 - Beiser, Alexa S A1 - Beyer, Frauke A1 - Brodaty, Henry A1 - Bryan, R Nick A1 - Bülow, Robin A1 - Dale, Anders M A1 - De Jager, Philip L A1 - Deary, Ian J A1 - DeCarli, Charles A1 - Fleischman, Debra A A1 - Gottesman, Rebecca F A1 - van der Grond, Jeroen A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Homuth, Georg A1 - Knopman, David S A1 - Kwok, John B A1 - Lewis, Cora E A1 - Li, Shuo A1 - Loeffler, Markus A1 - Lopez, Oscar L A1 - Maillard, Pauline A1 - El Marroun, Hanan A1 - Mather, Karen A A1 - Mosley, Thomas H A1 - Muetzel, Ryan L A1 - Nauck, Matthias A1 - Nyquist, Paul A A1 - Panizzon, Matthew S A1 - Pausova, Zdenka A1 - Psaty, Bruce M A1 - Rice, Ken A1 - Rotter, Jerome I A1 - Royle, Natalie A1 - Satizabal, Claudia L A1 - Schmidt, Reinhold A1 - Schofield, Peter R A1 - Schreiner, Pamela J A1 - Sidney, Stephen A1 - Stott, David J A1 - Thalamuthu, Anbupalam A1 - Uitterlinden, André G A1 - Valdés Hernández, Maria C A1 - Vernooij, Meike W A1 - Wen, Wei A1 - White, Tonya A1 - Witte, A Veronica A1 - Wittfeld, Katharina A1 - Wright, Margaret J A1 - Yanek, Lisa R A1 - Tiemeier, Henning A1 - Kremen, William S A1 - Bennett, David A A1 - Jukema, J Wouter A1 - Paus, Tomáš A1 - Wardlaw, Joanna M A1 - Schmidt, Helena A1 - Sachdev, Perminder S A1 - Villringer, Arno A1 - Grabe, Hans Jörgen A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J A1 - Seshadri, Sudha A1 - Ikram, M Arfan A1 - Fornage, Myriam AB -

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

VL - 9 IS - 1 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

VL - 50 IS - 4 ER - TY - JOUR T1 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nat Commun Y1 - 2018 A1 - Davies, Gail A1 - Lam, Max A1 - Harris, Sarah E A1 - Trampush, Joey W A1 - Luciano, Michelle A1 - Hill, W David A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Marioni, Riccardo E A1 - Fawns-Ritchie, Chloe A1 - Liewald, David C M A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Bis, Joshua C A1 - Burdick, Katherine E A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Hayward, Caroline A1 - Hofer, Edith A1 - Ikram, M Arfan A1 - Karlsson, Robert A1 - Knowles, Emma A1 - Lahti, Jari A1 - Leber, Markus A1 - Li, Shuo A1 - Mather, Karen A A1 - Melle, Ingrid A1 - Morris, Derek A1 - Oldmeadow, Christopher A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Petrovic, Katja A1 - Reynolds, Chandra A A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Windham, B Gwen A1 - Wright, Margaret J A1 - Yang, Jingyun A1 - Yu, Jin A1 - Ames, David A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Armstrong, Nicola J A1 - Assareh, Amelia A A1 - Attia, John R A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - Bennett, David A A1 - Böhmer, Anne C A1 - Boyle, Patricia A A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Cannon, Tyrone D A1 - Cirulli, Elizabeth T A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Dick, Danielle A1 - Dickinson, Dwight A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Ford, Ian A1 - Freimer, Nelson A A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Griswold, Michael E A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Heiss, Gerardo A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - Karlsson, Ida A1 - Kleineidam, Luca A1 - Knopman, David S A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Le Hellard, Stephanie A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Lundervold, Astri J A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Murray, Alison D A1 - Need, Anna C A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - Ollier, William A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poldrack, Russell A A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Riedel-Heller, Steffi G A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Sabb, Fred W A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Scott, Rodney J A1 - Scult, Matthew A A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Stefanis, Nikos C A1 - Stott, David J A1 - Straub, Richard E A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, Andre A1 - Vitart, Veronique A1 - Voineskos, Aristotle N A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Widen, Elisabeth A1 - Yang, Qiong A1 - Zhao, Wei A1 - Adams, Hieab H H A1 - Arking, Dan E A1 - Bilder, Robert M A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - De Jager, Philip L A1 - Debette, Stephanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - Glahn, David C A1 - Hägg, Sara A1 - Hansell, Narelle K A1 - Hariri, Ahmad R A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Keller, Matthew C A1 - Kremen, William S A1 - Launer, Lenore A1 - Lindenberger, Ulman A1 - Palotie, Aarno A1 - Pedersen, Nancy L A1 - Pendleton, Neil A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Raitakari, Olli T A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Schofield, Peter W A1 - Schofield, Peter R A1 - Starr, John M A1 - Steen, Vidar M A1 - Trollor, Julian N A1 - Turner, Steven T A1 - van Duijn, Cornelia M A1 - Villringer, Arno A1 - Weinberger, Daniel R A1 - Weir, David R A1 - Wilson, James F A1 - Malhotra, Anil A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Bressler, Jan A1 - Lencz, Todd A1 - Deary, Ian J AB -

