TY - JOUR T1 - Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. JF - Molecular 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 - Jessica Faul 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 - Sharon L R Kardia 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 - David R Weir A1 - Wilson, James F A1 - Wright, Margaret J A1 - Weinberger, Daniel R A1 - Debette, Stéphanie 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 KW - Genome KW - health outcomes KW - Memory KW - neurocognitive outcomes KW - polygenic score KW - Verbal Learning 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 - Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. JF - Nature Communications Y1 - 2018 A1 - Gail Davies A1 - Lam, Max A1 - Sarah E Harris A1 - Joey W Trampush A1 - Luciano, Michelle A1 - W David Hill A1 - Hagenaars, Saskia P A1 - Ritchie, Stuart J A1 - Riccardo E Marioni A1 - Fawns-Ritchie, Chloe A1 - David C Liewald A1 - Okely, Judith A A1 - Ahola-Olli, Ari V A1 - Barnes, Catriona L K A1 - Bertram, Lars A1 - Joshua C. Bis A1 - Katherine E Burdick A1 - Christoforou, Andrea A1 - DeRosse, Pamela A1 - Djurovic, Srdjan A1 - Espeseth, Thomas A1 - Giakoumaki, Stella A1 - Giddaluru, Sudheer A1 - Gustavson, Daniel E A1 - Caroline Hayward A1 - Edith Hofer 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 - Christopher J Oldmeadow A1 - Palviainen, Teemu A1 - Payton, Antony A1 - Pazoki, Raha A1 - Katja E Petrovic A1 - Chandra A Reynolds A1 - Sargurupremraj, Muralidharan A1 - Scholz, Markus A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Terzikhan, Natalie A1 - Thalamuthu, Anbupalam A1 - Trompet, Stella A1 - Sven J van der Lee A1 - Erin B Ware A1 - Windham, B Gwen A1 - Margaret J Wright 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 - John R. Attia A1 - Attix, Deborah A1 - Avramopoulos, Dimitrios A1 - David A Bennett A1 - Böhmer, Anne C A1 - Patricia A. Boyle A1 - Brodaty, Henry A1 - Campbell, Harry A1 - Tyrone D. Cannon A1 - Elizabeth T. Cirulli A1 - Congdon, Eliza A1 - Conley, Emily Drabant A1 - Corley, Janie A1 - Cox, Simon R A1 - Dale, Anders M A1 - Dehghan, Abbas A1 - Danielle M. Dick A1 - Dickinson, Dwight A1 - Johan G Eriksson A1 - Evangelou, Evangelos A1 - Jessica Faul A1 - Ford, Ian A1 - Nelson A. Freimer A1 - Gao, He A1 - Giegling, Ina A1 - Gillespie, Nathan A A1 - Gordon, Scott D A1 - Gottesman, Rebecca F A1 - Michael E Griswold A1 - Gudnason, Vilmundur A1 - Tamara B Harris A1 - Hartmann, Annette M A1 - Hatzimanolis, Alex A1 - Gerardo Heiss A1 - Holliday, Elizabeth G A1 - Joshi, Peter K A1 - Kähönen, Mika A1 - Sharon L R Kardia A1 - Ida Karlsson A1 - Kleineidam, Luca A1 - David S Knopman A1 - Kochan, Nicole A A1 - Konte, Bettina A1 - Kwok, John B A1 - Stephanie Le Hellard A1 - Lee, Teresa A1 - Lehtimäki, Terho A1 - Li, Shu-Chen A1 - Lill, Christina M A1 - Liu, Tian A1 - Koini, Marisa A1 - London, Edythe A1 - Longstreth, Will T A1 - Lopez, Oscar L A1 - Loukola, Anu A1 - Luck, Tobias A1 - Astri J Lundervold A1 - Lundquist, Anders A1 - Lyytikäinen, Leo-Pekka A1 - Nicholas G Martin A1 - Grant W Montgomery A1 - Murray, Alison D A1 - Anna C Need A1 - Noordam, Raymond A1 - Nyberg, Lars A1 - William E R Ollier A1 - Papenberg, Goran A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Russell A Poldrack A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Steffi G Riedel-Heller A1 - Rose, Richard J A1 - Rotter, Jerome I A1 - Roussos, Panos A1 - Rovio, Suvi P A1 - Saba, Yasaman A1 - Fred W Sabb A1 - Sachdev, Perminder S A1 - Satizabal, Claudia L A1 - Schmid, Matthias A1 - Rodney J Scott A1 - Matthew A Scult A1 - Simino, Jeannette A1 - Slagboom, P Eline A1 - Smyrnis, Nikolaos A1 - Soumaré, Aïcha A1 - Nikos C