@article {817, title = {Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study.}, journal = {Am J Hum Genet}, volume = {76}, year = {2005}, month = {2005 Mar}, pages = {463-77}, abstract = {

U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.

}, keywords = {African Americans, Aged, Aging, Algorithms, Cardiovascular Diseases, Cohort Studies, Female, Genetics, Population, Genotype, Humans, Male, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Socioeconomic Factors}, issn = {0002-9297}, doi = {10.1086/428654}, author = {Reiner, Alexander P and Ziv, Elad and Lind, Denise L and Nievergelt, Caroline M and Schork, Nicholas J and Cummings, Steven R and Phong, Angie and Burchard, Esteban Gonz{\'a}lez and Harris, Tamara B and Psaty, Bruce M and Kwok, Pui-Yan} } @article {986, title = {Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {197}, year = {2008}, month = {2008 Apr}, pages = {922-30}, abstract = {

Common polymorphisms in the CRP gene are associated with plasma CRP levels in population-based studies, but associations with age-related events are uncertain. A previous study of CRP haplotypes in older adults was broadened to include longevity and cause-specific mortality (all-cause, noncardiovascular (non-CV), and cardiovascular (CV)). Common haplotypes were inferred from four tagSNPs in 4512 whites and five tagSNPs in 812 blacks from the Cardiovascular Health Study, a longitudinal cohort of adults over age 65. Exploratory analyses addressed early versus late mortality. CRP haplotypes were not associated with all-cause mortality or longevity overall in either population, but associations with all-cause mortality differed during early and late periods. In blacks, the haplotype tagged by 3872A (rs1205) was associated with increased risk of non-CV mortality, relative to other haplotypes (adjusted hazard ratio for each additional copy: 1.42, 95\% CI: 1.07, 1.87). Relative to other haplotypes, this haplotype was associated with decreased risk of early but not decreased risk of late CV mortality in blacks; among whites, a haplotype tagged by 2667C (rs1800947) gave similar but nonsignificant findings. If confirmed, CRP genetic variants may be weakly associated with CV and non-CV mortality in older adults, particularly in self-identified blacks.

}, keywords = {African Americans, Aged, C-Reactive Protein, Cardiovascular Diseases, Cause of Death, Cohort Studies, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Linear Models, Longevity, Male, Polymorphism, Single Nucleotide, Proportional Hazards Models, United States}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2007.08.012}, author = {Hindorff, Lucia A and Rice, Kenneth M and Lange, Leslie A and Diehr, Paula and Halder, Indrani and Walston, Jeremy and Kwok, Pui and Ziv, Elad and Nievergelt, Caroline and Cummings, Steven R and Newman, Anne B and Tracy, Russell P and Psaty, Bruce M and Reiner, Alexander P} } @article {1104, title = {Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity.}, journal = {Aging Cell}, volume = {8}, year = {2009}, month = {2009 Aug}, pages = {460-72}, abstract = {

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95\%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95\%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.

}, keywords = {Aged, Aged, 80 and over, Female, Follow-Up Studies, Forkhead Box Protein O3, Forkhead Transcription Factors, Genome, Human, Genotype, Humans, Insulin, Insulin-Like Growth Factor I, Longevity, Male, Osteoporosis, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-akt, Signal Transduction}, issn = {1474-9726}, doi = {10.1111/j.1474-9726.2009.00493.x}, author = {Pawlikowska, Ludmila and Hu, Donglei and Huntsman, Scott and Sung, Andrew and Chu, Catherine and Chen, Justin and Joyner, Alexander H and Schork, Nicholas J and Hsueh, Wen-Chi and Reiner, Alexander P and Psaty, Bruce M and Atzmon, Gil and Barzilai, Nir and Cummings, Steven R and Browner, Warren S and Kwok, Pui-Yan and Ziv, Elad} } @article {8016, title = {Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 15}, pages = {491-501}, abstract = {

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 {\texttimes} 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 {\texttimes} 10(-4), Bonferroni corrected), of which six reached P < 5 {\texttimes} 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