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

VL - 9 IS - 1 ER - TY - JOUR T1 - Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation. JF - Mol Psychiatry Y1 - 2018 A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Kunkle, Brian W A1 - Chen, Yuning A1 - Hamilton-Nelson, Kara L A1 - Bush, William S A1 - Salerno, William J A1 - Lancour, Daniel A1 - Ma, Yiyi A1 - Renton, Alan E A1 - Marcora, Edoardo A1 - Farrell, John J A1 - Zhao, Yi A1 - Qu, Liming A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Amouyel, Philippe A1 - Beecham, Gary W A1 - Below, Jennifer E A1 - Campion, Dominique A1 - Charbonnier, Camille A1 - Chung, Jaeyoon A1 - Crane, Paul K A1 - Cruchaga, Carlos A1 - Cupples, L Adrienne A1 - Dartigues, Jean-François A1 - Debette, Stephanie A1 - Deleuze, Jean-Francois A1 - Fulton, Lucinda A1 - Gabriel, Stacey B A1 - Genin, Emmanuelle A1 - Gibbs, Richard A A1 - Goate, Alison A1 - Grenier-Boley, Benjamin A1 - Gupta, Namrata A1 - Haines, Jonathan L A1 - Havulinna, Aki S A1 - Helisalmi, Seppo A1 - Hiltunen, Mikko A1 - Howrigan, Daniel P A1 - Ikram, M Arfan A1 - Kaprio, Jaakko A1 - Konrad, Jan A1 - Kuzma, Amanda A1 - Lander, Eric S A1 - Lathrop, Mark A1 - Lehtimäki, Terho A1 - Lin, Honghuang A1 - Mattila, Kari A1 - Mayeux, Richard A1 - Muzny, Donna M A1 - Nasser, Waleed A1 - Neale, Benjamin A1 - Nho, Kwangsik A1 - Nicolas, Gaël A1 - Patel, Devanshi A1 - Pericak-Vance, Margaret A A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Quenez, Olivier A1 - Rajabli, Farid A1 - Redon, Richard A1 - Reitz, Christiane A1 - Remes, Anne M A1 - Salomaa, Veikko A1 - Sarnowski, Chloe A1 - Schmidt, Helena A1 - Schmidt, Michael A1 - Schmidt, Reinhold A1 - Soininen, Hilkka A1 - Thornton, Timothy A A1 - Tosto, Giuseppe A1 - Tzourio, Christophe A1 - van der Lee, Sven J A1 - van Duijn, Cornelia M A1 - Vardarajan, Badri A1 - Wang, Weixin A1 - Wijsman, Ellen A1 - Wilson, Richard K A1 - Witten, Daniela A1 - Worley, Kim C A1 - Zhang, Xiaoling A1 - Bellenguez, Céline A1 - Lambert, Jean-Charles A1 - Kurki, Mitja I A1 - Palotie, Aarno A1 - Daly, Mark A1 - Boerwinkle, Eric A1 - Lunetta, Kathryn L A1 - DeStefano, Anita L A1 - Dupuis, Josée A1 - Martin, Eden R A1 - Schellenberg, Gerard D A1 - Seshadri, Sudha A1 - Naj, Adam C A1 - Fornage, Myriam A1 - Farrer, Lindsay A AB -

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

ER - TY - JOUR T1 - Genetic architecture of subcortical brain structures in 38,851 individuals. JF - Nat Genet Y1 - 2019 A1 - Satizabal, Claudia L A1 - Adams, Hieab H H A1 - Hibar, Derrek P A1 - White, Charles C A1 - Knol, Maria J A1 - Stein, Jason L A1 - Scholz, Markus A1 - Sargurupremraj, Muralidharan A1 - Jahanshad, Neda A1 - Roshchupkin, Gennady V A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Luciano, Michelle A1 - Hofer, Edith A1 - Teumer, Alexander A1 - van der Lee, Sven J A1 - Yang, Jingyun A1 - Yanek, Lisa R A1 - Lee, Tom V A1 - Li, Shuo A1 - Hu, Yanhui A1 - Koh, Jia Yu A1 - Eicher, John D A1 - Desrivières, Sylvane A1 - Arias-Vasquez, Alejandro A1 - Chauhan, Ganesh A1 - Athanasiu, Lavinia A1 - Rentería, Miguel E A1 - Kim, Sungeun A1 - Hoehn, David A1 - Armstrong, Nicola J A1 - Chen, Qiang A1 - Holmes, Avram J A1 - den Braber, Anouk A1 - Kloszewska, Iwona A1 - Andersson, Micael A1 - Espeseth, Thomas A1 - Grimm, Oliver A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Milaneschi, Yuri A1 - Papmeyer, Martina A1 - Axelsson, Tomas A1 - Ehrlich, Stefan A1 - Roiz-Santiañez, Roberto A1 - Kraemer, Bernd A1 - Håberg, Asta K A1 - Jones, Hannah J A1 - Pike, G Bruce A1 - Stein, Dan J A1 - Stevens, Allison A1 - Bralten, Janita A1 - Vernooij, Meike W A1 - Harris, Tamara B A1 - Filippi, Irina A1 - Witte, A Veronica A1 - Guadalupe, Tulio A1 - Wittfeld, Katharina A1 - Mosley, Thomas H A1 - Becker, James T A1 - Doan, Nhat Trung A1 - Hagenaars, Saskia P A1 - Saba, Yasaman A1 - Cuellar-Partida, Gabriel A1 - Amin, Najaf A1 - Hilal, Saima A1 - Nho, Kwangsik A1 - Mirza-Schreiber, Nazanin A1 - Arfanakis, Konstantinos A1 - Becker, Diane M A1 - Ames, David A1 - Goldman, Aaron L A1 - Lee, Phil H A1 - Boomsma, Dorret I A1 - Lovestone, Simon A1 - Giddaluru, Sudheer A1 - Le Hellard, Stephanie A1 - Mattheisen, Manuel A1 - Bohlken, Marc M A1 - Kasperaviciute, Dalia A1 - Schmaal, Lianne A1 - Lawrie, Stephen M A1 - Agartz, Ingrid A1 - Walton, Esther A1 - Tordesillas-Gutierrez, Diana A1 - Davies, Gareth E A1 - Shin, Jean A1 - Ipser, Jonathan C A1 - Vinke, Louis N A1 - Hoogman, Martine