Stefanis A1 - Stott, David J A1 - Richard E Straub A1 - Sundet, Kjetil A1 - Taylor, Adele M A1 - Kent D Taylor A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - André G Uitterlinden A1 - Vitart, Veronique A1 - Aristotle N Voineskos A1 - Kaprio, Jaakko A1 - Wagner, Michael A1 - Wagner, Holger A1 - Weinhold, Leonie A1 - Wen, K Hoyan A1 - Elisabeth Widen A1 - Yang, Qiong A1 - Zhao, Wei A1 - Hieab H Adams A1 - Dan E Arking A1 - Robert M Bilder A1 - Bitsios, Panos A1 - Boerwinkle, Eric A1 - Chiba-Falek, Ornit A1 - Corvin, Aiden A1 - Philip L de Jager A1 - Debette, Stéphanie A1 - Donohoe, Gary A1 - Elliott, Paul A1 - Fitzpatrick, Annette L A1 - Gill, Michael A1 - David C. Glahn A1 - Hägg, Sara A1 - Narelle K Hansell A1 - Ahmad R Hariri A1 - Ikram, M Kamran A1 - Jukema, J Wouter A1 - Vuoksimaa, Eero A1 - Matthew C Keller A1 - Kremen, William S A1 - Lenore J Launer A1 - Lindenberger, Ulman A1 - Aarno Palotie A1 - Nancy L Pedersen A1 - Pendleton, Neil A1 - David J Porteous A1 - Katri Räikkönen A1 - Olli T Raitakari A1 - Ramirez, Alfredo A1 - Reinvang, Ivar A1 - Rudan, Igor A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Peter W Schofield A1 - Peter R Schofield A1 - John M Starr A1 - Vidar M Steen A1 - Trollor, Julian N A1 - Turner, Steven T A1 - Cornelia M van Duijn A1 - Villringer, Arno A1 - Daniel R Weinberger A1 - David R Weir A1 - James F Wilson A1 - Anil K. Malhotra A1 - McIntosh, Andrew M A1 - Gale, Catharine R A1 - Seshadri, Sudha A1 - Thomas H Mosley A1 - Bressler, Jan A1 - Lencz, Todd A1 - Ian J Deary KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cognition KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mental Disorders KW - Middle Aged KW - Multifactorial Inheritance KW - Neurodegenerative Diseases KW - Neurodevelopmental Disorders KW - Polymorphism, Single Nucleotide KW - Reaction Time KW - Young Adult 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 - GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. JF - Aging Cell Y1 - 2016 A1 - Amy M Matteini A1 - Toshiko Tanaka A1 - Karasik, David A1 - Atzmon, Gil A1 - Chou, Wen-Chi A1 - John D Eicher A1 - Andrew D Johnson A1 - Alice M. Arnold A1 - Michele L Callisaya A1 - Gail Davies A1 - Daniel S Evans A1 - Holtfreter, Birte A1 - Kurt Lohman A1 - Kathryn L Lunetta A1 - Mangino, Massimo A1 - Albert Vernon Smith A1 - Jennifer A Smith A1 - Teumer, Alexander A1 - Lei Yu A1 - Dan E Arking A1 - Aron S Buchman A1 - Chibinik, Lori B A1 - Philip L de Jager A1 - Jessica Faul A1 - Melissa E Garcia A1 - Gillham-Nasenya, Irina A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Hsu, Yi-Hsiang A1 - Ittermann, Till A1 - Lahousse, Lies A1 - David C Liewald A1 - Yongmei Liu A1 - Lopez, Lorna A1 - Fernando Rivadeneira A1 - Rotter, Jerome I A1 - Siggeirsdottir, Kristin A1 - John M Starr A1 - Thomson, Russell A1 - Tranah, Gregory J A1 - André G Uitterlinden A1 - Völker, Uwe A1 - Völzke, Henry A1 - David R Weir A1 - Kristine Yaffe A1 - Wei Zhao A1 - Wei Vivian Zhuang A1 - Zmuda, Joseph M A1 - David A Bennett A1 - Steven R Cummings A1 - Ian J Deary A1 - Luigi Ferrucci A1 - Tamara B Harris A1 - Sharon L R Kardia A1 - Kocher, Thomas A1 - Stephen B Kritchevsky A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Timothy Spector A1 - Velandai K Srikanth A1 - Beverly G Windham A1 - Zillikens, M Carola A1 - Anne B Newman A1 - Jeremy D Walston A1 - Douglas P Kiel A1 - Joanne M Murabito KW - Adult KW - Aged KW - Chromatin Immunoprecipitation KW - Cohort Studies KW - Epigenesis, Genetic KW - Genome-Wide Association Study KW - Hand Strength KW - Humans KW - Molecular Sequence Annotation KW - Muscle Strength KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results AB -