}, keywords = {Bone Density, Computational Biology, European Continental Ancestry Group, Extracellular Matrix Proteins, Female, Femur Neck, Fractures, Bone, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Lumbar Vertebrae, Male, Mitochondrial Membrane Transport Proteins, Osteoporosis, Phosphoproteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Spectrin}, issn = {1546-1718}, doi = {10.1038/ng.2249}, author = {Estrada, Karol and Styrkarsdottir, Unnur and Evangelou, Evangelos and Hsu, Yi-Hsiang and Duncan, Emma L and Ntzani, Evangelia E and Oei, Ling and Albagha, Omar M E and Amin, Najaf and Kemp, John P and Koller, Daniel L and Li, Guo and Liu, Ching-Ti and Minster, Ryan L and Moayyeri, Alireza and Vandenput, Liesbeth and Willner, Dana and Xiao, Su-Mei and Yerges-Armstrong, Laura M and Zheng, Hou-Feng and Alonso, Nerea and Eriksson, Joel and Kammerer, Candace M and Kaptoge, Stephen K and Leo, Paul J and Thorleifsson, Gudmar and Wilson, Scott G and Wilson, James F and Aalto, Ville and Alen, Markku and Aragaki, Aaron K and Aspelund, Thor and Center, Jacqueline R and Dailiana, Zoe and Duggan, David J and Garcia, Melissa and Garc{\'\i}a-Giralt, Natalia and Giroux, Sylvie and Hallmans, G{\"o}ran and Hocking, Lynne J and Husted, Lise Bjerre and Jameson, Karen A and Khusainova, Rita and Kim, Ghi Su and Kooperberg, Charles and Koromila, Theodora and Kruk, Marcin and Laaksonen, Marika and LaCroix, Andrea Z and Lee, Seung Hun and Leung, Ping C and Lewis, Joshua R and Masi, Laura and Mencej-Bedrac, Simona and Nguyen, Tuan V and Nogues, Xavier and Patel, Millan S and Prezelj, Janez and Rose, Lynda M and Scollen, Serena and Siggeirsdottir, Kristin and Smith, Albert V and Svensson, Olle and Trompet, Stella and Trummer, Olivia and van Schoor, Natasja M and Woo, Jean and Zhu, Kun and Balcells, Susana and Brandi, Maria Luisa and Buckley, Brendan M and Cheng, Sulin and Christiansen, Claus and Cooper, Cyrus and Dedoussis, George and Ford, Ian and Frost, Morten and Goltzman, David and Gonz{\'a}lez-Mac{\'\i}as, Jes{\'u}s and K{\"a}h{\"o}nen, Mika and Karlsson, Magnus and Khusnutdinova, Elza and Koh, Jung-Min and Kollia, Panagoula and Langdahl, Bente Lomholt and Leslie, William D and Lips, Paul and Ljunggren, Osten and Lorenc, Roman S and Marc, Janja and Mellstr{\"o}m, Dan and Obermayer-Pietsch, Barbara and Olmos, Jos{\'e} M and Pettersson-Kymmer, Ulrika and Reid, David M and Riancho, Jos{\'e} A and Ridker, Paul M and Rousseau, Fran{\c c}ois and Slagboom, P Eline and Tang, Nelson L S and Urreizti, Roser and Van Hul, Wim and Viikari, Jorma and Zarrabeitia, Mar{\'\i}a T and Aulchenko, Yurii S and Castano-Betancourt, Martha and Grundberg, Elin and Herrera, Lizbeth and Ingvarsson, Thorvaldur and Johannsdottir, Hrefna and Kwan, Tony and Li, Rui and Luben, Robert and Medina-G{\'o}mez, Carolina and Palsson, Stefan Th and Reppe, Sjur and Rotter, Jerome I and Sigurdsson, Gunnar and van Meurs, Joyce B J and Verlaan, Dominique and Williams, Frances M K and Wood, Andrew R and Zhou, Yanhua and Gautvik, Kaare M and Pastinen, Tomi and Raychaudhuri, Soumya and Cauley, Jane A and Chasman, Daniel I and Clark, Graeme R and Cummings, Steven R and Danoy, Patrick and Dennison, Elaine M and Eastell, Richard and Eisman, John A and Gudnason, Vilmundur and Hofman, Albert and Jackson, Rebecca D and Jones, Graeme and Jukema, J Wouter and Khaw, Kay-Tee and Lehtim{\"a}ki, Terho and Liu, Yongmei and Lorentzon, Mattias and McCloskey, Eugene and Mitchell, Braxton D and Nandakumar, Kannabiran and Nicholson, Geoffrey C and Oostra, Ben A and Peacock, Munro and Pols, Huibert A P and Prince, Richard L and Raitakari, Olli and Reid, Ian R and Robbins, John and Sambrook, Philip N and Sham, Pak Chung and Shuldiner, Alan R and Tylavsky, Frances A and van Duijn, Cornelia M and Wareham, Nick J and Cupples, L Adrienne and Econs, Michael J and Evans, David M and Harris, Tamara B and Kung, Annie Wai Chee and Psaty, Bruce M and Reeve, Jonathan and Spector, Timothy D and Streeten, Elizabeth A and Zillikens, M Carola and Thorsteinsdottir, Unnur and Ohlsson, Claes and Karasik, David and Richards, J Brent and Brown, Matthew A and Stefansson, Kari and Uitterlinden, Andr{\'e} G and Ralston, Stuart H and Ioannidis, John P A and Kiel, Douglas P and Rivadeneira, Fernando} } @article {5998, title = {The QT interval and risk of incident atrial fibrillation.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Oct}, pages = {1562-8}, abstract = {

BACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.

OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.

METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.

RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95\% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95\% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95\% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.

CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.

}, keywords = {Aged, Atrial Fibrillation, Cohort Studies, Electrocardiography, Female, Humans, Incidence, Long QT Syndrome, Male, Middle Aged, Risk Factors}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.07.023}, author = {Mandyam, Mala C and Soliman, Elsayed Z and Alonso, Alvaro and Dewland, Thomas A and Heckbert, Susan R and Vittinghoff, Eric and Cummings, Steven R and Ellinor, Patrick T and Chaitman, Bernard R and Stocke, Karen and Applegate, William B and Arking, Dan E and Butler, Javed and Loehr, Laura R and Magnani, Jared W and Murphy, Rachel A and Satterfield, Suzanne and Newman, Anne B and Marcus, Gregory M} } @article {6544, title = {Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Aug}, pages = {826-36}, abstract = {

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain \~{}8-10\% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