A1 - Jia, Tianye A1 - Burkhardt, Ralph A1 - Klein, Marieke A1 - Crivello, Fabrice A1 - Janowitz, Deborah A1 - Carmichael, Owen A1 - Haukvik, Unn K A1 - Aribisala, Benjamin S A1 - Schmidt, Helena A1 - Strike, Lachlan T A1 - Cheng, Ching-Yu A1 - Risacher, Shannon L A1 - Pütz, Benno A1 - Fleischman, Debra A A1 - Assareh, Amelia A A1 - Mattay, Venkata S A1 - Buckner, Randy L A1 - Mecocci, Patrizia A1 - Dale, Anders M A1 - Cichon, Sven A1 - Boks, Marco P A1 - Matarin, Mar A1 - Penninx, Brenda W J H A1 - Calhoun, Vince D A1 - Chakravarty, M Mallar A1 - Marquand, Andre F A1 - Macare, Christine A1 - Kharabian Masouleh, Shahrzad A1 - Oosterlaan, Jaap A1 - Amouyel, Philippe A1 - Hegenscheid, Katrin A1 - Rotter, Jerome I A1 - Schork, Andrew J A1 - Liewald, David C M A1 - de Zubicaray, Greig I A1 - Wong, Tien Yin A1 - Shen, Li A1 - Sämann, Philipp G A1 - Brodaty, Henry A1 - Roffman, Joshua L A1 - de Geus, Eco J C A1 - Tsolaki, Magda A1 - Erk, Susanne A1 - van Eijk, Kristel R A1 - Cavalleri, Gianpiero L A1 - van der Wee, Nic J A A1 - McIntosh, Andrew M A1 - Gollub, Randy L A1 - Bulayeva, Kazima B A1 - Bernard, Manon A1 - Richards, Jennifer S A1 - Himali, Jayandra J A1 - Loeffler, Markus A1 - Rommelse, Nanda A1 - Hoffmann, Wolfgang A1 - Westlye, Lars T A1 - Valdés Hernández, Maria C A1 - Hansell, Narelle K A1 - van Erp, Theo G M A1 - Wolf, Christiane A1 - Kwok, John B J A1 - Vellas, Bruno A1 - Heinz, Andreas A1 - Olde Loohuis, Loes M A1 - Delanty, Norman A1 - Ho, Beng-Choon A1 - Ching, Christopher R K A1 - Shumskaya, Elena A1 - Singh, Baljeet A1 - Hofman, Albert A1 - van der Meer, Dennis A1 - Homuth, Georg A1 - Psaty, Bruce M A1 - Bastin, Mark E A1 - Montgomery, Grant W A1 - Foroud, Tatiana M A1 - Reppermund, Simone A1 - Hottenga, Jouke-Jan A1 - Simmons, Andrew A1 - Meyer-Lindenberg, Andreas A1 - Cahn, Wiepke A1 - Whelan, Christopher D A1 - van Donkelaar, Marjolein M J A1 - Yang, Qiong A1 - Hosten, Norbert A1 - Green, Robert C A1 - Thalamuthu, Anbupalam A1 - Mohnke, Sebastian A1 - Hulshoff Pol, Hilleke E A1 - Lin, Honghuang A1 - Jack, Clifford R A1 - Schofield, Peter R A1 - Mühleisen, Thomas W A1 - Maillard, Pauline A1 - Potkin, Steven G A1 - Wen, Wei A1 - Fletcher, Evan A1 - Toga, Arthur W A1 - Gruber, Oliver A1 - Huentelman, Matthew A1 - Davey Smith, George A1 - Launer, Lenore J A1 - Nyberg, Lars A1 - Jönsson, Erik G A1 - Crespo-Facorro, Benedicto A1 - Koen, Nastassja A1 - Greve, Douglas N A1 - Uitterlinden, André G A1 - Weinberger, Daniel R A1 - Steen, Vidar M A1 - Fedko, Iryna O A1 - Groenewold, Nynke A A1 - Niessen, Wiro J A1 - Toro, Roberto A1 - Tzourio, Christophe A1 - Longstreth, William T A1 - Ikram, M Kamran A1 - Smoller, Jordan W A1 - van Tol, Marie-Jose A1 - Sussmann, Jessika E A1 - Paus, Tomáš A1 - Lemaître, Hervé A1 - Schroeter, Matthias L A1 - Mazoyer, Bernard A1 - Andreassen, Ole A A1 - Holsboer, Florian A1 - Depondt, Chantal A1 - Veltman, Dick J A1 - Turner, Jessica A A1 - Pausova, Zdenka A1 - Schumann, Gunter A1 - van Rooij, Daan A1 - Djurovic, Srdjan A1 - Deary, Ian J A1 - McMahon, Katie L A1 - Müller-Myhsok, Bertram A1 - Brouwer, Rachel M A1 - Soininen, Hilkka A1 - Pandolfo, Massimo A1 - Wassink, Thomas H A1 - Cheung, Joshua W A1 - Wolfers, Thomas A1 - Martinot, Jean-Luc A1 - Zwiers, Marcel P A1 - Nauck, Matthias A1 - Melle, Ingrid A1 - Martin, Nicholas G A1 - Kanai, Ryota A1 - Westman, Eric A1 - Kahn, René S A1 - Sisodiya, Sanjay M A1 - White, Tonya A1 - Saremi, Arvin A1 - van Bokhoven, Hans A1 - Brunner, Han G A1 - Völzke, Henry A1 - Wright, Margaret J A1 - van 't Ent, Dennis A1 - Nöthen, Markus M A1 - Ophoff, Roel A A1 - Buitelaar, Jan K A1 - Fernández, Guillén A1 - Sachdev, Perminder S A1 - Rietschel, Marcella A1 - van Haren, Neeltje E M A1 - Fisher, Simon E A1 - Beiser, Alexa S A1 - Francks, Clyde A1 - Saykin, Andrew J A1 - Mather, Karen A A1 - Romanczuk-Seiferth, Nina A1 - Hartman, Catharina A A1 - DeStefano, Anita L A1 - Heslenfeld, Dirk J A1 - Weiner, Michael W A1 - Walter, Henrik A1 - Hoekstra, Pieter J A1 - Nyquist, Paul A A1 - Franke, Barbara A1 - Bennett, David A A1 - Grabe, Hans J A1 - Johnson, Andrew D A1 - Chen, Christopher A1 - van Duijn, Cornelia M A1 - Lopez, Oscar L A1 - Fornage, Myriam A1 - Wardlaw, Joanna M A1 - Schmidt, Reinhold A1 - DeCarli, Charles A1 - De Jager, Philip L A1 - Villringer, Arno A1 - Debette, Stephanie A1 - Gudnason, Vilmundur A1 - Medland, Sarah E A1 - Shulman, Joshua M A1 - Thompson, Paul M A1 - Seshadri, Sudha A1 - Ikram, M Arfan AB -

