%0 Journal Article %J Neurobiol Aging %D 2011 %T A genome-wide association study of aging. %A Walter, Stefan %A Atzmon, Gil %A Demerath, Ellen W %A Garcia, Melissa E %A Kaplan, Robert C %A Kumari, Meena %A Lunetta, Kathryn L %A Milaneschi, Yuri %A Tanaka, Toshiko %A Tranah, Gregory J %A Völker, Uwe %A Yu, Lei %A Arnold, Alice %A Benjamin, Emelia J %A Biffar, Reiner %A Buchman, Aron S %A Boerwinkle, Eric %A Couper, David %A De Jager, Philip L %A Evans, Denis A %A Harris, Tamara B %A Hoffmann, Wolfgang %A Hofman, Albert %A Karasik, David %A Kiel, Douglas P %A Kocher, Thomas %A Kuningas, Maris %A Launer, Lenore J %A Lohman, Kurt K %A Lutsey, Pamela L %A Mackenbach, Johan %A Marciante, Kristin %A Psaty, Bruce M %A Reiman, Eric M %A Rotter, Jerome I %A Seshadri, Sudha %A Shardell, Michelle D %A Smith, Albert V %A van Duijn, Cornelia %A Walston, Jeremy %A Zillikens, M Carola %A Bandinelli, Stefania %A Baumeister, Sebastian E %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Kivimaki, Mika %A Liu, Yongmei %A Murabito, Joanne M %A Newman, Anne B %A Tiemeier, Henning %A Franceschini, Nora %K Aging %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Longevity %X

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

%B Neurobiol Aging %V 32 %P 2109.e15-28 %8 2011 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21782286?dopt=Abstract %R 10.1016/j.neurobiolaging.2011.05.026 %0 Journal Article %J Biol Psychiatry %D 2013 %T A genome-wide association study of depressive symptoms. %A Hek, Karin %A Demirkan, Ayse %A Lahti, Jari %A Terracciano, Antonio %A Teumer, Alexander %A Cornelis, Marilyn C %A Amin, Najaf %A Bakshis, Erin %A Baumert, Jens %A Ding, Jingzhong %A Liu, Yongmei %A Marciante, Kristin %A Meirelles, Osorio %A Nalls, Michael A %A Sun, Yan V %A Vogelzangs, Nicole %A Yu, Lei %A Bandinelli, Stefania %A Benjamin, Emelia J %A Bennett, David A %A Boomsma, Dorret %A Cannas, Alessandra %A Coker, Laura H %A de Geus, Eco %A De Jager, Philip L %A Diez-Roux, Ana V %A Purcell, Shaun %A Hu, Frank B %A Rimma, Eric B %A Hunter, David J %A Jensen, Majken K %A Curhan, Gary %A Rice, Kenneth %A Penman, Alan D %A Rotter, Jerome I %A Sotoodehnia, Nona %A Emeny, Rebecca %A Eriksson, Johan G %A Evans, Denis A %A Ferrucci, Luigi %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofman, Albert %A Illig, Thomas %A Kardia, Sharon %A Kelly-Hayes, Margaret %A Koenen, Karestan %A Kraft, Peter %A Kuningas, Maris %A Massaro, Joseph M %A Melzer, David %A Mulas, Antonella %A Mulder, Cornelis L %A Murray, Anna %A Oostra, Ben A %A Palotie, Aarno %A Penninx, Brenda %A Petersmann, Astrid %A Pilling, Luke C %A Psaty, Bruce %A Rawal, Rajesh %A Reiman, Eric M %A Schulz, Andrea %A Shulman, Joshua M %A Singleton, Andrew B %A Smith, Albert V %A Sutin, Angelina R %A Uitterlinden, André G %A Völzke, Henry %A Widen, Elisabeth %A Yaffe, Kristine %A Zonderman, Alan B %A Cucca, Francesco %A Harris, Tamara %A Ladwig, Karl-Heinz %A Llewellyn, David J %A Räikkönen, Katri %A Tanaka, Toshiko %A van Duijn, Cornelia M %A Grabe, Hans J %A Launer, Lenore J %A Lunetta, Kathryn L %A Mosley, Thomas H %A Newman, Anne B %A Tiemeier, Henning %A Murabito, Joanne %K Aged %K Aged, 80 and over %K Chromosomes, Human, Pair 5 %K Depression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.

METHODS: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.

RESULTS: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258).

CONCLUSIONS: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.

%B Biol Psychiatry %V 73 %P 667-78 %8 2013 Apr 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23290196?dopt=Abstract %R 10.1016/j.biopsych.2012.09.033 %0 Journal Article %J BMC Genet %D 2014 %T Genetic diversity is a predictor of mortality in humans. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Lunetta, Kathryn L %A Nalls, Mike %A Smith, Jennifer A %A Tanaka, Toshiko %A Davies, Gail %A Yu, Lei %A Mirza, Saira Saeed %A Teumer, Alexander %A Coresh, Josef %A Pankow, James S %A Franceschini, Nora %A Scaria, Anish %A Oshima, Junko %A Psaty, Bruce M %A Gudnason, Vilmundur %A Eiriksdottir, Gudny %A Harris, Tamara B %A Li, Hanyue %A Karasik, David %A Kiel, Douglas P %A Garcia, Melissa %A Liu, Yongmei %A Faul, Jessica D %A Kardia, Sharon Lr %A Zhao, Wei %A Ferrucci, Luigi %A Allerhand, Michael %A Liewald, David C %A Redmond, Paul %A Starr, John M %A De Jager, Philip L %A Evans, Denis A %A Direk, Nese %A Ikram, Mohammed Arfan %A Uitterlinden, Andre %A Homuth, Georg %A Lorbeer, Roberto %A Grabe, Hans J %A Launer, Lenore %A Murabito, Joanne M %A Singleton, Andrew B %A Weir, David R %A Bandinelli, Stefania %A Deary, Ian J %A Bennett, David A %A Tiemeier, Henning %A Kocher, Thomas %A Lumley, Thomas %A Arking, Dan E %K Genome-Wide Association Study %K Heterozygote %K Humans %K Mortality %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %X

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

%B BMC Genet %V 15 %P 159 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract %R 10.1186/s12863-014-0159-7 %0 Journal Article %J PLoS One %D 2014 %T Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. %A Escott-Price, Valentina %A Bellenguez, Céline %A Wang, Li-San %A Choi, Seung-Hoan %A Harold, Denise %A Jones, Lesley %A Holmans, Peter %A Gerrish, Amy %A Vedernikov, Alexey %A Richards, Alexander %A DeStefano, Anita L %A Lambert, Jean-Charles %A Ibrahim-Verbaas, Carla A %A Naj, Adam C %A Sims, Rebecca %A Jun, Gyungah %A Bis, Joshua C %A Beecham, Gary W %A Grenier-Boley, Benjamin %A Russo, Giancarlo %A Thornton-Wells, Tricia A %A Denning, Nicola %A Smith, Albert V %A Chouraki, Vincent %A Thomas, Charlene %A Ikram, M Arfan %A Zelenika, Diana %A Vardarajan, Badri N %A Kamatani, Yoichiro %A Lin, Chiao-Feng %A Schmidt, Helena %A Kunkle, Brian %A Dunstan, Melanie L %A Vronskaya, Maria %A Johnson, Andrew D %A Ruiz, Agustin %A Bihoreau, Marie-Thérèse %A Reitz, Christiane %A Pasquier, Florence %A Hollingworth, Paul %A Hanon, Olivier %A Fitzpatrick, Annette L %A Buxbaum, Joseph D %A Campion, Dominique %A Crane, Paul K %A Baldwin, Clinton %A Becker, Tim %A Gudnason, Vilmundur %A Cruchaga, Carlos %A Craig, David %A Amin, Najaf %A Berr, Claudine %A Lopez, Oscar L %A De Jager, Philip L %A Deramecourt, Vincent %A Johnston, Janet A %A Evans, Denis %A Lovestone, Simon %A Letenneur, Luc %A Hernandez, Isabel %A Rubinsztein, David C %A Eiriksdottir, Gudny %A Sleegers, Kristel %A Goate, Alison M %A Fiévet, Nathalie %A Huentelman, Matthew J %A Gill, Michael %A Brown, Kristelle %A Kamboh, M Ilyas %A Keller, Lina %A Barberger-Gateau, Pascale %A McGuinness, Bernadette %A Larson, Eric B %A Myers, Amanda J %A Dufouil, Carole %A Todd, Stephen %A Wallon, David %A Love, Seth %A Rogaeva, Ekaterina %A Gallacher, John %A George-Hyslop, Peter St %A Clarimon, Jordi %A Lleo, Alberto %A Bayer, Anthony %A Tsuang, Debby W %A Yu, Lei %A Tsolaki, Magda %A Bossù, Paola %A Spalletta, Gianfranco %A Proitsi, Petra %A Collinge, John %A Sorbi, Sandro %A Garcia, Florentino Sanchez %A Fox, Nick C %A Hardy, John %A Naranjo, Maria Candida Deniz %A Bosco, Paolo %A Clarke, Robert %A Brayne, Carol %A Galimberti, Daniela %A Scarpini, Elio %A Bonuccelli, Ubaldo %A Mancuso, Michelangelo %A Siciliano, Gabriele %A Moebus, Susanne %A Mecocci, Patrizia %A Zompo, Maria Del %A Maier, Wolfgang %A Hampel, Harald %A Pilotto, Alberto %A Frank-García, Ana %A Panza, Francesco %A Solfrizzi, Vincenzo %A Caffarra, Paolo %A Nacmias, Benedetta %A Perry, William %A Mayhaus, Manuel %A Lannfelt, Lars %A Hakonarson, Hakon %A Pichler, Sabrina %A Carrasquillo, Minerva M %A Ingelsson, Martin %A Beekly, Duane %A Alvarez, Victoria %A Zou, Fanggeng %A Valladares, Otto %A Younkin, Steven G %A Coto, Eliecer %A Hamilton-Nelson, Kara L %A Gu, Wei %A Razquin, Cristina %A Pastor, Pau %A Mateo, Ignacio %A Owen, Michael J %A Faber, Kelley M %A Jonsson, Palmi V %A Combarros, Onofre %A O'Donovan, Michael C %A Cantwell, Laura B %A Soininen, Hilkka %A Blacker, Deborah %A Mead, Simon %A Mosley, Thomas H %A Bennett, David A %A Harris, Tamara B %A Fratiglioni, Laura %A Holmes, Clive %A de Bruijn, Renee F A G %A Passmore, Peter %A Montine, Thomas J %A Bettens, Karolien %A Rotter, Jerome I %A Brice, Alexis %A Morgan, Kevin %A Foroud, Tatiana M %A Kukull, Walter A %A Hannequin, Didier %A Powell, John F %A Nalls, Michael A %A Ritchie, Karen %A Lunetta, Kathryn L %A Kauwe, John S K %A Boerwinkle, Eric %A Riemenschneider, Matthias %A Boada, Merce %A Hiltunen, Mikko %A Martin, Eden R %A Schmidt, Reinhold %A Rujescu, Dan %A Dartigues, Jean-François %A Mayeux, Richard %A Tzourio, Christophe %A Hofman, Albert %A Nöthen, Markus M %A Graff, Caroline %A Psaty, Bruce M %A Haines, Jonathan L %A Lathrop, Mark %A Pericak-Vance, Margaret A %A Launer, Lenore J %A Van Broeckhoven, Christine %A Farrer, Lindsay A %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Seshadri, Sudha %A Schellenberg, Gerard D %A Amouyel, Philippe %A Williams, Julie %K Alzheimer Disease %K Carrier Proteins %K Case-Control Studies %K Genome-Wide Association Study %K Heat-Shock Proteins %K Humans %K Polymorphism, Single Nucleotide %K Receptors, Antigen, B-Cell %X