}, keywords = {Adult, Aged, Arrhythmias, Cardiac, Calcium Signaling, Death, Sudden, Cardiac, Electrocardiography, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Long QT Syndrome, Male, Middle Aged, Myocardium, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.3014}, author = {Arking, Dan E and Pulit, Sara L and Crotti, Lia and van der Harst, Pim and Munroe, Patricia B and Koopmann, Tamara T and Sotoodehnia, Nona and Rossin, Elizabeth J and Morley, Michael and Wang, Xinchen and Johnson, Andrew D and Lundby, Alicia and Gudbjartsson, Daniel F and Noseworthy, Peter A and Eijgelsheim, Mark and Bradford, Yuki and Tarasov, Kirill V and D{\"o}rr, Marcus and M{\"u}ller-Nurasyid, Martina and Lahtinen, Annukka M and Nolte, Ilja M and Smith, Albert Vernon and Bis, Joshua C and Isaacs, Aaron and Newhouse, Stephen J and Evans, Daniel S and Post, Wendy S and Waggott, Daryl and Lyytik{\"a}inen, Leo-Pekka and Hicks, Andrew A and Eisele, Lewin and Ellinghaus, David and Hayward, Caroline and Navarro, Pau and Ulivi, Sheila and Tanaka, Toshiko and Tester, David J and Chatel, St{\'e}phanie and Gustafsson, Stefan and Kumari, Meena and Morris, Richard W and Naluai, {\r A}sa T and Padmanabhan, Sandosh and Kluttig, Alexander and Strohmer, Bernhard and Panayiotou, Andrie G and Torres, Maria and Knoflach, Michael and Hubacek, Jaroslav A and Slowikowski, Kamil and Raychaudhuri, Soumya and Kumar, Runjun D and Harris, Tamara B and Launer, Lenore J and Shuldiner, Alan R and Alonso, Alvaro and Bader, Joel S and Ehret, Georg and Huang, Hailiang and Kao, W H Linda and Strait, James B and Macfarlane, Peter W and Brown, Morris and Caulfield, Mark J and Samani, Nilesh J and Kronenberg, Florian and Willeit, Johann and Smith, J Gustav and Greiser, Karin H and Meyer Zu Schwabedissen, Henriette and Werdan, Karl and Carella, Massimo and Zelante, Leopoldo and Heckbert, Susan R and Psaty, Bruce M and Rotter, Jerome I and Kolcic, Ivana and Polasek, Ozren and Wright, Alan F and Griffin, Maura and Daly, Mark J and Arnar, David O and Holm, Hilma and Thorsteinsdottir, Unnur and Denny, Joshua C and Roden, Dan M and Zuvich, Rebecca L and Emilsson, Valur and Plump, Andrew S and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Yin, Xiaoyan and Bobbo, Marco and D{\textquoteright}Adamo, Adamo P and Iorio, Annamaria and Sinagra, Gianfranco and Carracedo, Angel and Cummings, Steven R and Nalls, Michael A and Jula, Antti and Kontula, Kimmo K and Marjamaa, Annukka and Oikarinen, Lasse and Perola, Markus and Porthan, Kimmo and Erbel, Raimund and Hoffmann, Per and J{\"o}ckel, Karl-Heinz and K{\"a}lsch, Hagen and N{\"o}then, Markus M and den Hoed, Marcel and Loos, Ruth J F and Thelle, Dag S and Gieger, Christian and Meitinger, Thomas and Perz, Siegfried and Peters, Annette and Prucha, Hanna and Sinner, Moritz F and Waldenberger, Melanie and de Boer, Rudolf A and Franke, Lude and van der Vleuten, Pieter A and Beckmann, Britt Maria and Martens, Eimo and Bardai, Abdennasser and Hofman, Nynke and Wilde, Arthur A M and Behr, Elijah R and Dalageorgou, Chrysoula and Giudicessi, John R and Medeiros-Domingo, Argelia and Barc, Julien and Kyndt, Florence and Probst, Vincent and Ghidoni, Alice and Insolia, Roberto and Hamilton, Robert M and Scherer, Stephen W and Brandimarto, Jeffrey and Margulies, Kenneth and Moravec, Christine E and del Greco M, Fabiola and Fuchsberger, Christian and O{\textquoteright}Connell, Jeffrey R and Lee, Wai K and Watt, Graham C M and Campbell, Harry and Wild, Sarah H and El Mokhtari, Nour E and Frey, Norbert and Asselbergs, Folkert W and Mateo Leach, Irene and Navis, Gerjan and van den Berg, Maarten P and van Veldhuisen, Dirk J and Kellis, Manolis and Krijthe, Bouwe P and Franco, Oscar H and Hofman, Albert and Kors, Jan A and Uitterlinden, Andr{\'e} G and Witteman, Jacqueline C M and Kedenko, Lyudmyla and Lamina, Claudia and Oostra, Ben A and Abecasis, Goncalo R and Lakatta, Edward G and Mulas, Antonella and Orr{\`u}, Marco and Schlessinger, David and Uda, Manuela and Markus, Marcello R P and V{\"o}lker, Uwe and Snieder, Harold and Spector, Timothy D and Arnl{\"o}v, Johan and Lind, Lars and Sundstr{\"o}m, Johan and Syv{\"a}nen, Ann-Christine and Kivimaki, Mika and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Raitakari, Olli T and Viikari, Jorma S and Adamkova, Vera and Kiechl, Stefan and Brion, Maria and Nicolaides, Andrew N and Paulweber, Bernhard and Haerting, Johannes and Dominiczak, Anna F and Nyberg, Fredrik and Whincup, Peter H and Hingorani, Aroon D and Schott, Jean-Jacques and Bezzina, Connie R and Ingelsson, Erik and Ferrucci, Luigi and Gasparini, Paolo and Wilson, James F and Rudan, Igor and Franke, Andre and M{\"u}hleisen, Thomas W and Pramstaller, Peter P and Lehtim{\"a}ki, Terho J and Paterson, Andrew D and Parsa, Afshin and Liu, Yongmei and van Duijn, Cornelia M and Siscovick, David S and Gudnason, Vilmundur and Jamshidi, Yalda and Salomaa, Veikko and Felix, Stephan B and Sanna, Serena and Ritchie, Marylyn D and Stricker, Bruno H and Stefansson, Kari and Boyer, Laurie A and Cappola, Thomas P and Olsen, Jesper V and Lage, Kasper and Schwartz, Peter J and K{\"a}{\"a}b, Stefan and Chakravarti, Aravinda and Ackerman, Michael J and Pfeufer, Arne and de Bakker, Paul I W and Newton-Cheh, Christopher} } @article {6585, title = {Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Aug}, pages = {e1004517}, abstract = {