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

VL - 51 IS - 11 ER - TY - JOUR T1 - Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. JF - Nat Genet Y1 - 2019 A1 - Kunkle, Brian W A1 - Grenier-Boley, Benjamin A1 - Sims, Rebecca A1 - Bis, Joshua C A1 - Damotte, Vincent A1 - Naj, Adam C A1 - Boland, Anne A1 - Vronskaya, Maria A1 - van der Lee, Sven J A1 - Amlie-Wolf, Alexandre A1 - Bellenguez, Céline A1 - Frizatti, Aura A1 - Chouraki, Vincent A1 - Martin, Eden R A1 - Sleegers, Kristel A1 - Badarinarayan, Nandini A1 - Jakobsdottir, Johanna A1 - Hamilton-Nelson, Kara L A1 - Moreno-Grau, Sonia A1 - Olaso, Robert A1 - Raybould, Rachel A1 - Chen, Yuning A1 - Kuzma, Amanda B A1 - Hiltunen, Mikko A1 - Morgan, Taniesha A1 - Ahmad, Shahzad A1 - Vardarajan, Badri N A1 - Epelbaum, Jacques A1 - Hoffmann, Per A1 - Boada, Merce A1 - Beecham, Gary W A1 - Garnier, Jean-Guillaume A1 - Harold, Denise A1 - Fitzpatrick, Annette L A1 - Valladares, Otto A1 - Moutet, Marie-Laure A1 - Gerrish, Amy A1 - Smith, Albert V A1 - Qu, Liming A1 - Bacq, Delphine A1 - Denning, Nicola A1 - Jian, Xueqiu A1 - Zhao, Yi A1 - Del Zompo, Maria A1 - Fox, Nick C A1 - Choi, Seung-Hoan A1 - Mateo, Ignacio A1 - Hughes, Joseph T A1 - Adams, Hieab H A1 - Malamon, John A1 - Sanchez-Garcia, Florentino A1 - Patel, Yogen A1 - Brody, Jennifer A A1 - Dombroski, Beth A A1 - Naranjo, Maria Candida Deniz A1 - Daniilidou, Makrina A1 - Eiriksdottir, Gudny A1 - Mukherjee, Shubhabrata A1 - Wallon, David A1 - Uphill, James A1 - Aspelund, Thor A1 - Cantwell, Laura B A1 - Garzia, Fabienne A1 - Galimberti, Daniela A1 - Hofer, Edith A1 - Butkiewicz, Mariusz A1 - Fin, Bertrand A1 - Scarpini, Elio A1 - Sarnowski, Chloe A1 - Bush, Will S A1 - Meslage, Stéphane A1 - Kornhuber, Johannes A1 - White, Charles C A1 - Song, Yuenjoo A1 - Barber, Robert C A1 - Engelborghs, Sebastiaan A1 - Sordon, Sabrina A1 - Voijnovic, Dina A1 - Adams, Perrie M A1 - Vandenberghe, Rik A1 - Mayhaus, Manuel A1 - Cupples, L Adrienne A1 - Albert, Marilyn S A1 - De Deyn, Peter P A1 - Gu, Wei A1 - Himali, Jayanadra J A1 - Beekly, Duane A1 - Squassina, Alessio A1 - Hartmann, Annette M A1 - Orellana, Adelina A1 - Blacker, Deborah A1 - Rodriguez-Rodriguez, Eloy A1 - Lovestone, Simon A1 - Garcia, Melissa E A1 - Doody, Rachelle S A1 - Munoz-Fernadez, Carmen A1 - Sussams, Rebecca A1 - Lin, Honghuang A1 - Fairchild, Thomas J A1 - Benito, Yolanda A A1 - Holmes, Clive A1 - Karamujić-Čomić, Hata A1 - Frosch, Matthew P A1 - Thonberg, Håkan A1 - Maier, Wolfgang A1 - Roschupkin, Gena A1 - Ghetti, Bernardino A1 - Giedraitis, Vilmantas A1 - Kawalia, Amit A1 - Li, Shuo A1 - Huebinger, Ryan M A1 - Kilander, Lena A1 - Moebus, Susanne A1 - Hernandez, Isabel A1 - Kamboh, M Ilyas A1 - Brundin, RoseMarie A1 - Turton, James A1 - Yang, Qiong A1 - Katz, Mindy J A1 - Concari, Letizia A1 - Lord, Jenny A1 - Beiser, Alexa S A1 - Keene, C Dirk A1 - Helisalmi, Seppo A1 - Kloszewska, Iwona A1 - Kukull, Walter A A1 - Koivisto, Anne Maria A1 - Lynch, Aoibhinn A1 - Tarraga, Lluis A1 - Larson, Eric B A1 - Haapasalo, Annakaisa A1 - Lawlor, Brian A1 - Mosley, Thomas H A1 - Lipton, Richard B A1 - Solfrizzi, Vincenzo A1 - Gill, Michael A1 - Longstreth, W T A1 - Montine, Thomas J A1 - Frisardi, Vincenza A1 - Diez-Fairen, Monica A1 - Rivadeneira, Fernando A1 - Petersen, Ronald C A1 - Deramecourt, Vincent A1 - Alvarez, Ignacio A1 - Salani, Francesca A1 - Ciaramella, Antonio A1 - Boerwinkle, Eric A1 - Reiman, Eric M A1 - Fiévet, Nathalie A1 - Rotter, Jerome I A1 - Reisch, Joan S A1 - Hanon, Olivier A1 - Cupidi, Chiara A1 - Andre Uitterlinden, A G A1 - Royall, Donald R A1 - Dufouil, Carole A1 - Maletta, Raffaele Giovanni A1 - de Rojas, Itziar A1 - Sano, Mary A1 - Brice, Alexis A1 - Cecchetti, Roberta A1 - George-Hyslop, Peter St A1 - Ritchie, Karen A1 - Tsolaki, Magda A1 - Tsuang, Debby W A1 - Dubois, Bruno A1 - Craig, David A1 - Wu, Chuang-Kuo A1 - Soininen, Hilkka A1 - Avramidou, Despoina A1 - Albin, Roger L A1 - Fratiglioni, Laura A1 - Germanou, Antonia A1 - Apostolova, Liana G A1 - Keller, Lina A1 - Koutroumani, Maria A1 - Arnold, Steven E A1 - Panza, Francesco A1 - Gkatzima, Olymbia A1 - Asthana, Sanjay A1 - Hannequin, Didier A1 - Whitehead, Patrice A1 - Atwood, Craig S A1 - Caffarra, Paolo A1 - Hampel, Harald A1 - Quintela, Inés A1 - Carracedo, Angel A1 - Lannfelt, Lars A1 - Rubinsztein, David C A1 - Barnes, Lisa L A1 - Pasquier, Florence A1 - Frölich, Lutz A1 - Barral, Sandra A1 - McGuinness, Bernadette A1 - Beach, Thomas G A1 - Johnston, Janet A A1 - Becker, James T A1 - Passmore, Peter A1 - Bigio, Eileen H A1 - Schott, Jonathan M A1 - Bird, Thomas D A1 - Warren, Jason D A1 - Boeve, Bradley F A1 - Lupton, Michelle K A1 - Bowen, James D A1 - Proitsi, Petra A1 - Boxer, Adam A1 - Powell, John F A1 - Burke, James R A1 - Kauwe, John S K A1 - Burns, Jeffrey M A1 - Mancuso, Michelangelo A1 - Buxbaum, Joseph D A1 - Bonuccelli, Ubaldo A1 - Cairns, Nigel J A1 - McQuillin, Andrew A1 - Cao, Chuanhai A1 - Livingston, Gill A1 - Carlson, Chris S A1 - Bass, Nicholas J A1 - Carlsson, Cynthia M A1 - Hardy, John A1 - Carney, Regina M A1 - Bras, Jose A1 - Carrasquillo, Minerva M A1 - Guerreiro, Rita A1 - Allen, Mariet A1 - Chui, Helena C A1 - Fisher, Elizabeth A1 - Masullo, Carlo