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

%B PLoS One %V 9 %P e94661 %8 2014 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/24922517?dopt=Abstract %R 10.1371/journal.pone.0094661 %0 Journal Article %J Neurobiol Aging %D 2015 %T Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. %A Chauhan, Ganesh %A Adams, Hieab H H %A Bis, Joshua C %A Weinstein, Galit %A Yu, Lei %A Töglhofer, Anna Maria %A Smith, Albert Vernon %A van der Lee, Sven J %A Gottesman, Rebecca F %A Thomson, Russell %A Wang, Jing %A Yang, Qiong %A Niessen, Wiro J %A Lopez, Oscar L %A Becker, James T %A Phan, Thanh G %A Beare, Richard J %A Arfanakis, Konstantinos %A Fleischman, Debra %A Vernooij, Meike W %A Mazoyer, Bernard %A Schmidt, Helena %A Srikanth, Velandai %A Knopman, David S %A Jack, Clifford R %A Amouyel, Philippe %A Hofman, Albert %A DeCarli, Charles %A Tzourio, Christophe %A van Duijn, Cornelia M %A Bennett, David A %A Schmidt, Reinhold %A Longstreth, William T %A Mosley, Thomas H %A Fornage, Myriam %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Debette, Stephanie %K Aging %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Brain %K Female %K Genome-Wide Association Study %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Organ Size %K Polymorphism, Single Nucleotide %K Risk %K Sialic Acid Binding Ig-like Lectin 3 %X

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.

%B Neurobiol Aging %V 36 %P 1765.e7-16 %8 2015 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract %R 10.1016/j.neurobiolaging.2014.12.028 %0 Journal Article %J Biol Psychiatry %D 2015 %T Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Debette, Stephanie %A Ibrahim Verbaas, Carla A %A Bressler, Jan %A Schuur, Maaike %A Smith, Albert %A Bis, Joshua C %A Davies, Gail %A Wolf, Christiane %A Gudnason, Vilmundur %A Chibnik, Lori B %A Yang, Qiong %A DeStefano, Anita L %A de Quervain, Dominique J F %A Srikanth, Velandai %A Lahti, Jari %A Grabe, Hans J %A Smith, Jennifer A %A Priebe, Lutz %A Yu, Lei %A Karbalai, Nazanin %A Hayward, Caroline %A Wilson, James F %A Campbell, Harry %A Petrovic, Katja %A Fornage, Myriam %A Chauhan, Ganesh %A Yeo, Robin %A Boxall, Ruth %A Becker, James %A Stegle, Oliver %A Mather, Karen A %A Chouraki, Vincent %A Sun, Qi %A Rose, Lynda M %A Resnick, Susan %A Oldmeadow, Christopher %A Kirin, Mirna %A Wright, Alan F %A Jonsdottir, Maria K %A Au, Rhoda %A Becker, Albert %A Amin, Najaf %A Nalls, Mike A %A Turner, Stephen T %A Kardia, Sharon L R %A Oostra, Ben %A Windham, Gwen %A Coker, Laura H %A Zhao, Wei %A Knopman, David S %A Heiss, Gerardo %A Griswold, Michael E %A Gottesman, Rebecca F %A Vitart, Veronique %A Hastie, Nicholas D %A Zgaga, Lina %A Rudan, Igor %A Polasek, Ozren %A Holliday, Elizabeth G %A Schofield, Peter %A Choi, Seung Hoan %A Tanaka, Toshiko %A An, Yang %A Perry, Rodney T %A Kennedy, Richard E %A Sale, Michèle M %A Wang, Jing %A Wadley, Virginia G %A Liewald, David C %A Ridker, Paul M %A Gow, Alan J %A Pattie, Alison %A Starr, John M %A Porteous, David %A Liu, Xuan %A Thomson, Russell %A Armstrong, Nicola J %A Eiriksdottir, Gudny %A Assareh, Arezoo A %A Kochan, Nicole A %A Widen, Elisabeth %A Palotie, Aarno %A Hsieh, Yi-Chen %A Eriksson, Johan G %A Vogler, Christian %A van Swieten, John C %A Shulman, Joshua M %A Beiser, Alexa %A Rotter, Jerome %A Schmidt, Carsten O %A Hoffmann, Wolfgang %A Nöthen, Markus M %A Ferrucci, Luigi %A Attia, John %A Uitterlinden, André G %A Amouyel, Philippe %A Dartigues, Jean-François %A Amieva, Hélène %A Räikkönen, Katri %A Garcia, Melissa %A Wolf, Philip A %A Hofman, Albert %A Longstreth, W T %A Psaty, Bruce M %A Boerwinkle, Eric %A DeJager, Philip L %A Sachdev, Perminder S %A Schmidt, Reinhold %A Breteler, Monique M B %A Teumer, Alexander %A Lopez, Oscar L %A Cichon, Sven %A Chasman, Daniel I %A Grodstein, Francine %A Müller-Myhsok, Bertram %A Tzourio, Christophe %A Papassotiropoulos, Andreas %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Mosley, Thomas H %K Aged %K Aged, 80 and over %K Aging %K Apolipoproteins E %K Claudin-5 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Proteins %K Proteoglycans %K Regression Analysis %K Sulfotransferases %K Verbal Learning %X

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

%B Biol Psychiatry %V 77 %P 749-63 %8 2015 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract %R 10.1016/j.biopsych.2014.08.027 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2015 %T GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. %A Broer, Linda %A Buchman, Aron S %A Deelen, Joris %A Evans, Daniel S %A Faul, Jessica D %A Lunetta, Kathryn L %A Sebastiani, Paola %A Smith, Jennifer A %A Smith, Albert V %A Tanaka, Toshiko %A Yu, Lei %A Arnold, Alice M %A Aspelund, Thor %A Benjamin, Emelia J %A De Jager, Philip L %A Eirkisdottir, Gudny %A Evans, Denis A %A Garcia, Melissa E %A Hofman, Albert %A Kaplan, Robert C %A Kardia, Sharon L R %A Kiel, Douglas P %A Oostra, Ben A %A Orwoll, Eric S %A Parimi, Neeta %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seshadri, Sudha %A Singleton, Andrew %A Tiemeier, Henning %A Uitterlinden, André G %A Zhao, Wei %A Bandinelli, Stefania %A Bennett, David A %A Ferrucci, Luigi %A Gudnason, Vilmundur %A Harris, Tamara B %A Karasik, David %A Launer, Lenore J %A Perls, Thomas T %A Slagboom, P Eline %A Tranah, Gregory J %A Weir, David R %A Newman, Anne B %A van Duijn, Cornelia M %A Murabito, Joanne M %K Aged %K Aged, 80 and over %K Apolipoproteins E %K Cell Adhesion Molecules %K Cohort Studies %K Female %K Forkhead Box Protein O3 %K Forkhead Transcription Factors %K Genome-Wide Association Study %K Humans %K Longevity %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Receptors, Kainic Acid %X

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.

%B J Gerontol A Biol Sci Med Sci %V 70 %P 110-8 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract %R 10.1093/gerona/glu166 %0 Journal Article %J Hum Mol Genet %D 2016 %T Common variants in DRD2 are associated with sleep duration: the CARe consortium. %A Cade, Brian E %A Gottlieb, Daniel J %A Lauderdale, Diane S %A Bennett, David A %A Buchman, Aron S %A Buxbaum, Sarah G %A De Jager, Philip L %A Evans, Daniel S %A Fulop, Tibor %A Gharib, Sina A %A Johnson, W Craig %A Kim, Hyun %A Larkin, Emma K %A Lee, Seung Ku %A Lim, Andrew S %A Punjabi, Naresh M %A Shin, Chol %A Stone, Katie L %A Tranah, Gregory J %A Weng, Jia %A Yaffe, Kristine %A Zee, Phyllis C %A Patel, Sanjay R %A Zhu, Xiaofeng %A Redline, Susan %A Saxena, Richa %K Cohort Studies %K Ethnic Groups %K Humans %K Polymorphism, Single Nucleotide %K Polysomnography %K Receptors, Dopamine D2 %K Sleep %K Time Factors %X

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.

%B Hum Mol Genet %V 25 %P 167-79 %8 2016 Jan 1 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26464489?dopt=Abstract %R 10.1093/hmg/ddv434 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Céline %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, André G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

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.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749 %0 Journal Article %J Aging Cell %D 2016 %T GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium. %A Matteini, Amy M %A Tanaka, Toshiko %A Karasik, David %A Atzmon, Gil %A Chou, Wen-Chi %A Eicher, John D %A Johnson, Andrew D %A Arnold, Alice M %A Callisaya, Michele L %A Davies, Gail %A Evans, Daniel S %A Holtfreter, Birte %A Lohman, Kurt %A Lunetta, Kathryn L %A Mangino, Massimo %A Smith, Albert V %A Smith, Jennifer A %A Teumer, Alexander %A Yu, Lei %A Arking, Dan E %A Buchman, Aron S %A Chibinik, Lori B %A De Jager, Philip L %A Evans, Denis A %A Faul, Jessica D %A Garcia, Melissa E %A Gillham-Nasenya, Irina %A Gudnason, Vilmundur %A Hofman, Albert %A Hsu, Yi-Hsiang %A Ittermann, Till %A Lahousse, Lies %A Liewald, David C %A Liu, Yongmei %A Lopez, Lorna %A Rivadeneira, Fernando %A Rotter, Jerome I %A Siggeirsdottir, Kristin %A Starr, John M %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Weir, David R %A Yaffe, Kristine %A Zhao, Wei %A Zhuang, Wei Vivian %A Zmuda, Joseph M %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Ferrucci, Luigi %A Harris, Tamara B %A Kardia, Sharon L R %A Kocher, Thomas %A Kritchevsky, Stephen B %A Psaty, Bruce M %A Seshadri, Sudha %A Spector, Timothy D %A Srikanth, Velandai K %A Windham, B Gwen %A Zillikens, M Carola %A Newman, Anne B %A Walston, Jeremy D %A Kiel, Douglas P %A Murabito, Joanne M %X

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.