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 {\texttimes} 10(-94)}, keywords = {African Americans, Diabetes Mellitus, Type 2, Genome-Wide Association Study, HLA-B27 Antigen, HMGA2 Protein, Humans, KCNQ1 Potassium Channel, Mutant Chimeric Proteins, Polymorphism, Single Nucleotide, Transcription Factor 7-Like 2 Protein}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004517}, author = {Ng, Maggie C Y and Shriner, Daniel and Chen, Brian H and Li, Jiang and Chen, Wei-Min and Guo, Xiuqing and Liu, Jiankang and Bielinski, Suzette J and Yanek, Lisa R and Nalls, Michael A and Comeau, Mary E and Rasmussen-Torvik, Laura J and Jensen, Richard A and Evans, Daniel S and Sun, Yan V and An, Ping and Patel, Sanjay R and Lu, Yingchang and Long, Jirong and Armstrong, Loren L and Wagenknecht, Lynne and Yang, Lingyao and Snively, Beverly M and Palmer, Nicholette D and Mudgal, Poorva and Langefeld, Carl D and Keene, Keith L and Freedman, Barry I and Mychaleckyj, Josyf C and Nayak, Uma and Raffel, Leslie J and Goodarzi, Mark O and Chen, Y-D Ida and Taylor, Herman A and Correa, Adolfo and Sims, Mario and Couper, David and Pankow, James S and Boerwinkle, Eric and Adeyemo, Adebowale and Doumatey, Ayo and Chen, Guanjie and Mathias, Rasika A and Vaidya, Dhananjay and Singleton, Andrew B and Zonderman, Alan B and Igo, Robert P and Sedor, John R and Kabagambe, Edmond K and Siscovick, David S and McKnight, Barbara and Rice, Kenneth and Liu, Yongmei and Hsueh, Wen-Chi and Zhao, Wei and Bielak, Lawrence F and Kraja, Aldi and Province, Michael A and Bottinger, Erwin P and Gottesman, Omri and Cai, Qiuyin and Zheng, Wei and Blot, William J and Lowe, William L and Pacheco, Jennifer A and Crawford, Dana C and Grundberg, Elin and Rich, Stephen S and Hayes, M Geoffrey and Shu, Xiao-Ou and Loos, Ruth J F and Borecki, Ingrid B and Peyser, Patricia A and Cummings, Steven R and Psaty, Bruce M and Fornage, Myriam and Iyengar, Sudha K and Evans, Michele K and Becker, Diane M and Kao, W H Linda and Wilson, James G and Rotter, Jerome I and Sale, Mich{\`e}le M and Liu, Simin and Rotimi, Charles N and Bowden, Donald W} } @article {6659, title = {Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Mar 6}, pages = {363-71}, abstract = {

BACKGROUND AND OBJECTIVES: CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study.

RESULTS: The development cohort included 828 participants who had a mean age of 80 ({\textpm}5.6) years and an eGFR of 47 ({\textpm}11) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-51) mg/g. The validation cohort included 789 participants who had a mean age of 74 ({\textpm}2.8) years and an eGFR of 50 ({\textpm}9) ml/min per 1.73 m(2), and median albumin-to-creatinine ratio of 13 (interquartile range 6-42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95\% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8\% among participants with the lowest scores to 83.6\% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95\% confidence interval, 0.64 to 0.74).

CONCLUSIONS: A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Albuminuria, Continental Population Groups, Creatinine, Diabetes Mellitus, Female, Glomerular Filtration Rate, Heart Failure, Humans, Male, Proportional Hazards Models, Regression Analysis, Renal Insufficiency, Chronic, Risk Factors, Sex Factors, Smoking, Stroke}, issn = {1555-905X}, doi = {10.2215/CJN.04650514}, author = {Bansal, Nisha and Katz, Ronit and de Boer, Ian H and Peralta, Carmen A and Fried, Linda F and Siscovick, David S and Rifkin, Dena E and Hirsch, Calvin and Cummings, Steven R and Harris, Tamara B and Kritchevsky, Stephen B and Sarnak, Mark J and Shlipak, Michael G and Ix, Joachim H} } @article {6875, title = {Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.}, journal = {PLoS One}, volume = {10}, year = {2015}, month = {2015}, pages = {e0140496}, abstract = {

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0{\texttimes}10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction >= 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

}, keywords = {African Americans, Aged, Antihypertensive Agents, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Treatment Outcome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0140496}, author = {Bis, Joshua C and Sitlani, Colleen and Irvin, Ryan and Avery, Christy L and Smith, Albert Vernon and Sun, Fangui and Evans, Daniel S and Musani, Solomon K and Li, Xiaohui and Trompet, Stella and Krijthe, Bouwe P and Harris, Tamara B and Quibrera, P Miguel and Brody, Jennifer A and Demissie, Serkalem and Davis, Barry R and Wiggins, Kerri L and Tranah, Gregory J and Lange, Leslie A and Sotoodehnia, Nona and Stott, David J and Franco, Oscar H and Launer, Lenore J and St{\"u}rmer, Til and Taylor, Kent D and Cupples, L Adrienne and Eckfeldt, John H and Smith, Nicholas L and Liu, Yongmei and Wilson, James G and Heckbert, Susan R and Buckley, Brendan M and Ikram, M Arfan and Boerwinkle, Eric and Chen, Yii-Der Ida and de Craen, Anton J M and Uitterlinden, Andr{\'e} G and Rotter, Jerome I and Ford, Ian and Hofman, Albert and Sattar, Naveed and Slagboom, P Eline and Westendorp, Rudi G J and Gudnason, Vilmundur and Vasan, Ramachandran S and Lumley, Thomas and Cummings, Steven R and Taylor, Herman A and Post, Wendy and Jukema, J Wouter and Stricker, Bruno H and Whitsel, Eric A and Psaty, Bruce M and Arnett, Donna} } @article {7259, title = {Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.}, journal = {Hum Mol Genet}, year = {2016}, month = {2016 Aug 29}, abstract = {