A1 - Crocco, Elizabeth A A1 - DeCarli, Charles A1 - Bisceglio, Gina A1 - Dick, Malcolm A1 - Ma, Li A1 - Duara, Ranjan A1 - Graff-Radford, Neill R A1 - Evans, Denis A A1 - Hodges, Angela A1 - Faber, Kelley M A1 - Scherer, Martin A1 - Fallon, Kenneth B A1 - Riemenschneider, Matthias A1 - Fardo, David W A1 - Heun, Reinhard A1 - Farlow, Martin R A1 - Kölsch, Heike A1 - Ferris, Steven A1 - Leber, Markus A1 - Foroud, Tatiana M A1 - Heuser, Isabella A1 - Galasko, Douglas R A1 - Giegling, Ina A1 - Gearing, Marla A1 - Hüll, Michael A1 - Geschwind, Daniel H A1 - Gilbert, John R A1 - Morris, John A1 - Green, Robert C A1 - Mayo, Kevin A1 - Growdon, John H A1 - Feulner, Thomas A1 - Hamilton, Ronald L A1 - Harrell, Lindy E A1 - Drichel, Dmitriy A1 - Honig, Lawrence S A1 - Cushion, Thomas D A1 - Huentelman, Matthew J A1 - Hollingworth, Paul A1 - Hulette, Christine M A1 - Hyman, Bradley T A1 - Marshall, Rachel A1 - Jarvik, Gail P A1 - Meggy, Alun A1 - Abner, Erin A1 - Menzies, Georgina E A1 - Jin, Lee-Way A1 - Leonenko, Ganna A1 - Real, Luis M A1 - Jun, Gyungah R A1 - Baldwin, Clinton T A1 - Grozeva, Detelina A1 - Karydas, Anna A1 - Russo, Giancarlo A1 - Kaye, Jeffrey A A1 - Kim, Ronald A1 - Jessen, Frank A1 - Kowall, Neil W A1 - Vellas, Bruno A1 - Kramer, Joel H A1 - Vardy, Emma A1 - LaFerla, Frank M A1 - Jöckel, Karl-Heinz A1 - Lah, James J A1 - Dichgans, Martin A1 - Leverenz, James B A1 - Mann, David A1 - Levey, Allan I A1 - Pickering-Brown, Stuart A1 - Lieberman, Andrew P A1 - Klopp, Norman A1 - Lunetta, Kathryn L A1 - Wichmann, H-Erich A1 - Lyketsos, Constantine G A1 - Morgan, Kevin A1 - Marson, Daniel C A1 - Brown, Kristelle A1 - Martiniuk, Frank A1 - Medway, Christopher A1 - Mash, Deborah C A1 - Nöthen, Markus M A1 - Masliah, Eliezer A1 - Hooper, Nigel M A1 - McCormick, Wayne C A1 - Daniele, Antonio A1 - McCurry, Susan M A1 - Bayer, Anthony A1 - McDavid, Andrew N A1 - Gallacher, John A1 - McKee, Ann C A1 - van den Bussche, Hendrik A1 - Mesulam, Marsel A1 - Brayne, Carol A1 - Miller, Bruce L A1 - Riedel-Heller, Steffi A1 - Miller, Carol A A1 - Miller, Joshua W A1 - Al-Chalabi, Ammar A1 - Morris, John C A1 - Shaw, Christopher E A1 - Myers, Amanda J A1 - Wiltfang, Jens A1 - O'Bryant, Sid A1 - Olichney, John M A1 - Alvarez, Victoria A1 - Parisi, Joseph E A1 - Singleton, Andrew B A1 - Paulson, Henry L A1 - Collinge, John A1 - Perry, William R A1 - Mead, Simon A1 - Peskind, Elaine A1 - Cribbs, David H A1 - Rossor, Martin A1 - Pierce, Aimee A1 - Ryan, Natalie S A1 - Poon, Wayne W A1 - Nacmias, Benedetta A1 - Potter, Huntington A1 - Sorbi, Sandro A1 - Quinn, Joseph F A1 - Sacchinelli, Eleonora A1 - Raj, Ashok A1 - Spalletta, Gianfranco A1 - Raskind, Murray A1 - Caltagirone, Carlo A1 - Bossù, Paola A1 - Orfei, Maria Donata A1 - Reisberg, Barry A1 - Clarke, Robert A1 - Reitz, Christiane A1 - Smith, A David A1 - Ringman, John M A1 - Warden, Donald A1 - Roberson, Erik D A1 - Wilcock, Gordon A1 - Rogaeva, Ekaterina A1 - Bruni, Amalia Cecilia A1 - Rosen, Howard J A1 - Gallo, Maura A1 - Rosenberg, Roger N A1 - Ben-Shlomo, Yoav A1 - Sager, Mark A A1 - Mecocci, Patrizia A1 - Saykin, Andrew J A1 - Pastor, Pau A1 - Cuccaro, Michael L A1 - Vance, Jeffery M A1 - Schneider, Julie A A1 - Schneider, Lori S A1 - Slifer, Susan A1 - Seeley, William W A1 - Smith, Amanda G A1 - Sonnen, Joshua A A1 - Spina, Salvatore A1 - Stern, Robert A A1 - Swerdlow, Russell H A1 - Tang, Mitchell A1 - Tanzi, Rudolph E A1 - Trojanowski, John Q A1 - Troncoso, Juan C A1 - Van Deerlin, Vivianna M A1 - Van Eldik, Linda J A1 - Vinters, Harry V A1 - Vonsattel, Jean Paul A1 - Weintraub, Sandra A1 - Welsh-Bohmer, Kathleen A A1 - Wilhelmsen, Kirk C A1 - Williamson, Jennifer A1 - Wingo, Thomas S A1 - Woltjer, Randall L A1 - Wright, Clinton B A1 - Yu, Chang-En A1 - Yu, Lei A1 - Saba, Yasaman A1 - Pilotto, Alberto A1 - Bullido, María J A1 - Peters, Oliver A1 - Crane, Paul K A1 - Bennett, David A1 - Bosco, Paola A1 - Coto, Eliecer A1 - Boccardi, Virginia A1 - De Jager, Phil L A1 - Lleo, Alberto A1 - Warner, Nick A1 - Lopez, Oscar L A1 - Ingelsson, Martin A1 - Deloukas, Panagiotis A1 - Cruchaga, Carlos A1 - Graff, Caroline A1 - Gwilliam, Rhian A1 - Fornage, Myriam A1 - Goate, Alison M A1 - Sánchez-Juan, Pascual A1 - Kehoe, Patrick G A1 - Amin, Najaf A1 - Ertekin-Taner, Nilifur A1 - Berr, Claudine A1 - Debette, Stephanie A1 - Love, Seth A1 - Launer, Lenore J A1 - Younkin, Steven G A1 - Dartigues, Jean-François A1 - Corcoran, Chris A1 - Ikram, M Arfan A1 - Dickson, Dennis W A1 - Nicolas, Gaël A1 - Campion, Dominique A1 - Tschanz, JoAnn A1 - Schmidt, Helena A1 - Hakonarson, Hakon A1 - Clarimon, Jordi A1 - Munger, Ron A1 - Schmidt, Reinhold A1 - Farrer, Lindsay A A1 - Van Broeckhoven, Christine A1 - C O'Donovan, Michael A1 - DeStefano, Anita L A1 - Jones, Lesley A1 - Haines, Jonathan L A1 - Deleuze, Jean-Francois A1 - Owen, Michael J A1 - Gudnason, Vilmundur A1 - Mayeux, Richard A1 - Escott-Price, Valentina A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Wang, Li-San A1 - Ruiz, Agustin A1 - van Duijn, Cornelia M A1 - Holmans, Peter A A1 - Seshadri, Sudha A1 - Williams, Julie A1 - Amouyel, Phillippe A1 - Schellenberg, Gerard D A1 - Lambert, Jean-Charles A1 - Pericak-Vance, Margaret A AB -