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

VL - 15 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract ER - TY - JOUR T1 - Directional dominance on stature and cognition in diverse human populations. JF - Nature Y1 - 2015 A1 - Joshi, Peter K A1 - Tõnu Esko A1 - Mattsson, Hannele A1 - Eklund, Niina A1 - Gandin, Ilaria A1 - Nutile, Teresa A1 - Jackson, Anne U A1 - Schurmann, Claudia A1 - Albert Vernon Smith A1 - Zhang, Weihua A1 - Okada, Yukinori A1 - Stančáková, Alena A1 - Jessica Faul A1 - Wei Zhao A1 - Traci M Bartz A1 - Maria Pina Concas A1 - Franceschini, Nora A1 - Enroth, Stefan A1 - Vitart, Veronique A1 - Trompet, Stella A1 - Guo, Xiuqing A1 - Daniel I Chasman A1 - Jeff O'Connell A1 - Corre, Tanguy A1 - Nongmaithem, Suraj S A1 - Chen, Yuning A1 - Mangino, Massimo A1 - Ruggiero, Daniela A1 - Traglia, Michela A1 - Farmaki, Aliki-Eleni A1 - Kacprowski, Tim A1 - Bjonnes, Andrew A1 - van der Spek, Ashley A1 - Wu, Ying A1 - Giri, Anil K A1 - Yanek, Lisa R A1 - Wang, Lihua A1 - Edith Hofer A1 - Cornelius A Rietveld A1 - McLeod, Olga A1 - Marilyn C Cornelis A1 - Pattaro, Cristian A1 - Verweij, Niek A1 - Baumbach, Clemens A1 - Abdel Abdellaoui A1 - Warren, Helen R A1 - Vuckovic, Dragana A1 - Mei, Hao A1 - Bouchard, Claude A1 - Perry, John R B A1 - Cappellani, Stefania A1 - Saira S Mirza A1 - Benton, Miles C A1 - Broeckel, Ulrich A1 - Sarah E Medland A1 - Penelope A Lind A1 - Malerba, Giovanni A1 - Alexander W Drong A1 - Yengo, Loic A1 - Bielak, Lawrence F A1 - Zhi, Degui A1 - van der Most, Peter J A1 - Daniel Shriner A1 - Mägi, Reedik A1 - Hemani, Gibran A1 - Karaderi, Tugce A1 - Wang, Zhaoming A1 - Tian Liu A1 - Demuth, Ilja A1 - Jing Hua Zhao A1 - Meng, Weihua A1 - Lataniotis, Lazaros A1 - van der Laan, Sander W A1 - Bradfield, Jonathan P A1 - Andrew R Wood A1 - Bonnefond, Amelie A1 - Ahluwalia, Tarunveer S A1 - Hall, Leanne M A1 - Salvi, Erika A1 - Yazar, Seyhan A1 - Carstensen, Lisbeth A1 - de Haan, Hugoline G A1 - Abney, Mark A1 - Afzal, Uzma A1 - Matthew A. Allison A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Barr, R Graham A1 - Baumeister, Sebastian E A1 - Daniel J. Benjamin A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Erwin P Bottinger A1 - Campbell, Archie A1 - Chakravarti, Aravinda A1 - Chan, Yingleong A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Yii-Der I Chen A1 - Collins, Francis S A1 - Connell, John A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Gail Davies A1 - Dörr, Marcus A1 - Georg B Ehret A1 - Ellis, Stephen B A1 - Feenstra, Bjarke A1 - Feitosa, Mary F A1 - Ford, Ian A1 - Caroline S Fox A1 - Timothy M Frayling A1 - Friedrich, Nele A1 - Geller, Frank A1 - Scotland, Generation A1 - Gillham-Nasenya, Irina A1 - Gottesman, Omri