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 {\texttimes} 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 {\texttimes} 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 {\texttimes} 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 {\texttimes} 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 {\texttimes} 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddw284}, author = {Evans, Daniel S and Avery, Christy L and Nalls, Mike A and Li, Guo and Barnard, John and Smith, Erin N and Tanaka, Toshiko and Butler, Anne M and Buxbaum, Sarah G and Alonso, Alvaro and Arking, Dan E and Berenson, Gerald S and Bis, Joshua C and Buyske, Steven and Carty, Cara L and Chen, Wei and Chung, Mina K and Cummings, Steven R and Deo, Rajat and Eaton, Charles B and Fox, Ervin R and Heckbert, Susan R and Heiss, Gerardo and Hindorff, Lucia A and Hsueh, Wen-Chi and Isaacs, Aaron and Jamshidi, Yalda and Kerr, Kathleen F and Liu, Felix and Liu, Yongmei and Lohman, Kurt K and Magnani, Jared W and Maher, Joseph F and Mehra, Reena and Meng, Yan A and Musani, Solomon K and Newton-Cheh, Christopher and North, Kari E and Psaty, Bruce M and Redline, Susan and Rotter, Jerome I and Schnabel, Renate B and Schork, Nicholas J and Shohet, Ralph V and Singleton, Andrew B and Smith, Jonathan D and Soliman, Elsayed Z and Srinivasan, Sathanur R and Taylor, Herman A and Van Wagoner, David R and Wilson, James G and Young, Taylor and Zhang, Zhu-Ming and Zonderman, Alan B and Evans, Michele K and Ferrucci, Luigi and Murray, Sarah S and Tranah, Gregory J and Whitsel, Eric A and Reiner, Alex P and Sotoodehnia, Nona} } @article {7168, title = {Genetic variants in RBFOX3 are associated with sleep latency.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 Oct}, pages = {1488-95}, abstract = {

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 {\texttimes} 10(-08), 6.59 {\texttimes} 10(-)(08) and 9.17 {\texttimes} 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 {\texttimes} 10(-)(02), 7.0 {\texttimes} 10(-)(03) and 2.5 {\texttimes} 10(-)(03); combined meta-analysis P-values=5.5 {\texttimes} 10(-07), 5.4 {\texttimes} 10(-07) and 1.0 {\texttimes} 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 {\texttimes} 10(-316)) and the central nervous system (P-value=7.5 {\texttimes} 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 {\texttimes} 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.

}, issn = {1476-5438}, doi = {10.1038/ejhg.2016.31}, author = {Amin, Najaf and Allebrandt, Karla V and van der Spek, Ashley and M{\"u}ller-Myhsok, Bertram and Hek, Karin and Teder-Laving, Maris and Hayward, Caroline and Esko, T{\~o}nu and van Mill, Josine G and Mbarek, Hamdi and Watson, Nathaniel F and Melville, Scott A and Del Greco, Fabiola M and Byrne, Enda M and Oole, Edwin and Kolcic, Ivana and Chen, Ting-Hsu and Evans, Daniel S and Coresh, Josef and Vogelzangs, Nicole and Karjalainen, Juha and Willemsen, Gonneke and Gharib, Sina A and Zgaga, Lina and Mihailov, Evelin and Stone, Katie L and Campbell, Harry and Brouwer, Rutger Ww and Demirkan, Ayse and Isaacs, Aaron and Dogas, Zoran and Marciante, Kristin D and Campbell, Susan and Borovecki, Fran and Luik, Annemarie I and Li, Man and Hottenga, Jouke Jan and Huffman, Jennifer E and van den Hout, Mirjam Cgn and Cummings, Steven R and Aulchenko, Yurii S and Gehrman, Philip R and Uitterlinden, Andr{\'e} G and Wichmann, Heinz-Erich and M{\"u}ller-Nurasyid, Martina and Fehrmann, Rudolf Sn and Montgomery, Grant W and Hofman, Albert and Kao, Wen Hong Linda and Oostra, Ben A and Wright, Alan F and Vink, Jacqueline M and Wilson, James F and Pramstaller, Peter P and Hicks, Andrew A and Polasek, Ozren and Punjabi, Naresh M and Redline, Susan and Psaty, Bruce M and Heath, Andrew C and Merrow, Martha and Tranah, Gregory J and Gottlieb, Daniel J and Boomsma, Dorret I and Martin, Nicholas G and Rudan, Igor and Tiemeier, Henning and van IJcken, Wilfred Fj and Penninx, Brenda W and Metspalu, Andres and Meitinger, Thomas and Franke, Lude and Roenneberg, Till and van Duijn, Cornelia M} } @article {7142, title = {GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium.}, journal = {Aging Cell}, volume = {15}, year = {2016}, month = {2016 Oct}, pages = {792-800}, abstract = {

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~{\texttimes}~10(-8) ) and 39 suggestive (P-value< 5~{\texttimes}~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~{\texttimes}~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.