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

VL - 51 IS - 3 ER - TY - JOUR T1 - Association of low-frequency and rare coding variants with information processing speed. JF - Transl Psychiatry Y1 - 2021 A1 - Bressler, Jan A1 - Davies, Gail A1 - Smith, Albert V A1 - Saba, Yasaman A1 - Bis, Joshua C A1 - Jian, Xueqiu A1 - Hayward, Caroline A1 - Yanek, Lisa A1 - Smith, Jennifer A A1 - Mirza, Saira S A1 - Wang, Ruiqi A1 - Adams, Hieab H H A1 - Becker, Diane A1 - Boerwinkle, Eric A1 - Campbell, Archie A1 - Cox, Simon R A1 - Eiriksdottir, Gudny A1 - Fawns-Ritchie, Chloe A1 - Gottesman, Rebecca F A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hofer, Edith A1 - Kardia, Sharon L R A1 - Knol, Maria J A1 - Koini, Marisa A1 - Lopez, Oscar L A1 - Marioni, Riccardo E A1 - Nyquist, Paul A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rudan, Igor A1 - Satizabal, Claudia L A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Sidney, Stephen A1 - Simino, Jeannette A1 - Smith, Blair H A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Ware, Erin B A1 - Whitmer, Rachel A A1 - Yaffe, Kristine A1 - Yang, Qiong A1 - Zhao, Wei A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Fitzpatrick, Annette L A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Arfan Ikram, M A1 - van Duijn, Cornelia M A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Deary, Ian J KW - Adult KW - Aging KW - Cognition KW - Genome-Wide Association Study KW - Geroscience KW - Humans KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

VL - 11 IS - 1 ER - TY - JOUR T1 - Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. JF - Mol Psychiatry Y1 - 2022 A1 - Lahti, Jari A1 - Tuominen, Samuli A1 - Yang, Qiong A1 - Pergola, Giulio A1 - Ahmad, Shahzad A1 - Amin, Najaf A1 - Armstrong, Nicola J A1 - Beiser, Alexa A1 - Bey, Katharina A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Bressler, Jan A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chen, Qiang A1 - Corley, Janie A1 - Cox, Simon R A1 - Davies, Gail A1 - De Jager, Philip L A1 - Derks, Eske M A1 - Faul, Jessica D A1 - Fitzpatrick, Annette L A1 - Fohner, Alison E A1 - Ford, Ian A1 - Fornage, Myriam A1 - Gerring, Zachary A1 - Grabe, Hans J A1 - Grodstein, Francine A1 - Gudnason, Vilmundur A1 - Simonsick, Eleanor A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kajantie, Eero A1 - Kaprio, Jaakko A1 - Karell, Pauliina A1 - Kleineidam, Luca A1 - Knol, Maria J A1 - Kochan, Nicole A A1 - Kwok, John B A1 - Leber, Markus A1 - Lam, Max A1 - Lee, Teresa A1 - Li, Shuo A1 - Loukola, Anu A1 - Luck, Tobias A1 - Marioni, Riccardo E A1 - Mather, Karen A A1 - Medland, Sarah A1 - Mirza, Saira S A1 - Nalls, Mike A A1 - Nho, Kwangsik A1 - O'Donnell, Adrienne A1 - Oldmeadow, Christopher A1 - Painter, Jodie A1 - Pattie, Alison A1 - Reppermund, Simone A1 - Risacher, Shannon L A1 - Rose, Richard J A1 - Sadashivaiah, Vijay A1 - Scholz, Markus A1 - Satizabal, Claudia L A1 - Schofield, Peter W A1 - Schraut, Katharina E A1 - Scott, Rodney J A1 - Simino, Jeannette A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Stott, David J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Turner, Stephen T A1 - van der Lee, Sven J A1 - Villringer, Arno A1 - Völker, Uwe A1 - Wilson, Robert S A1 - Wittfeld, Katharina A1 - Vuoksimaa, Eero A1 - Xia, Rui A1 - Yaffe, Kristine A1 - Yu, Lei A1 - Zare, Habil A1 - Zhao, Wei A1 - Ames, David A1 - Attia, John A1 - Bennett, David A A1 - Brodaty, Henry A1 - Chasman, Daniel I A1 - Goldman, Aaron L A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon L R A1 - Lencz, Todd A1 - Loeffler, Markus A1 - Mattay, Venkata S A1 - Palotie, Aarno A1 - Psaty, Bruce M A1 - Ramirez, Alfredo A1 - Ridker, Paul M A1 - Riedel-Heller, Steffi G A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Scherer, Martin A1 - Schofield, Peter R A1 - Sidney, Stephen A1 - Starr, John M A1 - Trollor, Julian A1 - Ulrich, William A1 - Wagner, Michael A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Margaret J A1 - Weinberger, Daniel R A1 - Debette, Stephanie A1 - Eriksson, Johan G A1 - Mosley, Thomas H A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Deary, Ian J A1 - Seshadri, Sudha A1 - Räikkönen, Katri AB -