%B Aging Cell %V 15 %P 792-800 %8 2016 Oct %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/27325353?dopt=Abstract %R 10.1111/acel.12468 %0 Journal Article %J Psychosom Med %D 2017 %T Bivariate Genome-Wide Association Study of Depressive Symptoms with Type 2 Diabetes and Quantitative Glycemic Traits. %A Haljas, Kadri %A Amare, Azmeraw T %A Alizadeh, Behrooz Z %A Hsu, Yi-Hsiang %A Mosley, Thomas %A Newman, Anne %A Murabito, Joanne %A Tiemeier, Henning %A Tanaka, Toshiko %A van Duijn, Cornelia %A Ding, Jingzhong %A Llewellyn, David J %A Bennett, David A %A Terracciano, Antonio %A Launer, Lenore %A Ladwig, Karl-Heinz %A Cornelis, Marylin C %A Teumer, Alexander %A Grabe, Hans %A Kardia, Sharon L R %A Ware, Erin B %A Smith, Jennifer A %A Snieder, Harold %A Eriksson, Johan G %A Groop, Leif %A Räikkönen, Katri %A Lahti, Jari %X

OBJECTIVE: Shared genetic background may explain phenotypic associations between depression and Type-2-Diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits.

METHODS: We estimated SNP-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the LD Score Regression (LDSC) by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by Diagram consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, HOMA-β, and HOMA-IR by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate GWAS approach with summary statistics from GWAS meta-analyses and reported loci with genome-wide significant bivariate association p-value (p < 5x10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases.

RESULTS: The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the LDSC analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). Yet, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes).

CONCLUSIONS: We found no significant overall genetic correlations between depressive symptoms, T2D or glycemic traits suggesting major differences in underlying biology of these traits. Yet, several potential pleiotropic loci were identified between depressive symptoms, T2D and fasting glucose suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.

%B Psychosom Med %8 2017 Dec 27 %G eng %R 10.1097/PSY.0000000000000555 %0 Journal Article %J Aging (Albany NY) %D 2017 %T The complex genetics of gait speed: genome-wide meta-analysis approach. %A Ben-Avraham, Dan %A Karasik, David %A Verghese, Joe %A Lunetta, Kathryn L %A Smith, Jennifer A %A Eicher, John D %A Vered, Rotem %A Deelen, Joris %A Arnold, Alice M %A Buchman, Aron S %A Tanaka, Toshiko %A Faul, Jessica D %A Nethander, Maria %A Fornage, Myriam %A Adams, Hieab H %A Matteini, Amy M %A Callisaya, Michele L %A Smith, Albert V %A Yu, Lei %A De Jager, Philip L %A Evans, Denis A %A Gudnason, Vilmundur %A Hofman, Albert %A Pattie, Alison %A Corley, Janie %A Launer, Lenore J %A Knopman, Davis S %A Parimi, Neeta %A Turner, Stephen T %A Bandinelli, Stefania %A Beekman, Marian %A Gutman, Danielle %A Sharvit, Lital %A Mooijaart, Simon P %A Liewald, David C %A Houwing-Duistermaat, Jeanine J %A Ohlsson, Claes %A Moed, Matthijs %A Verlinden, Vincent J %A Mellström, Dan %A van der Geest, Jos N %A Karlsson, Magnus %A Hernandez, Dena %A McWhirter, Rebekah %A Liu, Yongmei %A Thomson, Russell %A Tranah, Gregory J %A Uitterlinden, André G %A Weir, David R %A Zhao, Wei %A Starr, John M %A Johnson, Andrew D %A Ikram, M Arfan %A Bennett, David A %A Cummings, Steven R %A Deary, Ian J %A Harris, Tamara B %A Kardia, Sharon L R %A Mosley, Thomas H %A Srikanth, Velandai K %A Windham, Beverly G %A Newman, Ann B %A Walston, Jeremy D %A Davies, Gail %A Evans, Daniel S %A Slagboom, Eline P %A Ferrucci, Luigi %A Kiel, Douglas P %A Murabito, Joanne M %A Atzmon, Gil %X

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

%B Aging (Albany NY) %V 9 %P 209-246 %8 2017 Jan 10 %G eng %N 1 %R 10.18632/aging.101151 %0 Journal Article %J Nat Commun %D 2017 %T Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. %A Zillikens, M Carola %A Demissie, Serkalem %A Hsu, Yi-Hsiang %A Yerges-Armstrong, Laura M %A Chou, Wen-Chi %A Stolk, Lisette %A Livshits, Gregory %A Broer, Linda %A Johnson, Toby %A Koller, Daniel L %A Kutalik, Zoltán %A Luan, Jian'an %A Malkin, Ida %A Ried, Janina S %A Smith, Albert V %A Thorleifsson, Gudmar %A Vandenput, Liesbeth %A Hua Zhao, Jing %A Zhang, Weihua %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Baier, Leslie J %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Biffar, Rainer %A Bochud, Murielle %A Boehnke, Michael %A Borecki, Ingrid B %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos Obanda, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Cederberg, Henna %A Chen, Zhao %A Cho, Nam H %A Jin Choi, Hyung %A Claussnitzer, Melina %A Collins, Francis %A Cummings, Steven R %A De Jager, Philip L %A Demuth, Ilja %A Dhonukshe-Rutten, Rosalie A M %A Diatchenko, Luda %A Eiriksdottir, Gudny %A Enneman, Anke W %A Erdos, Mike %A Eriksson, Johan G %A Eriksson, Joel %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Garcia, Melissa %A Gieger, Christian %A Girke, Thomas %A Glazer, Nicole L %A Grallert, Harald %A Grewal, Jagvir %A Han, Bok-Ghee %A Hanson, Robert L %A Hayward, Caroline %A Hofman, Albert %A Hoffman, Eric P %A Homuth, Georg %A Hsueh, Wen-Chi %A Hubal, Monica J %A Hubbard, Alan %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koistinen, Heikki A %A Kraus, William E %A Kritchevsky, Stephen %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Launer, Lenore J %A Lee, Jong-Young %A Lerch, Markus M %A Lewis, Joshua R %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Liu, Tian %A Liu, Youfang %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A Maixner, William %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Melov, Simon %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Newman, Anne %A Nielson, Carrie M %A O'Connell, Jeffrey R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Parker, Stephen C J %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Prince, Richard L %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schadt, Eric E %A Schipf, Sabine %A Scott, Laura %A Sehmi, Joban %A Shen, Jian %A Soo Shin, Chan %A Sigurdsson, Gunnar %A Smith, Shad %A Soranzo, Nicole %A Stančáková, Alena %A Steinhagen-Thiessen, Elisabeth %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Tan, Sian-Tsung %A Tarnopolsky, Mark A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Tuomilehto, Jaakko %A van Schoor, Natasja M %A Verma, Arjun %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A Weedon, Michael N %A Welch, Ryan %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Xie, Weijia %A Yu, Lei %A Zhou, Yanhua %A Chambers, John C %A Döring, Angela %A van Duijn, Cornelia M %A Econs, Michael J %A Gudnason, Vilmundur %A Kooner, Jaspal S %A Psaty, Bruce M %A Spector, Timothy D %A Stefansson, Kari %A Rivadeneira, Fernando %A Uitterlinden, André G %A Wareham, Nicholas J %A Ossowski, Vicky %A Waterworth, Dawn %A Loos, Ruth J F %A Karasik, David %A Harris, Tamara B %A Ohlsson, Claes %A Kiel, Douglas P %X