A1 - Graff, Misa A1 - Grodstein, Francine A1 - Gu, Charles A1 - Haley, Chris A1 - Hammond, Christopher J A1 - Sarah E Harris A1 - Tamara B Harris A1 - Nicholas D Hastie A1 - Heard-Costa, Nancy L A1 - Heikkilä, Kauko A1 - Lynne J Hocking A1 - Homuth, Georg A1 - Jouke-Jan Hottenga A1 - Huang, Jinyan A1 - Huffman, Jennifer E A1 - Hysi, Pirro G A1 - Mohammed Arfan Ikram A1 - Ingelsson, Erik A1 - Joensuu, Anni A1 - Johansson, Åsa A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanoni, Stavroula A1 - Kerr, Shona M A1 - Khan, Nazir M A1 - Philipp D Koellinger A1 - Koistinen, Heikki A A1 - Kooner, Manraj K A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lahti, Jari A1 - Lenore J Launer A1 - Lea, Rodney A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - David C Liewald A1 - Lars Lind A1 - Loh, Marie A1 - Lokki, Marja-Liisa A1 - London, Stephanie J A1 - Loomis, Stephanie J A1 - Loukola, Anu A1 - Lu, Yingchang A1 - Lumley, Thomas A1 - Lundqvist, Annamari A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Masciullo, Corrado A1 - Matchan, Angela A1 - Mathias, Rasika A A1 - Matsuda, Koichi A1 - Meigs, James B A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Mentch, Frank D A1 - Mihailov, Evelin A1 - Lili Milani A1 - Montasser, May E A1 - Grant W Montgomery A1 - Alanna C Morrison A1 - Myers, Richard H A1 - Nadukuru, Rajiv A1 - Navarro, Pau A1 - Nelis, Mari A1 - Nieminen, Markku S A1 - Ilja M Nolte A1 - O'Connor, George T A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Walter R Palmas A1 - Pankow, James S A1 - Patarcic, Inga A1 - Pavani, Francesca A1 - Peyser, Patricia A A1 - Pietilainen, Kirsi A1 - Neil Poulter A1 - Prokopenko, Inga A1 - Ralhan, Sarju A1 - Redmond, Paul A1 - Rich, Stephen S A1 - Rissanen, Harri A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rose, Richard A1 - Cinzia Felicita Sala A1 - Babatunde Salako A1 - Veikko Salomaa A1 - Sarin, Antti-Pekka A1 - Saxena, Richa A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sennblad, Bengt A1 - Seshadri, Sudha A1 - Peter Sever A1 - Shrestha, Smeeta A1 - Smith, Blair H A1 - Jennifer A Smith A1 - Soranzo, Nicole A1 - Sotoodehnia, Nona A1 - Southam, Lorraine A1 - Stanton, Alice V A1 - Stathopoulou, Maria G A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Suderman, Matthew J A1 - Tandon, Nikhil A1 - Tang, Sian-Tsun A1 - Kent D Taylor A1 - Bamidele O Tayo A1 - Töglhofer, Anna Maria A1 - Tomaszewski, Maciej A1 - Tšernikova, Natalia A1 - Tuomilehto, Jaakko A1 - André G Uitterlinden A1 - Vaidya, Dhananjay A1 - van Hylckama Vlieg, Astrid A1 - van Setten, Jessica A1 - Vasankari, Tuula A1 - Vedantam, Sailaja A1 - Vlachopoulou, Efthymia A1 - Vozzi, Diego A1 - Vuoksimaa, Eero A1 - Waldenberger, Melanie A1 - Erin