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

ER - TY - JOUR T1 - New insights into the genetic etiology of Alzheimer's disease and related dementias. JF - Nat Genet Y1 - 2022 A1 - Bellenguez, Céline A1 - Küçükali, Fahri A1 - Jansen, Iris E A1 - Kleineidam, Luca A1 - Moreno-Grau, Sonia A1 - Amin, Najaf A1 - Naj, Adam C A1 - Campos-Martin, Rafael A1 - Grenier-Boley, Benjamin A1 - Andrade, Victor A1 - Holmans, Peter A A1 - Boland, Anne A1 - Damotte, Vincent A1 - van der Lee, Sven J A1 - Costa, Marcos R A1 - Kuulasmaa, Teemu A1 - Yang, Qiong A1 - de Rojas, Itziar A1 - Bis, Joshua C A1 - Yaqub, Amber A1 - Prokic, Ivana A1 - Chapuis, Julien A1 - Ahmad, Shahzad A1 - Giedraitis, Vilmantas A1 - Aarsland, Dag A1 - Garcia-Gonzalez, Pablo A1 - Abdelnour, Carla A1 - Alarcón-Martín, Emilio A1 - Alcolea, Daniel A1 - Alegret, Montserrat A1 - Alvarez, Ignacio A1 - Alvarez, Victoria A1 - Armstrong, Nicola J A1 - Tsolaki, Anthoula A1 - Antunez, Carmen A1 - Appollonio, Ildebrando A1 - Arcaro, Marina A1 - Archetti, Silvana A1 - Pastor, Alfonso Arias A1 - Arosio, Beatrice A1 - Athanasiu, Lavinia A1 - Bailly, Henri A1 - Banaj, Nerisa A1 - Baquero, Miquel A1 - Barral, Sandra A1 - Beiser, Alexa A1 - Pastor, Ana Belén A1 - Below, Jennifer E A1 - Benchek, Penelope A1 - Benussi, Luisa A1 - Berr, Claudine A1 - Besse, Céline A1 - Bessi, Valentina A1 - Binetti, Giuliano A1 - Bizarro, Alessandra A1 - Blesa, Rafael A1 - Boada, Merce A1 - Boerwinkle, Eric A1 - Borroni, Barbara A1 - Boschi, Silvia A1 - Bossù, Paola A1 - Bråthen, Geir A1 - Bressler, Jan A1 - Bresner, Catherine A1 - Brodaty, Henry A1 - Brookes, Keeley J A1 - Brusco, Luis Ignacio A1 - Buiza-Rueda, Dolores A1 - Bûrger, Katharina A1 - Burholt, Vanessa A1 - Bush, William S A1 - Calero, Miguel A1 - Cantwell, Laura B A1 - Chene, Geneviève A1 - Chung, Jaeyoon A1 - Cuccaro, Michael L A1 - Carracedo, Angel A1 - Cecchetti, Roberta A1 - Cervera-Carles, Laura A1 - Charbonnier, Camille A1 - Chen, Hung-Hsin A1 - Chillotti, Caterina A1 - Ciccone, Simona A1 - Claassen, Jurgen A H R A1 - Clark, Christopher A1 - Conti, Elisa A1 - Corma-Gómez, Anaïs A1 - Costantini, Emanuele A1 - Custodero, Carlo A1 - Daian, Delphine A1 - Dalmasso, Maria Carolina A1 - Daniele, Antonio A1 - Dardiotis, Efthimios A1 - Dartigues, Jean-François A1 - de Deyn, Peter Paul A1 - de Paiva Lopes, Katia A1 - de Witte, Lot D A1 - Debette, Stephanie A1 - Deckert, Jürgen A1 - Del Ser, Teodoro A1 - Denning, Nicola A1 - DeStefano, Anita A1 - Dichgans, Martin A1 - Diehl-Schmid, Janine A1 - Diez-Fairen, Monica A1 - Rossi, Paolo Dionigi A1 - Djurovic, Srdjan A1 - Duron, Emmanuelle A1 - Düzel, Emrah A1 - Dufouil, Carole A1 - Eiriksdottir, Gudny A1 - Engelborghs, Sebastiaan A1 - Escott-Price, Valentina A1 - Espinosa, Ana A1 - Ewers, Michael A1 - Faber, Kelley M A1 - Fabrizio, Tagliavini A1 - Nielsen, Sune Fallgaard A1 - Fardo, David W A1 - Farotti, Lucia A1 - Fenoglio, Chiara A1 - Fernández-Fuertes, Marta A1 - Ferrari, Raffaele A1 - Ferreira, Catarina B A1 - Ferri, Evelyn A1 - Fin, Bertrand A1 - Fischer, Peter A1 - Fladby, Tormod A1 - Fließbach, Klaus A1 - Fongang, Bernard A1 - Fornage, Myriam A1 - Fortea, Juan A1 - Foroud, Tatiana M A1 - Fostinelli, Silvia A1 - Fox, Nick C A1 - Franco-Macías, Emlio A1 - Bullido, María J A1 - Frank-García, Ana A1 - Froelich, Lutz A1 - Fulton-Howard, Brian A1 - Galimberti, Daniela A1 - García-Alberca, Jose Maria A1 - Garcia-Gonzalez, Pablo A1 - Garcia-Madrona, Sebastian A1 - Garcia-Ribas, Guillermo A1 - Ghidoni, Roberta A1 - Giegling, Ina A1 - Giorgio, Giaccone A1 - Goate, Alison M A1 - Goldhardt, Oliver A1 - Gomez-Fonseca, Duber A1 - González-Perez, Antonio A1 - Graff, Caroline A1 - Grande, Giulia A1 - Green, Emma A1 - Grimmer, Timo A1 - Grünblatt, Edna A1 - Grunin, Michelle A1 - Gudnason, Vilmundur A1 - Guetta-Baranes, Tamar A1 - Haapasalo, Annakaisa A1 - Hadjigeorgiou, Georgios A1 - Haines, Jonathan L A1 - Hamilton-Nelson, Kara L A1 - Hampel, Harald A1 - Hanon, Olivier A1 - Hardy, John A1 - Hartmann, Annette M A1 - Hausner, Lucrezia A1 - Harwood, Janet A1 - Heilmann-Heimbach, Stefanie A1 - Helisalmi, Seppo A1 - Heneka, Michael T A1 - Hernandez, Isabel A1 - Herrmann, Martin J A1 - Hoffmann, Per A1 - Holmes, Clive A1 - Holstege, Henne A1 - Vilas, Raquel Huerto A1 - Hulsman, Marc A1 - Humphrey, Jack A1 - Biessels, Geert Jan A1 - Jian, Xueqiu A1 - Johansson, Charlotte A1 - Jun, Gyungah R A1 - Kastumata, Yuriko A1 - Kauwe, John A1 - Kehoe, Patrick G A1 - Kilander, Lena A1 - Ståhlbom, Anne Kinhult A1 - Kivipelto, Miia A1 - Koivisto, Anne A1 - Kornhuber, Johannes A1 - Kosmidis, Mary H A1 - Kukull, Walter A A1 - Kuksa, Pavel P A1 - Kunkle, Brian W A1 - Kuzma, Amanda B A1 - Lage, Carmen A1 - Laukka, Erika