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

%B Nat Commun %V 8 %P 80 %8 2017 Jul 19 %G eng %N 1 %R 10.1038/s41467-017-00031-7 %0 Journal Article %J Nat Genet %D 2017 %T Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. %A Sims, Rebecca %A van der Lee, Sven J %A Naj, Adam C %A Bellenguez, Céline %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Kunkle, Brian W %A Boland, Anne %A Raybould, Rachel %A Bis, Joshua C %A Martin, Eden R %A Grenier-Boley, Benjamin %A Heilmann-Heimbach, Stefanie %A Chouraki, Vincent %A Kuzma, Amanda B %A Sleegers, Kristel %A Vronskaya, Maria %A Ruiz, Agustin %A Graham, Robert R %A Olaso, Robert %A Hoffmann, Per %A Grove, Megan L %A Vardarajan, Badri N %A Hiltunen, Mikko %A Nöthen, Markus M %A White, Charles C %A Hamilton-Nelson, Kara L %A Epelbaum, Jacques %A Maier, Wolfgang %A Choi, Seung-Hoan %A Beecham, Gary W %A Dulary, Cécile %A Herms, Stefan %A Smith, Albert V %A Funk, Cory C %A Derbois, Céline %A Forstner, Andreas J %A Ahmad, Shahzad %A Li, Hongdong %A Bacq, Delphine %A Harold, Denise %A Satizabal, Claudia L %A Valladares, Otto %A Squassina, Alessio %A Thomas, Rhodri %A Brody, Jennifer A %A Qu, Liming %A Sánchez-Juan, Pascual %A Morgan, Taniesha %A Wolters, Frank J %A Zhao, Yi %A Garcia, Florentino Sanchez %A Denning, Nicola %A Fornage, Myriam %A Malamon, John %A Naranjo, Maria Candida Deniz %A Majounie, Elisa %A Mosley, Thomas H %A Dombroski, Beth %A Wallon, David %A Lupton, Michelle K %A Dupuis, Josée %A Whitehead, Patrice %A Fratiglioni, Laura %A Medway, Christopher %A Jian, Xueqiu %A Mukherjee, Shubhabrata %A Keller, Lina %A Brown, Kristelle %A Lin, Honghuang %A Cantwell, Laura B %A Panza, Francesco %A McGuinness, Bernadette %A Moreno-Grau, Sonia %A Burgess, Jeremy D %A Solfrizzi, Vincenzo %A Proitsi, Petra %A Adams, Hieab H %A Allen, Mariet %A Seripa, Davide %A Pastor, Pau %A Cupples, L Adrienne %A Price, Nathan D %A Hannequin, Didier %A Frank-García, Ana %A Levy, Daniel %A Chakrabarty, Paramita %A Caffarra, Paolo %A Giegling, Ina %A Beiser, Alexa S %A Giedraitis, Vilmantas %A Hampel, Harald %A Garcia, Melissa E %A Wang, Xue %A Lannfelt, Lars %A Mecocci, Patrizia %A Eiriksdottir, Gudny %A Crane, Paul K %A Pasquier, Florence %A Boccardi, Virginia %A Henández, Isabel %A Barber, Robert C %A Scherer, Martin %A Tarraga, Lluis %A Adams, Perrie M %A Leber, Markus %A Chen, Yuning %A Albert, Marilyn S %A Riedel-Heller, Steffi %A Emilsson, Valur %A Beekly, Duane %A Braae, Anne %A Schmidt, Reinhold %A Blacker, Deborah %A Masullo, Carlo %A Schmidt, Helena %A Doody, Rachelle S %A Spalletta, Gianfranco %A Jr, W T Longstreth %A Fairchild, Thomas J %A Bossù, Paola %A Lopez, Oscar L %A Frosch, Matthew P %A Sacchinelli, Eleonora %A Ghetti, Bernardino %A Yang, Qiong %A Huebinger, Ryan M %A Jessen, Frank %A Li, Shuo %A Kamboh, M Ilyas %A Morris, John %A Sotolongo-Grau, Oscar %A Katz, Mindy J %A Corcoran, Chris %A Dunstan, Melanie %A Braddel, Amy %A Thomas, Charlene %A Meggy, Alun %A Marshall, Rachel %A Gerrish, Amy %A Chapman, Jade %A Aguilar, Miquel %A Taylor, Sarah %A Hill, Matt %A Fairén, Mònica Díez %A Hodges, Angela %A Vellas, Bruno %A Soininen, Hilkka %A Kloszewska, Iwona %A Daniilidou, Makrina %A Uphill, James %A Patel, Yogen %A Hughes, Joseph T %A Lord, Jenny %A Turton, James %A Hartmann, Annette M %A Cecchetti, Roberta %A Fenoglio, Chiara %A Serpente, Maria %A Arcaro, Marina %A Caltagirone, Carlo %A Orfei, Maria Donata %A Ciaramella, Antonio %A Pichler, Sabrina %A Mayhaus, Manuel %A Gu, Wei %A Lleo, Alberto %A Fortea, Juan %A Blesa, Rafael %A Barber, Imelda S %A Brookes, Keeley %A Cupidi, Chiara %A Maletta, Raffaele Giovanni %A Carrell, David %A Sorbi, Sandro %A Moebus, Susanne %A Urbano, Maria %A Pilotto, Alberto %A Kornhuber, Johannes %A Bosco, Paolo %A Todd, Stephen %A Craig, David %A Johnston, Janet %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Fox, Nick C %A Hardy, John %A Albin, Roger L %A Apostolova, Liana G %A Arnold, Steven E %A Asthana, Sanjay %A Atwood, Craig S %A Baldwin, Clinton T %A Barnes, Lisa L %A Barral, Sandra %A Beach, Thomas G %A Becker, James T %A Bigio, Eileen H %A Bird, Thomas D %A Boeve, Bradley F %A Bowen, James D %A Boxer, Adam %A Burke, James R %A Burns, Jeffrey M %A Buxbaum, Joseph D %A Cairns, Nigel J %A Cao, Chuanhai %A Carlson, Chris S %A Carlsson, Cynthia M %A Carney, Regina M %A Carrasquillo, Minerva M %A Carroll, Steven L %A Diaz, Carolina Ceballos %A Chui, Helena C %A Clark, David G %A Cribbs, David H %A Crocco, Elizabeth A %A DeCarli, Charles %A Dick, Malcolm %A Duara, Ranjan %A Evans, Denis A %A Faber, Kelley M %A Fallon, Kenneth B %A Fardo, David W %A Farlow, Martin R %A Ferris, Steven %A Foroud, Tatiana M %A Galasko, Douglas R %A Gearing, Marla %A Geschwind, Daniel H %A Gilbert, John R %A Graff-Radford, Neill R %A Green, Robert C %A Growdon, John H %A Hamilton, Ronald L %A Harrell, Lindy E %A Honig, Lawrence S %A Huentelman, Matthew J %A Hulette, Christine M %A Hyman, Bradley T %A Jarvik, Gail P %A Abner, Erin %A Jin, Lee-Way %A Jun, Gyungah %A Karydas, Anna %A Kaye, Jeffrey A %A Kim, Ronald %A Kowall, Neil W %A Kramer, Joel H %A LaFerla, Frank M %A Lah, James J %A Leverenz, James B %A Levey, Allan I %A Li, Ge %A Lieberman, Andrew P %A Lunetta, Kathryn L %A Lyketsos, Constantine G %A Marson, Daniel C %A Martiniuk, Frank %A Mash, Deborah C %A Masliah, Eliezer %A McCormick, Wayne C %A McCurry, Susan M %A McDavid, Andrew N %A McKee, Ann C %A Mesulam, Marsel %A Miller, Bruce L %A Miller, Carol A %A Miller, Joshua W %A Morris, John C %A Murrell, Jill R %A Myers, Amanda J %A O'Bryant, Sid %A Olichney, John M %A Pankratz, Vernon S %A Parisi, Joseph E %A Paulson, Henry L %A Perry, William %A Peskind, Elaine %A Pierce, Aimee %A Poon, Wayne W %A Potter, Huntington %A Quinn, Joseph F %A Raj, Ashok %A Raskind, Murray %A Reisberg, Barry %A Reitz, Christiane %A Ringman, John M %A Roberson, Erik D %A Rogaeva, Ekaterina %A Rosen, Howard J %A Rosenberg, Roger N %A Sager, Mark A %A Saykin, Andrew J %A Schneider, Julie A %A Schneider, Lon S %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tanzi, Rudolph E %A Thornton-Wells, Tricia A %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Garzia, Fabienne %A Golamaully, Feroze %A Septier, Gislain %A Engelborghs, Sebastien %A Vandenberghe, Rik %A De Deyn, Peter P %A Fernadez, Carmen Muñoz %A Benito, Yoland Aladro %A Thonberg, Håkan %A Forsell, Charlotte %A Lilius, Lena %A Kinhult-Ståhlbom, Anne %A Kilander, Lena %A Brundin, RoseMarie %A Concari, Letizia %A Helisalmi, Seppo %A Koivisto, Anne Maria %A Haapasalo, Annakaisa %A Dermecourt, Vincent %A Fiévet, Nathalie %A Hanon, Olivier %A Dufouil, Carole %A Brice, Alexis %A Ritchie, Karen %A Dubois, Bruno %A Himali, Jayanadra J %A Keene, C Dirk %A Tschanz, JoAnn %A Fitzpatrick, Annette L %A Kukull, Walter A %A Norton, Maria %A Aspelund, Thor %A Larson, Eric B %A Munger, Ron %A Rotter, Jerome I %A Lipton, Richard B %A Bullido, María J %A Hofman, Albert %A Montine, Thomas J %A Coto, Eliecer %A Boerwinkle, Eric %A Petersen, Ronald C %A Alvarez, Victoria %A Rivadeneira, Fernando %A Reiman, Eric M %A Gallo, Maura %A O'Donnell, Christopher J %A Reisch, Joan S %A Bruni, Amalia Cecilia %A Royall, Donald R %A Dichgans, Martin %A Sano, Mary %A Galimberti, Daniela %A St George-Hyslop, Peter %A Scarpini, Elio %A Tsuang, Debby W %A Mancuso, Michelangelo %A Bonuccelli, Ubaldo %A Winslow, Ashley R %A Daniele, Antonio %A Wu, Chuang-Kuo %A Peters, Oliver %A Nacmias, Benedetta %A Riemenschneider, Matthias %A Heun, Reinhard %A Brayne, Carol %A Rubinsztein, David C %A Bras, Jose %A Guerreiro, Rita %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Collinge, John %A Mann, David %A Tsolaki, Magda %A Clarimon, Jordi %A Sussams, Rebecca %A Lovestone, Simon %A O'Donovan, Michael C %A Owen, Michael J %A Behrens, Timothy W %A Mead, Simon %A Goate, Alison M %A Uitterlinden, André G %A Holmes, Clive %A Cruchaga, Carlos %A Ingelsson, Martin %A Bennett, David A %A Powell, John %A Golde, Todd E %A Graff, Caroline %A De Jager, Philip L %A Morgan, Kevin %A Ertekin-Taner, Nilufer %A Combarros, Onofre %A Psaty, Bruce M %A Passmore, Peter %A Younkin, Steven G %A Berr, Claudine %A Gudnason, Vilmundur %A Rujescu, Dan %A Dickson, Dennis W %A Dartigues, Jean-François %A DeStefano, Anita L %A Ortega-Cubero, Sara %A Hakonarson, Hakon %A Campion, Dominique %A Boada, Merce %A Kauwe, John Keoni %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A Ikram, M Arfan %A Jones, Lesley %A Haines, Jonathan L %A Tzourio, Christophe %A Launer, Lenore J %A Escott-Price, Valentina %A Mayeux, Richard %A Deleuze, Jean-Francois %A Amin, Najaf %A Holmans, Peter A %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Wang, Li-San %A Lambert, Jean-Charles %A Seshadri, Sudha %A Williams, Julie %A Schellenberg, Gerard D %K Adaptor Proteins, Signal Transducing %K Alzheimer Disease %K Amino Acid Sequence %K Case-Control Studies %K Exome %K Gene Expression Profiling %K Gene Frequency %K Genetic Predisposition to Disease %K Genotype %K Humans %K Immunity, Innate %K Linkage Disequilibrium %K Membrane Glycoproteins %K Microglia %K Odds Ratio %K Phospholipase C gamma %K Polymorphism, Single Nucleotide %K Protein Interaction Maps %K Receptors, Immunologic %K Sequence Homology, Amino Acid %X

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.