}, issn = {1474-9726}, doi = {10.1111/acel.12468}, author = {Matteini, Amy M and Tanaka, Toshiko and Karasik, David and Atzmon, Gil and Chou, Wen-Chi and Eicher, John D and Johnson, Andrew D and Arnold, Alice M and Callisaya, Michele L and Davies, Gail and Evans, Daniel S and Holtfreter, Birte and Lohman, Kurt and Lunetta, Kathryn L and Mangino, Massimo and Smith, Albert V and Smith, Jennifer A and Teumer, Alexander and Yu, Lei and Arking, Dan E and Buchman, Aron S and Chibinik, Lori B and De Jager, Philip L and Evans, Denis A and Faul, Jessica D and Garcia, Melissa E and Gillham-Nasenya, Irina and Gudnason, Vilmundur and Hofman, Albert and Hsu, Yi-Hsiang and Ittermann, Till and Lahousse, Lies and Liewald, David C and Liu, Yongmei and Lopez, Lorna and Rivadeneira, Fernando and Rotter, Jerome I and Siggeirsdottir, Kristin and Starr, John M and Thomson, Russell and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Weir, David R and Yaffe, Kristine and Zhao, Wei and Zhuang, Wei Vivian and Zmuda, Joseph M and Bennett, David A and Cummings, Steven R and Deary, Ian J and Ferrucci, Luigi and Harris, Tamara B and Kardia, Sharon L R and Kocher, Thomas and Kritchevsky, Stephen B and Psaty, Bruce M and Seshadri, Sudha and Spector, Timothy D and Srikanth, Velandai K and Windham, B Gwen and Zillikens, M Carola and Newman, Anne B and Walston, Jeremy D and Kiel, Douglas P and Murabito, Joanne M} } @article {7358, title = {Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Dec}, pages = {835-845}, abstract = {

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1{\texttimes}10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5{\texttimes}10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103966}, author = {Postmus, Iris and Warren, Helen R and Trompet, Stella and Arsenault, Benoit J and Avery, Christy L and Bis, Joshua C and Chasman, Daniel I and de Keyser, Catherine E and Deshmukh, Harshal A and Evans, Daniel S and Feng, QiPing and Li, Xiaohui and Smit, Roelof A J and Smith, Albert V and Sun, Fangui and Taylor, Kent D and Arnold, Alice M and Barnes, Michael R and Barratt, Bryan J and Betteridge, John and Boekholdt, S Matthijs and Boerwinkle, Eric and Buckley, Brendan M and Chen, Y-D Ida and de Craen, Anton J M and Cummings, Steven R and Denny, Joshua C and Dub{\'e}, Marie Pierre and Durrington, Paul N and Eiriksdottir, Gudny and Ford, Ian and Guo, Xiuqing and Harris, Tamara B and Heckbert, Susan R and Hofman, Albert and Hovingh, G Kees and Kastelein, John J P and Launer, Leonore J and Liu, Ching-Ti and Liu, Yongmei and Lumley, Thomas and McKeigue, Paul M and Munroe, Patricia B and Neil, Andrew and Nickerson, Deborah A and Nyberg, Fredrik and O{\textquoteright}Brien, Eoin and O{\textquoteright}Donnell, Christopher J and Post, Wendy and Poulter, Neil and Vasan, Ramachandran S and Rice, Kenneth and Rich, Stephen S and Rivadeneira, Fernando and Sattar, Naveed and Sever, Peter and Shaw-Hawkins, Sue and Shields, Denis C and Slagboom, P Eline and Smith, Nicholas L and Smith, Joshua D and Sotoodehnia, Nona and Stanton, Alice and Stott, David J and Stricker, Bruno H and St{\"u}rmer, Til and Uitterlinden, Andr{\'e} G and Wei, Wei-Qi and Westendorp, Rudi G J and Whitsel, Eric A and Wiggins, Kerri L and Wilke, Russell A and Ballantyne, Christie M and Colhoun, Helen M and Cupples, L Adrienne and Franco, Oscar H and Gudnason, Vilmundur and Hitman, Graham and Palmer, Colin N A and Psaty, Bruce M and Ridker, Paul M and Stafford, Jeanette M and Stein, Charles M and Tardif, Jean-Claude and Caulfield, Mark J and Jukema, J Wouter and Rotter, Jerome I and Krauss, Ronald M} } @article {7340, title = {The complex genetics of gait speed: genome-wide meta-analysis approach.}, journal = {Aging (Albany NY)}, volume = {9}, year = {2017}, month = {2017 Jan 10}, pages = {209-246}, abstract = {

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.

}, issn = {1945-4589}, doi = {10.18632/aging.101151}, author = {Ben-Avraham, Dan and Karasik, David and Verghese, Joe and Lunetta, Kathryn L and Smith, Jennifer A and Eicher, John D and Vered, Rotem and Deelen, Joris and Arnold, Alice M and Buchman, Aron S and Tanaka, Toshiko and Faul, Jessica D and Nethander, Maria and Fornage, Myriam and Adams, Hieab H and Matteini, Amy M and Callisaya, Michele L and Smith, Albert V and Yu, Lei and De Jager, Philip L and Evans, Denis A and Gudnason, Vilmundur and Hofman, Albert and Pattie, Alison and Corley, Janie and Launer, Lenore J and Knopman, Davis S and Parimi, Neeta and Turner, Stephen T and Bandinelli, Stefania and Beekman, Marian and Gutman, Danielle and Sharvit, Lital and Mooijaart, Simon P and Liewald, David C and Houwing-Duistermaat, Jeanine J and Ohlsson, Claes and Moed, Matthijs and Verlinden, Vincent J and Mellstr{\"o}m, Dan and van der Geest, Jos N and Karlsson, Magnus and Hernandez, Dena and McWhirter, Rebekah and Liu, Yongmei and Thomson, Russell and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and Weir, David R and Zhao, Wei and Starr, John M and Johnson, Andrew D and Ikram, M Arfan and Bennett, David A and Cummings, Steven R and Deary, Ian J and Harris, Tamara B and Kardia, Sharon L R and Mosley, Thomas H and Srikanth, Velandai K and Windham, Beverly G and Newman, Ann B and Walston, Jeremy D and Davies, Gail and Evans, Daniel S and Slagboom, Eline P and Ferrucci, Luigi and Kiel, Douglas P and Murabito, Joanne M and Atzmon, Gil} } @article {7353, title = {A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.}, journal = {J Med Genet}, volume = {54}, year = {2017}, month = {2017 May}, pages = {313-323}, abstract = {