B Ware A1 - Wentworth-Shields, William A1 - Whitfield, John B A1 - Sarah Wild A1 - Gonneke Willemsen A1 - Yajnik, Chittaranjan S A1 - Yao, Jie A1 - Zaza, Gianluigi A1 - Zhu, Xiaofeng A1 - Salem, Rany M A1 - Melbye, Mads A1 - Bisgaard, Hans A1 - Nilesh J Samani A1 - Cusi, Daniele A1 - Mackey, David A A1 - Cooper, Richard S A1 - Froguel, Philippe A1 - Pasterkamp, Gerard A1 - Grant, Struan F A A1 - Hakonarson, Hakon A1 - Luigi Ferrucci A1 - Scott, Robert A A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - George Dedoussis A1 - Deloukas, Panos A1 - Bertram, Lars A1 - Lindenberger, Ulman A1 - Berndt, Sonja I A1 - Lindgren, Cecilia M A1 - Nicholas J Timpson A1 - Tönjes, Anke A1 - Munroe, Patricia B A1 - Thorkild I. A. Sørensen A1 - Charles N Rotimi A1 - Donna K Arnett A1 - Oldehinkel, Albertine J A1 - Sharon L R Kardia A1 - Balkau, Beverley A1 - Gambaro, Giovanni A1 - Morris, Andrew P A1 - Johan G Eriksson A1 - Margaret J Wright A1 - Nicholas G Martin A1 - Hunt, Steven C A1 - John M Starr A1 - Ian J Deary A1 - Griffiths, Lyn R A1 - Henning Tiemeier A1 - Nicola Pirastu A1 - Kaprio, Jaakko A1 - Wareham, Nicholas J A1 - Pérusse, Louis A1 - Wilson, James G A1 - Giorgia G Girotto A1 - Caulfield, Mark J A1 - Olli T Raitakari A1 - Dorret I Boomsma A1 - Gieger, Christian A1 - van der Harst, Pim A1 - Hicks, Andrew A A1 - Kraft, Peter A1 - Sinisalo, Juha A1 - Knekt, Paul A1 - Johannesson, Magnus A1 - Patrik K E Magnusson A1 - Hamsten, Anders A1 - Schmidt, Reinhold A1 - Ingrid B Borecki A1 - Vartiainen, Erkki A1 - Becker, Diane M A1 - Bharadwaj, Dwaipayan A1 - Mohlke, Karen L A1 - Boehnke, Michael A1 - Cornelia M van Duijn A1 - Sanghera, Dharambir K A1 - Teumer, Alexander A1 - Zeggini, Eleftheria A1 - Andres Metspalu A1 - Paolo P. Gasparini A1 - Ulivi, Sheila A1 - Ober, Carole A1 - Toniolo, Daniela A1 - Rudan, Igor A1 - David J Porteous A1 - Ciullo, Marina A1 - Timothy Spector A1 - Caroline Hayward A1 - Dupuis, Josée A1 - Ruth J F Loos A1 - Alan F Wright A1 - Chandak, Giriraj R A1 - Vollenweider, Peter A1 - Alan R Shuldiner A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Sattar, Naveed A1 - Gyllensten, Ulf A1 - Kari E North A1 - Pirastu, Mario A1 - Psaty, Bruce M A1 - David R Weir A1 - Laakso, Markku A1 - Gudnason, Vilmundur A1 - Takahashi, Atsushi A1 - Chambers, John C A1 - Kooner, Jaspal S A1 - David P Strachan A1 - Campbell, Harry A1 - Joel N Hirschhron A1 - Markus Perola A1 - Polasek, Ozren A1 - James F Wilson KW - Biological Evolution KW - Blood pressure KW - Body Height KW - Cholesterol KW - Cognitive Ability KW - Cohort Studies KW - Education KW - Female KW - Forced Expiratory Volume KW - Genome KW - Homozygote KW - Humans KW - Lung Volume Measurements KW - Male KW - Phenotype AB -