%B Nat Genet %V 49 %P 1373-1384 %8 2017 Sep %G eng %N 9 %R 10.1038/ng.3916 %0 Journal Article %J Nat Commun %D 2018 %T Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. %A Vojinovic, Dina %A Adams, Hieab H %A Jian, Xueqiu %A Yang, Qiong %A Smith, Albert Vernon %A Bis, Joshua C %A Teumer, Alexander %A Scholz, Markus %A Armstrong, Nicola J %A Hofer, Edith %A Saba, Yasaman %A Luciano, Michelle %A Bernard, Manon %A Trompet, Stella %A Yang, Jingyun %A Gillespie, Nathan A %A van der Lee, Sven J %A Neumann, Alexander %A Ahmad, Shahzad %A Andreassen, Ole A %A Ames, David %A Amin, Najaf %A Arfanakis, Konstantinos %A Bastin, Mark E %A Becker, Diane M %A Beiser, Alexa S %A Beyer, Frauke %A Brodaty, Henry %A Bryan, R Nick %A Bülow, Robin %A Dale, Anders M %A De Jager, Philip L %A Deary, Ian J %A DeCarli, Charles %A Fleischman, Debra A %A Gottesman, Rebecca F %A van der Grond, Jeroen %A Gudnason, Vilmundur %A Harris, Tamara B %A Homuth, Georg %A Knopman, David S %A Kwok, John B %A Lewis, Cora E %A Li, Shuo %A Loeffler, Markus %A Lopez, Oscar L %A Maillard, Pauline %A El Marroun, Hanan %A Mather, Karen A %A Mosley, Thomas H %A Muetzel, Ryan L %A Nauck, Matthias %A Nyquist, Paul A %A Panizzon, Matthew S %A Pausova, Zdenka %A Psaty, Bruce M %A Rice, Ken %A Rotter, Jerome I %A Royle, Natalie %A Satizabal, Claudia L %A Schmidt, Reinhold %A Schofield, Peter R %A Schreiner, Pamela J %A Sidney, Stephen %A Stott, David J %A Thalamuthu, Anbupalam %A Uitterlinden, André G %A Valdés Hernández, Maria C %A Vernooij, Meike W %A Wen, Wei %A White, Tonya %A Witte, A Veronica %A Wittfeld, Katharina %A Wright, Margaret J %A Yanek, Lisa R %A Tiemeier, Henning %A Kremen, William S %A Bennett, David A %A Jukema, J Wouter %A Paus, Tomáš %A Wardlaw, Joanna M %A Schmidt, Helena %A Sachdev, Perminder S %A Villringer, Arno %A Grabe, Hans Jörgen %A Longstreth, W T %A van Duijn, Cornelia M %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Fornage, Myriam %X

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.

%B Nat Commun %V 9 %P 3945 %8 2018 Sep 26 %G eng %N 1 %R 10.1038/s41467-018-06234-w %0 Journal Article %J Nat Commun %D 2018 %T Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. %A Davies, Gail %A Lam, Max %A Harris, Sarah E %A Trampush, Joey W %A Luciano, Michelle %A Hill, W David %A Hagenaars, Saskia P %A Ritchie, Stuart J %A Marioni, Riccardo E %A Fawns-Ritchie, Chloe %A Liewald, David C M %A Okely, Judith A %A Ahola-Olli, Ari V %A Barnes, Catriona L K %A Bertram, Lars %A Bis, Joshua C %A Burdick, Katherine E %A Christoforou, Andrea %A DeRosse, Pamela %A Djurovic, Srdjan %A Espeseth, Thomas %A Giakoumaki, Stella %A Giddaluru, Sudheer %A Gustavson, Daniel E %A Hayward, Caroline %A Hofer, Edith %A Ikram, M Arfan %A Karlsson, Robert %A Knowles, Emma %A Lahti, Jari %A Leber, Markus %A Li, Shuo %A Mather, Karen A %A Melle, Ingrid %A Morris, Derek %A Oldmeadow, Christopher %A Palviainen, Teemu %A Payton, Antony %A Pazoki, Raha %A Petrovic, Katja %A Reynolds, Chandra A %A Sargurupremraj, Muralidharan %A Scholz, Markus %A Smith, Jennifer A %A Smith, Albert V %A Terzikhan, Natalie %A Thalamuthu, Anbupalam %A Trompet, Stella %A van der Lee, Sven J %A Ware, Erin B %A Windham, B Gwen %A Wright, Margaret J %A Yang, Jingyun %A Yu, Jin %A Ames, David %A Amin, Najaf %A Amouyel, Philippe %A Andreassen, Ole A %A Armstrong, Nicola J %A Assareh, Amelia A %A Attia, John R %A Attix, Deborah %A Avramopoulos, Dimitrios %A Bennett, David A %A Böhmer, Anne C %A Boyle, Patricia A %A Brodaty, Henry %A Campbell, Harry %A Cannon, Tyrone D %A Cirulli, Elizabeth T %A Congdon, Eliza %A Conley, Emily Drabant %A Corley, Janie %A Cox, Simon R %A Dale, Anders M %A Dehghan, Abbas %A Dick, Danielle %A Dickinson, Dwight %A Eriksson, Johan G %A Evangelou, Evangelos %A Faul, Jessica D %A Ford, Ian %A Freimer, Nelson A %A Gao, He %A Giegling, Ina %A Gillespie, Nathan A %A Gordon, Scott D %A Gottesman, Rebecca F %A Griswold, Michael E %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartmann, Annette M %A Hatzimanolis, Alex %A Heiss, Gerardo %A Holliday, Elizabeth G %A Joshi, Peter K %A Kähönen, Mika %A Kardia, Sharon L R %A Karlsson, Ida %A Kleineidam, Luca %A Knopman, David S %A Kochan, Nicole A %A Konte, Bettina %A Kwok, John B %A Le Hellard, Stephanie %A Lee, Teresa %A Lehtimäki, Terho %A Li, Shu-Chen %A Liu, Tian %A Koini, Marisa %A London, Edythe %A Longstreth, Will T %A Lopez, Oscar L %A Loukola, Anu %A Luck, Tobias %A Lundervold, Astri J %A Lundquist, Anders %A Lyytikäinen, Leo-Pekka %A Martin, Nicholas G %A Montgomery, Grant W %A Murray, Alison D %A Need, Anna C %A Noordam, Raymond %A Nyberg, Lars %A Ollier, William %A Papenberg, Goran %A Pattie, Alison %A Polasek, Ozren %A Poldrack, Russell A %A Psaty, Bruce M %A Reppermund, Simone %A Riedel-Heller, Steffi G %A Rose, Richard J %A Rotter, Jerome I %A Roussos, Panos %A Rovio, Suvi P %A Saba, Yasaman %A Sabb, Fred W %A Sachdev, Perminder S %A Satizabal, Claudia L %A Schmid, Matthias %A Scott, Rodney J %A Scult, Matthew A %A Simino, Jeannette %A Slagboom, P Eline %A Smyrnis, Nikolaos %A Soumaré, Aïcha %A Stefanis, Nikos C %A Stott, David J %A Straub, Richard E %A Sundet, Kjetil %A Taylor, Adele M %A Taylor, Kent D %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, Andre %A Vitart, Veronique %A Voineskos, Aristotle N %A Kaprio, Jaakko %A Wagner, Michael %A Wagner, Holger %A Weinhold, Leonie %A Wen, K Hoyan %A Widen, Elisabeth %A Yang, Qiong %A Zhao, Wei %A Adams, Hieab H H %A Arking, Dan E %A Bilder, Robert M %A Bitsios, Panos %A Boerwinkle, Eric %A Chiba-Falek, Ornit %A Corvin, Aiden %A De Jager, Philip L %A Debette, Stephanie %A Donohoe, Gary %A Elliott, Paul %A Fitzpatrick, Annette L %A Gill, Michael %A Glahn, David C %A Hägg, Sara %A Hansell, Narelle K %A Hariri, Ahmad R %A Ikram, M Kamran %A Jukema, J Wouter %A Vuoksimaa, Eero %A Keller, Matthew C %A Kremen, William S %A Launer, Lenore %A Lindenberger, Ulman %A Palotie, Aarno %A Pedersen, Nancy L %A Pendleton, Neil %A Porteous, David J %A Räikkönen, Katri %A Raitakari, Olli T %A Ramirez, Alfredo %A Reinvang, Ivar %A Rudan, Igor %A Schmidt, Reinhold %A Schmidt, Helena %A Schofield, Peter W %A Schofield, Peter R %A Starr, John M %A Steen, Vidar M %A Trollor, Julian N %A Turner, Steven T %A van Duijn, Cornelia M %A Villringer, Arno %A Weinberger, Daniel R %A Weir, David R %A Wilson, James F %A Malhotra, Anil %A McIntosh, Andrew M %A Gale, Catharine R %A Seshadri, Sudha %A Mosley, Thomas H %A Bressler, Jan %A Lencz, Todd %A Deary, Ian J %X

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.