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-104112}, author = {Noordam, Raymond and Sitlani, Colleen M and Avery, Christy L and Stewart, James D and Gogarten, Stephanie M and Wiggins, Kerri L and Trompet, Stella and Warren, Helen R and Sun, Fangui and Evans, Daniel S and Li, Xiaohui and Li, Jin and Smith, Albert V and Bis, Joshua C and Brody, Jennifer A and Busch, Evan L and Caulfield, Mark J and Chen, Yii-der I and Cummings, Steven R and Cupples, L Adrienne and Duan, Qing and Franco, Oscar H and M{\'e}ndez-Gir{\'a}ldez, R{\'a}ul and Harris, Tamara B and Heckbert, Susan R and van Heemst, Diana and Hofman, Albert and Floyd, James S and Kors, Jan A and Launer, Lenore J and Li, Yun and Li-Gao, Ruifang and Lange, Leslie A and Lin, Henry J and de Mutsert, Ren{\'e}e and Napier, Melanie D and Newton-Cheh, Christopher and Poulter, Neil and Reiner, Alexander P and Rice, Kenneth M and Roach, Jeffrey and Rodriguez, Carlos J and Rosendaal, Frits R and Sattar, Naveed and Sever, Peter and Seyerle, Amanda A and Slagboom, P Eline and Soliman, Elsayed Z and Sotoodehnia, Nona and Stott, David J and St{\"u}rmer, Til and Taylor, Kent D and Thornton, Timothy A and Uitterlinden, Andr{\'e} G and Wilhelmsen, Kirk C and Wilson, James G and Gudnason, Vilmundur and Jukema, J Wouter and Laurie, Cathy C and Liu, Yongmei and Mook-Kanamori, Dennis O and Munroe, Patricia B and Rotter, Jerome I and Vasan, Ramachandran S and Psaty, Bruce M and Stricker, Bruno H and Whitsel, Eric A} } @article {7600, title = {Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 Jul 19}, pages = {80}, abstract = {

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 {\texttimes} 10-8) or suggestively genome wide (p < 2.3 {\texttimes} 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.