J A1 - Launer, Lenore A1 - Lauria, Alessandra A1 - Lee, Chien-Yueh A1 - Lehtisalo, Jenni A1 - Lerch, Ondrej A1 - Lleo, Alberto A1 - Longstreth, William A1 - Lopez, Oscar A1 - de Munain, Adolfo Lopez A1 - Love, Seth A1 - Löwemark, Malin A1 - Luckcuck, Lauren A1 - Lunetta, Kathryn L A1 - Ma, Yiyi A1 - Macías, Juan A1 - MacLeod, Catherine A A1 - Maier, Wolfgang A1 - Mangialasche, Francesca A1 - Spallazzi, Marco A1 - Marquié, Marta A1 - Marshall, Rachel A1 - Martin, Eden R A1 - Montes, Angel Martín A1 - Rodríguez, Carmen Martínez A1 - Masullo, Carlo A1 - Mayeux, Richard A1 - Mead, Simon A1 - Mecocci, Patrizia A1 - Medina, Miguel A1 - Meggy, Alun A1 - Mehrabian, Shima A1 - Mendoza, Silvia A1 - Menéndez-González, Manuel A1 - Mir, Pablo A1 - Moebus, Susanne A1 - Mol, Merel A1 - Molina-Porcel, Laura A1 - Montrreal, Laura A1 - Morelli, Laura A1 - Moreno, Fermin A1 - Morgan, Kevin A1 - Mosley, Thomas A1 - Nöthen, Markus M A1 - Muchnik, Carolina A1 - Mukherjee, Shubhabrata A1 - Nacmias, Benedetta A1 - Ngandu, Tiia A1 - Nicolas, Gaël A1 - Nordestgaard, Børge G A1 - Olaso, Robert A1 - Orellana, Adelina A1 - Orsini, Michela A1 - Ortega, Gemma A1 - Padovani, Alessandro A1 - Paolo, Caffarra A1 - Papenberg, Goran A1 - Parnetti, Lucilla A1 - Pasquier, Florence A1 - Pastor, Pau A1 - Peloso, Gina A1 - Pérez-Cordón, Alba A1 - Pérez-Tur, Jordi A1 - Pericard, Pierre A1 - Peters, Oliver A1 - Pijnenburg, Yolande A L A1 - Pineda, Juan A A1 - Piñol-Ripoll, Gerard A1 - Pisanu, Claudia A1 - Polak, Thomas A1 - Popp, Julius A1 - Posthuma, Danielle A1 - Priller, Josef A1 - Puerta, Raquel A1 - Quenez, Olivier A1 - Quintela, Inés A1 - Thomassen, Jesper Qvist A1 - Rábano, Alberto A1 - Rainero, Innocenzo A1 - Rajabli, Farid A1 - Ramakers, Inez A1 - Real, Luis M A1 - Reinders, Marcel J T A1 - Reitz, Christiane A1 - Reyes-Dumeyer, Dolly A1 - Ridge, Perry A1 - Riedel-Heller, Steffi A1 - Riederer, Peter A1 - Roberto, Natalia A1 - Rodriguez-Rodriguez, Eloy A1 - Rongve, Arvid A1 - Allende, Irene Rosas A1 - Rosende-Roca, Maitée A1 - Royo, Jose Luis A1 - Rubino, Elisa A1 - Rujescu, Dan A1 - Sáez, María Eugenia A1 - Sakka, Paraskevi A1 - Saltvedt, Ingvild A1 - Sanabria, Ángela A1 - Sánchez-Arjona, María Bernal A1 - Sanchez-Garcia, Florentino A1 - Juan, Pascual Sánchez A1 - Sánchez-Valle, Raquel A1 - Sando, Sigrid B A1 - Sarnowski, Chloe A1 - Satizabal, Claudia L A1 - Scamosci, Michela A1 - Scarmeas, Nikolaos A1 - Scarpini, Elio A1 - Scheltens, Philip A1 - Scherbaum, Norbert A1 - Scherer, Martin A1 - Schmid, Matthias A1 - Schneider, Anja A1 - Schott, Jonathan M A1 - Selbæk, Geir A1 - Seripa, Davide A1 - Serrano, Manuel A1 - Sha, Jin A1 - Shadrin, Alexey A A1 - Skrobot, Olivia A1 - Slifer, Susan A1 - Snijders, Gijsje J L A1 - Soininen, Hilkka A1 - Solfrizzi, Vincenzo A1 - Solomon, Alina A1 - Song, Yeunjoo A1 - Sorbi, Sandro A1 - Sotolongo-Grau, Oscar A1 - Spalletta, Gianfranco A1 - Spottke, Annika A1 - Squassina, Alessio A1 - Stordal, Eystein A1 - Tartan, Juan Pablo A1 - Tarraga, Lluis A1 - Tesí, Niccolo A1 - Thalamuthu, Anbupalam A1 - Thomas, Tegos A1 - Tosto, Giuseppe A1 - Traykov, Latchezar A1 - Tremolizzo, Lucio A1 - Tybjærg-Hansen, Anne A1 - Uitterlinden, Andre A1 - Ullgren, Abbe A1 - Ulstein, Ingun A1 - Valero, Sergi A1 - Valladares, Otto A1 - Broeckhoven, Christine Van A1 - Vance, Jeffery A1 - Vardarajan, Badri N A1 - van der Lugt, Aad A1 - Dongen, Jasper Van A1 - van Rooij, Jeroen A1 - van Swieten, John A1 - Vandenberghe, Rik A1 - Verhey, Frans A1 - Vidal, Jean-Sébastien A1 - Vogelgsang, Jonathan A1 - Vyhnalek, Martin A1 - Wagner, Michael A1 - Wallon, David A1 - Wang, Li-San A1 - Wang, Ruiqi A1 - Weinhold, Leonie A1 - Wiltfang, Jens A1 - Windle, Gill A1 - Woods, Bob A1 - Yannakoulia, Mary A1 - Zare, Habil A1 - Zhao, Yi A1 - Zhang, Xiaoling A1 - Zhu, Congcong A1 - Zulaica, Miren A1 - Farrer, Lindsay A A1 - Psaty, Bruce M A1 - Ghanbari, Mohsen A1 - Raj, Towfique A1 - Sachdev, Perminder A1 - Mather, Karen A1 - Jessen, Frank A1 - Ikram, M Arfan A1 - de Mendonça, Alexandre A1 - Hort, Jakub A1 - Tsolaki, Magda A1 - Pericak-Vance, Margaret A A1 - Amouyel, Philippe A1 - Williams, Julie A1 - Frikke-Schmidt, Ruth A1 - Clarimon, Jordi A1 - Deleuze, Jean-Francois A1 - Rossi, Giacomina A1 - Seshadri, Sudha A1 - Andreassen, Ole A A1 - Ingelsson, Martin A1 - Hiltunen, Mikko A1 - Sleegers, Kristel A1 - Schellenberg, Gerard D A1 - van Duijn, Cornelia M A1 - Sims, Rebecca A1 - van der Flier, Wiesje M A1 - Ruiz, Agustin A1 - Ramirez, Alfredo A1 - Lambert, Jean-Charles KW - Alzheimer Disease KW - Cognitive Dysfunction KW - Genome-Wide Association Study KW - Humans KW - tau Proteins AB -

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

VL - 54 IS - 4 ER -