%B Nat Commun %V 9 %P 2098 %8 2018 May 29 %G eng %N 1 %R 10.1038/s41467-018-04362-x %0 Journal Article %J Nat Commun %D 2019 %T Associations of autozygosity with a broad range of human phenotypes. %A Clark, David W %A Okada, Yukinori %A Moore, Kristjan H S %A Mason, Dan %A Pirastu, Nicola %A Gandin, Ilaria %A Mattsson, Hannele %A Barnes, Catriona L K %A Lin, Kuang %A Zhao, Jing Hua %A Deelen, Patrick %A Rohde, Rebecca %A Schurmann, Claudia %A Guo, Xiuqing %A Giulianini, Franco %A Zhang, Weihua %A Medina-Gómez, Carolina %A Karlsson, Robert %A Bao, Yanchun %A Bartz, Traci M %A Baumbach, Clemens %A Biino, Ginevra %A Bixley, Matthew J %A Brumat, Marco %A Chai, Jin-Fang %A Corre, Tanguy %A Cousminer, Diana L %A Dekker, Annelot M %A Eccles, David A %A van Eijk, Kristel R %A Fuchsberger, Christian %A Gao, He %A Germain, Marine %A Gordon, Scott D %A de Haan, Hugoline G %A Harris, Sarah E %A Hofer, Edith %A Huerta-Chagoya, Alicia %A Igartua, Catherine %A Jansen, Iris E %A Jia, Yucheng %A Kacprowski, Tim %A Karlsson, Torgny %A Kleber, Marcus E %A Li, Shengchao Alfred %A Li-Gao, Ruifang %A Mahajan, Anubha %A Matsuda, Koichi %A Meidtner, Karina %A Meng, Weihua %A Montasser, May E %A van der Most, Peter J %A Munz, Matthias %A Nutile, Teresa %A Palviainen, Teemu %A Prasad, Gauri %A Prasad, Rashmi B %A Priyanka, Tallapragada Divya Sri %A Rizzi, Federica %A Salvi, Erika %A Sapkota, Bishwa R %A Shriner, Daniel %A Skotte, Line %A Smart, Melissa C %A Smith, Albert Vernon %A van der Spek, Ashley %A Spracklen, Cassandra N %A Strawbridge, Rona J %A Tajuddin, Salman M %A Trompet, Stella %A Turman, Constance %A Verweij, Niek %A Viberti, Clara %A Wang, Lihua %A Warren, Helen R %A Wootton, Robyn E %A Yanek, Lisa R %A Yao, Jie %A Yousri, Noha A %A Zhao, Wei %A Adeyemo, Adebowale A %A Afaq, Saima %A Aguilar-Salinas, Carlos Alberto %A Akiyama, Masato %A Albert, Matthew L %A Allison, Matthew A %A Alver, Maris %A Aung, Tin %A Azizi, Fereidoun %A Bentley, Amy R %A Boeing, Heiner %A Boerwinkle, Eric %A Borja, Judith B %A de Borst, Gert J %A Bottinger, Erwin P %A Broer, Linda %A Campbell, Harry %A Chanock, Stephen %A Chee, Miao-Li %A Chen, Guanjie %A Chen, Yii-der I %A Chen, Zhengming %A Chiu, Yen-Feng %A Cocca, Massimiliano %A Collins, Francis S %A Concas, Maria Pina %A Corley, Janie %A Cugliari, Giovanni %A van Dam, Rob M %A Damulina, Anna %A Daneshpour, Maryam S %A Day, Felix R %A Delgado, Graciela E %A Dhana, Klodian %A Doney, Alexander S F %A Dörr, Marcus %A Doumatey, Ayo P %A Dzimiri, Nduna %A Ebenesersdóttir, S Sunna %A Elliott, Joshua %A Elliott, Paul %A Ewert, Ralf %A Felix, Janine F %A Fischer, Krista %A Freedman, Barry I %A Girotto, Giorgia %A Goel, Anuj %A Gögele, Martin %A Goodarzi, Mark O %A Graff, Mariaelisa %A Granot-Hershkovitz, Einat %A Grodstein, Francine %A Guarrera, Simonetta %A Gudbjartsson, Daniel F %A Guity, Kamran %A Gunnarsson, Bjarni %A Guo, Yu %A Hagenaars, Saskia P %A Haiman, Christopher A %A Halevy, Avner %A Harris, Tamara B %A Hedayati, Mehdi %A van Heel, David A %A Hirata, Makoto %A Höfer, Imo %A Hsiung, Chao Agnes %A Huang, Jinyan %A Hung, Yi-Jen %A Ikram, M Arfan %A Jagadeesan, Anuradha %A Jousilahti, Pekka %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerrison, Nicola D %A Kessler, Thorsten %A Khaw, Kay-Tee %A Khor, Chiea Chuen %A de Kleijn, Dominique P V %A Koh, Woon-Puay %A Kolcic, Ivana %A Kraft, Peter %A Krämer, Bernhard K %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lawlor, Deborah A %A Lee, I-Te %A Lee, Wen-Jane %A Lerch, Markus M %A Li, Liming %A Liu, Jianjun %A Loh, Marie %A London, Stephanie J %A Loomis, Stephanie %A Lu, Yingchang %A Luan, Jian'an %A Mägi, Reedik %A Manichaikul, Ani W %A Manunta, Paolo %A Másson, Gísli %A Matoba, Nana %A Mei, Xue W %A Meisinger, Christa %A Meitinger, Thomas %A Mezzavilla, Massimo %A Milani, Lili %A Millwood, Iona Y %A Momozawa, Yukihide %A Moore, Amy %A Morange, Pierre-Emmanuel %A Moreno-Macias, Hortensia %A Mori, Trevor A %A Morrison, Alanna C %A Muka, Taulant %A Murakami, Yoshinori %A Murray, Alison D %A de Mutsert, Renée %A Mychaleckyj, Josyf C %A Nalls, Mike A %A Nauck, Matthias %A Neville, Matt J %A Nolte, Ilja M %A Ong, Ken K %A Orozco, Lorena %A Padmanabhan, Sandosh %A Pálsson, Gunnar %A Pankow, James S %A Pattaro, Cristian %A Pattie, Alison %A Polasek, Ozren %A Poulter, Neil %A Pramstaller, Peter P %A Quintana-Murci, Lluis %A Räikkönen, Katri %A Ralhan, Sarju %A Rao, Dabeeru C %A van Rheenen, Wouter %A Rich, Stephen S %A Ridker, Paul M %A Rietveld, Cornelius A %A Robino, Antonietta %A van Rooij, Frank J A %A Ruggiero, Daniela %A Saba, Yasaman %A Sabanayagam, Charumathi %A Sabater-Lleal, Maria %A Sala, Cinzia Felicita %A Salomaa, Veikko %A Sandow, Kevin %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sedaghati-Khayat, Bahareh %A Sennblad, Bengt %A van Setten, Jessica %A Sever, Peter J %A Sheu, Wayne H-H %A Shi, Yuan %A Shrestha, Smeeta %A Shukla, Sharvari Rahul %A Sigurdsson, Jon K %A Sikka, Timo Tonis %A Singh, Jai Rup %A Smith, Blair H %A Stančáková, Alena %A Stanton, Alice %A Starr, John M %A Stefansdottir, Lilja %A Straker, Leon %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Swertz, Morris A %A Taylor, Adele M %A Taylor, Kent D %A Terzikhan, Natalie %A Tham, Yih-Chung %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tillander, Annika %A Tracy, Russell P %A Tusié-Luna, Teresa %A Tzoulaki, Ioanna %A Vaccargiu, Simona %A Vangipurapu, Jagadish %A Veldink, Jan H %A Vitart, Veronique %A Völker, Uwe %A Vuoksimaa, Eero %A Wakil, Salma M %A Waldenberger, Melanie %A Wander, Gurpreet S %A Wang, Ya Xing %A Wareham, Nicholas J %A Wild, Sarah %A Yajnik, Chittaranjan S %A Yuan, Jian-Min %A Zeng, Lingyao %A Zhang, Liang %A Zhou, Jie %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Becker, Diane M %A Lehne, Benjamin %A Bennett, David A %A van den Berg, Leonard H %A Berndt, Sonja I %A Bharadwaj, Dwaipayan %A Bielak, Lawrence F %A Bochud, Murielle %A Boehnke, Mike %A Bouchard, Claude %A Bradfield, Jonathan P %A Brody, Jennifer A %A Campbell, Archie %A Carmi, Shai %A Caulfield, Mark J %A Cesarini, David %A Chambers, John C %A Chandak, Giriraj Ratan %A Cheng, Ching-Yu %A Ciullo, Marina %A Cornelis, Marilyn %A Cusi, Daniele %A Smith, George Davey %A Deary, Ian J %A Dorajoo, Rajkumar %A van Duijn, Cornelia M %A Ellinghaus, David %A Erdmann, Jeanette %A Eriksson, Johan G %A Evangelou, Evangelos %A Evans, Michele K %A Faul, Jessica D %A Feenstra, Bjarke %A Feitosa, Mary %A Foisy, Sylvain %A Franke, Andre %A Friedlander, Yechiel %A Gasparini, Paolo %A Gieger, Christian %A Gonzalez, Clicerio %A Goyette, Philippe %A Grant, Struan F A %A Griffiths, Lyn R %A Groop, Leif %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hakonarson, Hakon %A Hamsten, Anders %A van der Harst, Pim %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hochner, Hagit %A Huikuri, Heikki %A Hunt, Steven C %A Jaddoe, Vincent W V %A De Jager, Philip L %A Johannesson, Magnus %A Johansson, Asa %A Jonas, Jost B %A Jukema, J Wouter %A Junttila, Juhani %A Kaprio, Jaakko %A Kardia, Sharon L R %A Karpe, Fredrik %A Kumari, Meena %A Laakso, Markku %A van der Laan, Sander W %A Lahti, Jari %A Laudes, Matthias %A Lea, Rodney A %A Lieb, Wolfgang %A Lumley, Thomas %A Martin, Nicholas G %A März, Winfried %A Matullo, Giuseppe %A McCarthy, Mark I %A Medland, Sarah E %A Merriman, Tony R %A Metspalu, Andres %A Meyer, Brian F %A Mohlke, Karen L %A Montgomery, Grant W %A Mook-Kanamori, Dennis %A Munroe, Patricia B %A North, Kari E %A Nyholt, Dale R %A O'Connell, Jeffery R %A Ober, Carole %A Oldehinkel, Albertine J %A Palmas, Walter %A Palmer, Colin %A Pasterkamp, Gerard G %A Patin, Etienne %A Pennell, Craig E %A Perusse, Louis %A Peyser, Patricia A %A Pirastu, Mario %A Polderman, Tinca J C %A Porteous, David J %A Posthuma, Danielle %A Psaty, Bruce M %A Rioux, John D %A Rivadeneira, Fernando %A Rotimi, Charles %A Rotter, Jerome I %A Rudan, Igor %A den Ruijter, Hester M %A Sanghera, Dharambir K %A Sattar, Naveed %A Schmidt, Reinhold %A Schulze, Matthias B %A Schunkert, Heribert %A Scott, Robert A %A Shuldiner, Alan R %A Sim, Xueling %A Small, Neil %A Smith, Jennifer A %A Sotoodehnia, Nona %A Tai, E-Shyong %A Teumer, Alexander %A Timpson, Nicholas J %A Toniolo, Daniela %A Trégouët, David-Alexandre %A Tuomi, Tiinamaija %A Vollenweider, Peter %A Wang, Carol A %A Weir, David R %A Whitfield, John B %A Wijmenga, Cisca %A Wong, Tien-Yin %A Wright, John %A Yang, Jingyun %A Yu, Lei %A Zemel, Babette S %A Zonderman, Alan B %A Perola, Markus %A Magnusson, Patrik K E %A Uitterlinden, André G %A Kooner, Jaspal S %A Chasman, Daniel I %A Loos, Ruth J F %A Franceschini, Nora %A Franke, Lude %A Haley, Chris S %A Hayward, Caroline %A Walters, Robin G %A Perry, John R B %A Esko, Tõnu %A Helgason, Agnar %A Stefansson, Kari %A Joshi, Peter K %A Kubo, Michiaki %A Wilson, James F %X

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

%B Nat Commun %V 10 %P 4957 %8 2019 Oct 31 %G eng %N 1 %R 10.1038/s41467-019-12283-6 %0 Journal Article %J Am J Clin Nutr %D 2019 %T Disentangling the genetics of lean mass. %A Karasik, David %A Zillikens, M Carola %A Hsu, Yi-Hsiang %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Bochud, Murielle %A Borecki, Ingrid B %A Broer, Linda %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos-Obando, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Chambers, John C %A Chen, Zhao %A Cho, Nam H %A Choi, Hyung Jin %A Chou, Wen-Chi %A Cummings, Steven R %A de Groot, Lisette C P G M %A De Jager, Phillip L %A Demuth, Ilja %A Diatchenko, Luda %A Econs, Michael J %A Eiriksdottir, Gudny %A Enneman, Anke W %A Eriksson, Joel %A Eriksson, Johan G %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Gieger, Christian %A Grallert, Harald %A Gudnason, Vilmundur %A Lenore, Launer J %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Johnson, Toby %A Biffar, Reiner %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koller, Daniel L %A Kooner, Jaspal S %A Kraus, William E %A Kritchevsky, Stephen %A Kutalik, Zoltán %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Lerch, Markus M %A Lewis, Joshua R %A Lill, Christina %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Livshits, Gregory %A Ljunggren, Osten %A Loos, Ruth J F %A Lorentzon, Mattias %A Luan, Jian'an %A Luben, Robert N %A Malkin, Ida %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Nethander, Maria %A Newman, Anne B %A O'Connell, Jeffery R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Prince, Richard L %A Psaty, Bruce M %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schipf, Sabine %A Shin, Chan Soo %A Smith, Albert V %A Smith, Shad B %A Soranzo, Nicole %A Spector, Timothy D %A Stančáková, Alena %A Stefansson, Kari %A Steinhagen-Thiessen, Elisabeth %A Stolk, Lisette %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Uitterlinden, André G %A van Duijn, Cornelia M %A van Schoor, Natasja M %A Vandenput, Liesbeth %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A J Wareham, Nicholas %A Waterworth, Dawn %A Weedon, Michael N %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Yerges-Armstrong, Laura M %A Yu, Lei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhou, Yanhua %A Nielson, Carrie M %A Harris, Tamara B %A Demissie, Serkalem %A Kiel, Douglas P %A Ohlsson, Claes %X