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

VL - 523 IS - 7561 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract ER - TY - JOUR T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Broer, Linda A1 - Aron S Buchman A1 - Deelen, Joris A1 - Daniel S Evans A1 - Jessica Faul A1 - Kathryn L Lunetta A1 - Sebastiani, Paola A1 - Jennifer A Smith A1 - Albert Vernon Smith A1 - Toshiko Tanaka A1 - Lei Yu A1 - Alice M. Arnold A1 - Aspelund, Thor A1 - Emelia J Benjamin A1 - Philip L de Jager A1 - Guðny Eiríksdóttir A1 - Melissa E Garcia A1 - Hofman, Albert A1 - Kaplan, Robert C A1 - Sharon L R Kardia A1 - Douglas P Kiel A1 - Ben A Oostra A1 - Orwoll, Eric S A1 - Parimi, Neeta A1 - Psaty, Bruce M A1 - Fernando Rivadeneira A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Andrew B Singleton A1 - Henning Tiemeier A1 - André G Uitterlinden A1 - Wei Zhao A1 - Bandinelli, Stefania A1 - David A Bennett A1 - Luigi Ferrucci A1 - Gudnason, Vilmundur A1 - Tamara B Harris A1 - Karasik, David A1 - Lenore J Launer A1 - Thomas T Perls A1 - Eline P Slagboom A1 - Tranah, Gregory J A1 - David R Weir A1 - Anne B Newman A1 - Cornelia M van Duijn A1 - Joanne M Murabito KW - Aged KW - Aged, 80 and over KW - Apolipoproteins E KW - Cell Adhesion Molecules KW - Cohort Studies KW - Female KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Kainic Acid AB -

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

VL - 70 UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296168/ IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a brief dementia screening indicator for primary care. JF - Alzheimers Dement Y1 - 2014 A1 - Deborah E Barnes A1 - Alexa S. Beiser A1 - Anne Lee A1 - Kenneth M. Langa A1 - Alain Koyama A1 - Sarah R Preis A1 - John Neuhaus A1 - Ryan J McCammon A1 - Kristine Yaffe A1 - Seshadri, Sudha A1 - Mary Haan A1 - David R Weir KW - Aged KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Male KW - Mass Screening KW - Predictive Value of Tests KW - Primary Health Care KW - Proportional Hazards Models KW - Risk Assessment AB -

BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.

METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening.

RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).

CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.

PB - 10 VL - 10 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84893186546andpartnerID=40andmd5=3b617dce24578e022db389d90ad9ddd1 IS - 6 N1 - Export Date: 21 April 2014 Source: Scopus Article in Press U1 - http://www.ncbi.nlm.nih.gov/pubmed/24491321?dopt=Abstract U2 - PMC4119094 U4 - Dementia/Primary care/Risk prediction modeling/Screening/Cognitive Impairment ER -