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

%B Am J Clin Nutr %V 109 %P 276-287 %8 2019 Feb 01 %G eng %N 2 %R 10.1093/ajcn/nqy272 %0 Journal Article %J Nat Genet %D 2019 %T Genetic architecture of subcortical brain structures in 38,851 individuals. %A Satizabal, Claudia L %A Adams, Hieab H H %A Hibar, Derrek P %A White, Charles C %A Knol, Maria J %A Stein, Jason L %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Jahanshad, Neda %A Roshchupkin, Gennady V %A Smith, Albert V %A Bis, Joshua C %A Jian, Xueqiu %A Luciano, Michelle %A Hofer, Edith %A Teumer, Alexander %A van der Lee, Sven J %A Yang, Jingyun %A Yanek, Lisa R %A Lee, Tom V %A Li, Shuo %A Hu, Yanhui %A Koh, Jia Yu %A Eicher, John D %A Desrivières, Sylvane %A Arias-Vasquez, Alejandro %A Chauhan, Ganesh %A Athanasiu, Lavinia %A Rentería, Miguel E %A Kim, Sungeun %A Hoehn, David %A Armstrong, Nicola J %A Chen, Qiang %A Holmes, Avram J %A den Braber, Anouk %A Kloszewska, Iwona %A Andersson, Micael %A Espeseth, Thomas %A Grimm, Oliver %A Abramovic, Lucija %A Alhusaini, Saud %A Milaneschi, Yuri %A Papmeyer, Martina %A Axelsson, Tomas %A Ehrlich, Stefan %A Roiz-Santiañez, Roberto %A Kraemer, Bernd %A Håberg, Asta K %A Jones, Hannah J %A Pike, G Bruce %A Stein, Dan J %A Stevens, Allison %A Bralten, Janita %A Vernooij, Meike W %A Harris, Tamara B %A Filippi, Irina %A Witte, A Veronica %A Guadalupe, Tulio %A Wittfeld, Katharina %A Mosley, Thomas H %A Becker, James T %A Doan, Nhat Trung %A Hagenaars, Saskia P %A Saba, Yasaman %A Cuellar-Partida, Gabriel %A Amin, Najaf %A Hilal, Saima %A Nho, Kwangsik %A Mirza-Schreiber, Nazanin %A Arfanakis, Konstantinos %A Becker, Diane M %A Ames, David %A Goldman, Aaron L %A Lee, Phil H %A Boomsma, Dorret I %A Lovestone, Simon %A Giddaluru, Sudheer %A Le Hellard, Stephanie %A Mattheisen, Manuel %A Bohlken, Marc M %A Kasperaviciute, Dalia %A Schmaal, Lianne %A Lawrie, Stephen M %A Agartz, Ingrid %A Walton, Esther %A Tordesillas-Gutierrez, Diana %A Davies, Gareth E %A Shin, Jean %A Ipser, Jonathan C %A Vinke, Louis N %A Hoogman, Martine %A Jia, Tianye %A Burkhardt, Ralph %A Klein, Marieke %A Crivello, Fabrice %A Janowitz, Deborah %A Carmichael, Owen %A Haukvik, Unn K %A Aribisala, Benjamin S %A Schmidt, Helena %A Strike, Lachlan T %A Cheng, Ching-Yu %A Risacher, Shannon L %A Pütz, Benno %A Fleischman, Debra A %A Assareh, Amelia A %A Mattay, Venkata S %A Buckner, Randy L %A Mecocci, Patrizia %A Dale, Anders M %A Cichon, Sven %A Boks, Marco P %A Matarin, Mar %A Penninx, Brenda W J H %A Calhoun, Vince D %A Chakravarty, M Mallar %A Marquand, Andre F %A Macare, Christine %A Kharabian Masouleh, Shahrzad %A Oosterlaan, Jaap %A Amouyel, Philippe %A Hegenscheid, Katrin %A Rotter, Jerome I %A Schork, Andrew J %A Liewald, David C M %A de Zubicaray, Greig I %A Wong, Tien Yin %A Shen, Li %A Sämann, Philipp G %A Brodaty, Henry %A Roffman, Joshua L %A de Geus, Eco J C %A Tsolaki, Magda %A Erk, Susanne %A van Eijk, Kristel R %A Cavalleri, Gianpiero L %A van der Wee, Nic J A %A McIntosh, Andrew M %A Gollub, Randy L %A Bulayeva, Kazima B %A Bernard, Manon %A Richards, Jennifer S %A Himali, Jayandra J %A Loeffler, Markus %A Rommelse, Nanda %A Hoffmann, Wolfgang %A Westlye, Lars T %A Valdés Hernández, Maria C %A Hansell, Narelle K %A van Erp, Theo G M %A Wolf, Christiane %A Kwok, John B J %A Vellas, Bruno %A Heinz, Andreas %A Olde Loohuis, Loes M %A Delanty, Norman %A Ho, Beng-Choon %A Ching, Christopher R K %A Shumskaya, Elena %A Singh, Baljeet %A Hofman, Albert %A van der Meer, Dennis %A Homuth, Georg %A Psaty, Bruce M %A Bastin, Mark E %A Montgomery, Grant W %A Foroud, Tatiana M %A Reppermund, Simone %A Hottenga, Jouke-Jan %A Simmons, Andrew %A Meyer-Lindenberg, Andreas %A Cahn, Wiepke %A Whelan, Christopher D %A van Donkelaar, Marjolein M J %A Yang, Qiong %A Hosten, Norbert %A Green, Robert C %A Thalamuthu, Anbupalam %A Mohnke, Sebastian %A Hulshoff Pol, Hilleke E %A Lin, Honghuang %A Jack, Clifford R %A Schofield, Peter R %A Mühleisen, Thomas W %A Maillard, Pauline %A Potkin, Steven G %A Wen, Wei %A Fletcher, Evan %A Toga, Arthur W %A Gruber, Oliver %A Huentelman, Matthew %A Davey Smith, George %A Launer, Lenore J %A Nyberg, Lars %A Jönsson, Erik G %A Crespo-Facorro, Benedicto %A Koen, Nastassja %A Greve, Douglas N %A Uitterlinden, André G %A Weinberger, Daniel R %A Steen, Vidar M %A Fedko, Iryna O %A Groenewold, Nynke A %A Niessen, Wiro J %A Toro, Roberto %A Tzourio, Christophe %A Longstreth, William T %A Ikram, M Kamran %A Smoller, Jordan W %A van Tol, Marie-Jose %A Sussmann, Jessika E %A Paus, Tomáš %A Lemaître, Hervé %A Schroeter, Matthias L %A Mazoyer, Bernard %A Andreassen, Ole A %A Holsboer, Florian %A Depondt, Chantal %A Veltman, Dick J %A Turner, Jessica A %A Pausova, Zdenka %A Schumann, Gunter %A van Rooij, Daan %A Djurovic, Srdjan %A Deary, Ian J %A McMahon, Katie L %A Müller-Myhsok, Bertram %A Brouwer, Rachel M %A Soininen, Hilkka %A Pandolfo, Massimo %A Wassink, Thomas H %A Cheung, Joshua W %A Wolfers, Thomas %A Martinot, Jean-Luc %A Zwiers, Marcel P %A Nauck, Matthias %A Melle, Ingrid %A Martin, Nicholas G %A Kanai, Ryota %A Westman, Eric %A Kahn, René S %A Sisodiya, Sanjay M %A White, Tonya %A Saremi, Arvin %A van Bokhoven, Hans %A Brunner, Han G %A Völzke, Henry %A Wright, Margaret J %A van 't Ent, Dennis %A Nöthen, Markus M %A Ophoff, Roel A %A Buitelaar, Jan K %A Fernández, Guillén %A Sachdev, Perminder S %A Rietschel, Marcella %A van Haren, Neeltje E M %A Fisher, Simon E %A Beiser, Alexa S %A Francks, Clyde %A Saykin, Andrew J %A Mather, Karen A %A Romanczuk-Seiferth, Nina %A Hartman, Catharina A %A DeStefano, Anita L %A Heslenfeld, Dirk J %A Weiner, Michael W %A Walter, Henrik %A Hoekstra, Pieter J %A Nyquist, Paul A %A Franke, Barbara %A Bennett, David A %A Grabe, Hans J %A Johnson, Andrew D %A Chen, Christopher %A van Duijn, Cornelia M %A Lopez, Oscar L %A Fornage, Myriam %A Wardlaw, Joanna M %A Schmidt, Reinhold %A DeCarli, Charles %A De Jager, Philip L %A Villringer, Arno %A Debette, Stephanie %A Gudnason, Vilmundur %A Medland, Sarah E %A Shulman, Joshua M %A Thompson, Paul M %A Seshadri, Sudha %A Ikram, M Arfan %X

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.

%B Nat Genet %V 51 %P 1624-1636 %8 2019 Nov %G eng %N 11 %R 10.1038/s41588-019-0511-y %0 Journal Article %J Mol Psychiatry %D 2022 %T Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. %A Lahti, Jari %A Tuominen, Samuli %A Yang, Qiong %A Pergola, Giulio %A Ahmad, Shahzad %A Amin, Najaf %A Armstrong, Nicola J %A Beiser, Alexa %A Bey, Katharina %A Bis, Joshua C %A Boerwinkle, Eric %A Bressler, Jan %A Campbell, Archie %A Campbell, Harry %A Chen, Qiang %A Corley, Janie %A Cox, Simon R %A Davies, Gail %A De Jager, Philip L %A Derks, Eske M %A Faul, Jessica D %A Fitzpatrick, Annette L %A Fohner, Alison E %A Ford, Ian %A Fornage, Myriam %A Gerring, Zachary %A Grabe, Hans J %A Grodstein, Francine %A Gudnason, Vilmundur %A Simonsick, Eleanor %A Holliday, Elizabeth G %A Joshi, Peter K %A Kajantie, Eero %A Kaprio, Jaakko %A Karell, Pauliina %A Kleineidam, Luca %A Knol, Maria J %A Kochan, Nicole A %A Kwok, John B %A Leber, Markus %A Lam, Max %A Lee, Teresa %A Li, Shuo %A Loukola, Anu %A Luck, Tobias %A Marioni, Riccardo E %A Mather, Karen A %A Medland, Sarah %A Mirza, Saira S %A Nalls, Mike A %A Nho, Kwangsik %A O'Donnell, Adrienne %A Oldmeadow, Christopher %A Painter, Jodie %A Pattie, Alison %A Reppermund, Simone %A Risacher, Shannon L %A Rose, Richard J %A Sadashivaiah, Vijay %A Scholz, Markus %A Satizabal, Claudia L %A Schofield, Peter W %A Schraut, Katharina E %A Scott, Rodney J %A Simino, Jeannette %A Smith, Albert V %A Smith, Jennifer A %A Stott, David J %A Surakka, Ida %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Trompet, Stella %A Turner, Stephen T %A van der Lee, Sven J %A Villringer, Arno %A Völker, Uwe %A Wilson, Robert S %A Wittfeld, Katharina %A Vuoksimaa, Eero %A Xia, Rui %A Yaffe, Kristine %A Yu, Lei %A Zare, Habil %A Zhao, Wei %A Ames, David %A Attia, John %A Bennett, David A %A Brodaty, Henry %A Chasman, Daniel I %A Goldman, Aaron L %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon L R %A Lencz, Todd %A Loeffler, Markus %A Mattay, Venkata S %A Palotie, Aarno %A Psaty, Bruce M %A Ramirez, Alfredo %A Ridker, Paul M %A Riedel-Heller, Steffi G %A Sachdev, Perminder S %A Saykin, Andrew J %A Scherer, Martin %A Schofield, Peter R %A Sidney, Stephen %A Starr, John M %A Trollor, Julian %A Ulrich, William %A Wagner, Michael %A Weir, David R %A Wilson, James F %A Wright, Margaret J %A Weinberger, Daniel R %A Debette, Stephanie %A Eriksson, Johan G %A Mosley, Thomas H %A Launer, Lenore J %A van Duijn, Cornelia M %A Deary, Ian J %A Seshadri, Sudha %A Räikkönen, Katri %X

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.

%B Mol Psychiatry %8 2022 Aug 16 %G eng %R 10.1038/s41380-022-01710-8 %0 Journal Article %J Nature %D 2022 %T Stroke genetics informs drug discovery and risk prediction across ancestries. %A Mishra, Aniket %A Malik, Rainer %A Hachiya, Tsuyoshi %A Jürgenson, Tuuli %A Namba, Shinichi %A Posner, Daniel C %A Kamanu, Frederick K %A Koido, Masaru %A Le Grand, Quentin %A Shi, Mingyang %A He, Yunye %A Georgakis, Marios K %A Caro, Ilana %A Krebs, Kristi %A Liaw, Yi-Ching %A Vaura, Felix C %A Lin, Kuang %A Winsvold, Bendik Slagsvold %A Srinivasasainagendra, Vinodh %A Parodi, Livia %A Bae, Hee-Joon %A Chauhan, Ganesh %A Chong, Michael R %A Tomppo, Liisa %A Akinyemi, Rufus %A Roshchupkin, Gennady V %A Habib, Naomi %A Jee, Yon Ho %A Thomassen, Jesper Qvist %A Abedi, Vida %A Cárcel-Márquez, Jara %A Nygaard, Marianne %A Leonard, Hampton L %A Yang, Chaojie %A Yonova-Doing, Ekaterina %A Knol, Maria J %A Lewis, Adam J %A Judy, Renae L %A Ago, Tetsuro %A Amouyel, Philippe %A Armstrong, Nicole D %A Bakker, Mark K %A Bartz, Traci M %A Bennett, David A %A Bis, Joshua C %A Bordes, Constance %A Børte, Sigrid %A Cain, Anael %A Ridker, Paul M %A Cho, Kelly %A Chen, Zhengming %A Cruchaga, Carlos %A Cole, John W %A De Jager, Phil L %A de Cid, Rafael %A Endres, Matthias %A Ferreira, Leslie E %A Geerlings, Mirjam I %A Gasca, Natalie C %A Gudnason, Vilmundur %A Hata, Jun %A He, Jing %A Heath, Alicia K %A Ho, Yuk-Lam %A Havulinna, Aki S %A Hopewell, Jemma C %A Hyacinth, Hyacinth I %A Inouye, Michael %A Jacob, Mina A %A Jeon, Christina E %A Jern, Christina %A Kamouchi, Masahiro %A Keene, Keith L %A Kitazono, Takanari %A Kittner, Steven J %A Konuma, Takahiro %A Kumar, Amit %A Lacaze, Paul %A Launer, Lenore J %A Lee, Keon-Joo %A Lepik, Kaido %A Li, Jiang %A Li, Liming %A Manichaikul, Ani %A Markus, Hugh S %A Marston, Nicholas A %A Meitinger, Thomas %A Mitchell, Braxton D %A Montellano, Felipe A %A Morisaki, Takayuki %A Mosley, Thomas H %A Nalls, Mike A %A Nordestgaard, Børge G %A O'Donnell, Martin J %A Okada, Yukinori %A Onland-Moret, N Charlotte %A Ovbiagele, Bruce %A Peters, Annette %A Psaty, Bruce M %A Rich, Stephen S %A Rosand, Jonathan %A Sabatine, Marc S %A Sacco, Ralph L %A Saleheen, Danish %A Sandset, Else Charlotte %A Salomaa, Veikko %A Sargurupremraj, Muralidharan %A Sasaki, Makoto %A Satizabal, Claudia L %A Schmidt, Carsten O %A Shimizu, Atsushi %A Smith, Nicholas L %A Sloane, Kelly L %A Sutoh, Yoichi %A Sun, Yan V %A Tanno, Kozo %A Tiedt, Steffen %A Tatlisumak, Turgut %A Torres-Aguila, Nuria P %A Tiwari, Hemant K %A Trégouët, David-Alexandre %A Trompet, Stella %A Tuladhar, Anil Man %A Tybjærg-Hansen, Anne %A van Vugt, Marion %A Vibo, Riina %A Verma, Shefali S %A Wiggins, Kerri L %A Wennberg, Patrik %A Woo, Daniel %A Wilson, Peter W F %A Xu, Huichun %A Yang, Qiong %A Yoon, Kyungheon %A Millwood, Iona Y %A Gieger, Christian %A Ninomiya, Toshiharu %A Grabe, Hans J %A Jukema, J Wouter %A Rissanen, Ina L %A Strbian, Daniel %A Kim, Young Jin %A Chen, Pei-Hsin %A Mayerhofer, Ernst %A Howson, Joanna M M %A Irvin, Marguerite R %A Adams, Hieab %A Wassertheil-Smoller, Sylvia %A Christensen, Kaare %A Ikram, Mohammad A %A Rundek, Tatjana %A Worrall, Bradford B %A Lathrop, G Mark %A Riaz, Moeen %A Simonsick, Eleanor M %A Kõrv, Janika %A França, Paulo H C %A Zand, Ramin %A Prasad, Kameshwar %A Frikke-Schmidt, Ruth %A de Leeuw, Frank-Erik %A Liman, Thomas %A Haeusler, Karl Georg %A Ruigrok, Ynte M %A Heuschmann, Peter Ulrich %A Longstreth, W T %A Jung, Keum Ji %A Bastarache, Lisa %A Paré, Guillaume %A Damrauer, Scott M %A Chasman, Daniel I %A Rotter, Jerome I %A Anderson, Christopher D %A Zwart, John-Anker %A Niiranen, Teemu J %A Fornage, Myriam %A Liaw, Yung-Po %A Seshadri, Sudha %A Fernandez-Cadenas, Israel %A Walters, Robin G %A Ruff, Christian T %A Owolabi, Mayowa O %A Huffman, Jennifer E %A Milani, Lili %A Kamatani, Yoichiro %A Dichgans, Martin %A Debette, Stephanie %X

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

%B Nature %8 2022 Sep 30 %G eng %R 10.1038/s41586-022-05165-3 %0 Journal Article %J JAMA Netw Open %D 2023 %T CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk. %A Huque, Md Hamidul %A Kootar, Scherazad %A Eramudugolla, Ranmalee %A Han, S Duke %A Carlson, Michelle C %A Lopez, Oscar L %A Bennett, David A %A Peters, Ruth %A Anstey, Kaarin J %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Australia %K Cohort Studies %K Female %K Heart Disease Risk Factors %K Humans %K Male %K Risk Factors %X

IMPORTANCE: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited.

OBJECTIVE: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI).

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023.

MAIN OUTCOMES AND MEASURES: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk.

RESULTS: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar.

CONCLUSIONS AND RELEVANCE: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

%B JAMA Netw Open %V 6 %P e2331460 %8 2023 Aug 01 %G eng %N 8 %R 10.1001/jamanetworkopen.2023.31460 %0 Journal Article %J Alzheimers Res Ther %D 2024 %T Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. %A Mei, Hao %A Simino, Jeannette %A Li, Lianna %A Jiang, Fan %A Bis, Joshua C %A Davies, Gail %A Hill, W David %A Xia, Charley %A Gudnason, Vilmundur %A Yang, Qiong %A Lahti, Jari %A Smith, Jennifer A %A Kirin, Mirna %A De Jager, Philip %A Armstrong, Nicola J %A Ghanbari, Mohsen %A Kolcic, Ivana %A Moran, Christopher %A Teumer, Alexander %A Sargurupremraj, Murali %A Mahmud, Shamsed %A Fornage, Myriam %A Zhao, Wei %A Satizabal, Claudia L %A Polasek, Ozren %A Räikkönen, Katri %A Liewald, David C %A Homuth, Georg %A Callisaya, Michele %A Mather, Karen A %A Windham, B Gwen %A Zemunik, Tatijana %A Palotie, Aarno %A Pattie, Alison %A van der Auwera, Sandra %A Thalamuthu, Anbupalam %A Knopman, David S %A Rudan, Igor %A Starr, John M %A Wittfeld, Katharina %A Kochan, Nicole A %A Griswold, Michael E %A Vitart, Veronique %A Brodaty, Henry %A Gottesman, Rebecca %A Cox, Simon R %A Psaty, Bruce M %A Boerwinkle, Eric %A Chasman, Daniel I %A Grodstein, Francine %A Sachdev, Perminder S %A Srikanth, Velandai %A Hayward, Caroline %A Wilson, James F %A Eriksson, Johan G %A Kardia, Sharon L R %A Grabe, Hans J %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Bressler, Jan %A Debette, Stephanie %A Mosley, Thomas H %K Aged %K Cognition %K Genome-Wide Association Study %K Humans %K Memory %K MicroRNAs %K Multiomics %K Polymorphism, Single Nucleotide %X

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

%B Alzheimers Res Ther %V 16 %P 14 %8 2024 Jan 20 %G eng %N 1 %R 10.1186/s13195-023-01376-6