}, issn = {2041-1723}, doi = {10.1038/s41467-017-00031-7}, author = {Zillikens, M Carola and Demissie, Serkalem and Hsu, Yi-Hsiang and Yerges-Armstrong, Laura M and Chou, Wen-Chi and Stolk, Lisette and Livshits, Gregory and Broer, Linda and Johnson, Toby and Koller, Daniel L and Kutalik, Zolt{\'a}n and Luan, Jian{\textquoteright}an and Malkin, Ida and Ried, Janina S and Smith, Albert V and Thorleifsson, Gudmar and Vandenput, Liesbeth and Hua Zhao, Jing and Zhang, Weihua and Aghdassi, Ali and {\r A}kesson, Kristina and Amin, Najaf and Baier, Leslie J and Barroso, In{\^e}s and Bennett, David A and Bertram, Lars and Biffar, Rainer and Bochud, Murielle and Boehnke, Michael and Borecki, Ingrid B and Buchman, Aron S and Byberg, Liisa and Campbell, Harry and Campos Obanda, Natalia and Cauley, Jane A and Cawthon, Peggy M and Cederberg, Henna and Chen, Zhao and Cho, Nam H and Jin Choi, Hyung and Claussnitzer, Melina and Collins, Francis and Cummings, Steven R and De Jager, Philip L and Demuth, Ilja and Dhonukshe-Rutten, Rosalie A M and Diatchenko, Luda and Eiriksdottir, Gudny and Enneman, Anke W and Erdos, Mike and Eriksson, Johan G and Eriksson, Joel and Estrada, Karol and Evans, Daniel S and Feitosa, Mary F and Fu, Mao and Garcia, Melissa and Gieger, Christian and Girke, Thomas and Glazer, Nicole L and Grallert, Harald and Grewal, Jagvir and Han, Bok-Ghee and Hanson, Robert L and Hayward, Caroline and Hofman, Albert and Hoffman, Eric P and Homuth, Georg and Hsueh, Wen-Chi and Hubal, Monica J and Hubbard, Alan and Huffman, Kim M and Husted, Lise B and Illig, Thomas and Ingelsson, Erik and Ittermann, Till and Jansson, John-Olov and Jordan, Joanne M and Jula, Antti and Karlsson, Magnus and Khaw, Kay-Tee and Kilpel{\"a}inen, Tuomas O and Klopp, Norman and Kloth, Jacqueline S L and Koistinen, Heikki A and Kraus, William E and Kritchevsky, Stephen and Kuulasmaa, Teemu and Kuusisto, Johanna and Laakso, Markku and Lahti, Jari and Lang, Thomas and Langdahl, Bente L and Launer, Lenore J and Lee, Jong-Young and Lerch, Markus M and Lewis, Joshua R and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Liu, Tian and Liu, Youfang and Ljunggren, Osten and Lorentzon, Mattias and Luben, Robert N and Maixner, William and McGuigan, Fiona E and Medina-G{\'o}mez, Carolina and Meitinger, Thomas and Melhus, H{\r a}kan and Mellstr{\"o}m, Dan and Melov, Simon and Micha{\"e}lsson, Karl and Mitchell, Braxton D and Morris, Andrew P and Mosekilde, Leif and Newman, Anne and Nielson, Carrie M and O{\textquoteright}Connell, Jeffrey R and Oostra, Ben A and Orwoll, Eric S and Palotie, Aarno and Parker, Stephen C J and Peacock, Munro and Perola, Markus and Peters, Annette and Polasek, Ozren and Prince, Richard L and R{\"a}ikk{\"o}nen, Katri and Ralston, Stuart H and Ripatti, Samuli and Robbins, John A and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Satterfield, Suzanne and Schadt, Eric E and Schipf, Sabine and Scott, Laura and Sehmi, Joban and Shen, Jian and Soo Shin, Chan and Sigurdsson, Gunnar and Smith, Shad and Soranzo, Nicole and Stan{\v c}{\'a}kov{\'a}, Alena and Steinhagen-Thiessen, Elisabeth and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Swart, Karin M A and Tan, Sian-Tsung and Tarnopolsky, Mark A and Thompson, Patricia and Thomson, Cynthia A and Thorsteinsdottir, Unnur and Tikkanen, Emmi and Tranah, Gregory J and Tuomilehto, Jaakko and van Schoor, Natasja M and Verma, Arjun and Vollenweider, Peter and V{\"o}lzke, Henry and Wactawski-Wende, Jean and Walker, Mark and Weedon, Michael N and Welch, Ryan and Wichmann, H-Erich and Widen, Elisabeth and Williams, Frances M K and Wilson, James F and Wright, Nicole C and Xie, Weijia and Yu, Lei and Zhou, Yanhua and Chambers, John C and D{\"o}ring, Angela and van Duijn, Cornelia M and Econs, Michael J and Gudnason, Vilmundur and Kooner, Jaspal S and Psaty, Bruce M and Spector, Timothy D and Stefansson, Kari and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Ossowski, Vicky and Waterworth, Dawn and Loos, Ruth J F and Karasik, David and Harris, Tamara B and Ohlsson, Claes and Kiel, Douglas P} } @article {7448, title = {PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, pages = {e001632}, abstract = {

BACKGROUND: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.

METHODS AND RESULTS: These 9 studies together included 17 459 blacks with 403 (2.3\%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1\%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95\% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95\% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95\% CI, 0.28-0.92) in blacks and 0.82 (95\% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95\% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95\% CI, 0.80-1.41 in whites).

CONCLUSIONS: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001632}, author = {Kent, Shia T and Rosenson, Robert S and Avery, Christy L and Chen, Yii-der I and Correa, Adolfo and Cummings, Steven R and Cupples, L Adrienne and Cushman, Mary and Evans, Daniel S and Gudnason, Vilmundur and Harris, Tamara B and Howard, George and Irvin, Marguerite R and Judd, Suzanne E and Jukema, J Wouter and Lange, Leslie and Levitan, Emily B and Li, Xiaohui and Liu, Yongmei and Post, Wendy S and Postmus, Iris and Psaty, Bruce M and Rotter, Jerome I and Safford, Monika M and Sitlani, Colleen M and Smith, Albert V and Stewart, James D and Trompet, Stella and Sun, Fangui and Vasan, Ramachandran S and Woolley, J Michael and Whitsel, Eric A and Wiggins, Kerri L and Wilson, James G and Muntner, Paul} } @article {7974, title = {Disentangling the genetics of lean mass.}, journal = {Am J Clin Nutr}, volume = {109}, year = {2019}, month = {2019 Feb 01}, pages = {276-287}, abstract = {

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.

}, issn = {1938-3207}, doi = {10.1093/ajcn/nqy272}, author = {Karasik, David and Zillikens, M Carola and Hsu, Yi-Hsiang and Aghdassi, Ali and {\r A}kesson, Kristina and Amin, Najaf and Barroso, In{\^e}s and Bennett, David A and Bertram, Lars and Bochud, Murielle and Borecki, Ingrid B and Broer, Linda and Buchman, Aron S and Byberg, Liisa and Campbell, Harry and Campos-Obando, Natalia and Cauley, Jane A and Cawthon, Peggy M and Chambers, John C and Chen, Zhao and Cho, Nam H and Choi, Hyung Jin and Chou, Wen-Chi and Cummings, Steven R and de Groot, Lisette C P G M and De Jager, Phillip L and Demuth, Ilja and Diatchenko, Luda and Econs, Michael J and Eiriksdottir, Gudny and Enneman, Anke W and Eriksson, Joel and Eriksson, Johan G and Estrada, Karol and Evans, Daniel S and Feitosa, Mary F and Fu, Mao and Gieger, Christian and Grallert, Harald and Gudnason, Vilmundur and Lenore, Launer J and Hayward, Caroline and Hofman, Albert and Homuth, Georg and Huffman, Kim M and Husted, Lise B and Illig, Thomas and Ingelsson, Erik and Ittermann, Till and Jansson, John-Olov and Johnson, Toby and Biffar, Reiner and Jordan, Joanne M and Jula, Antti and Karlsson, Magnus and Khaw, Kay-Tee and Kilpel{\"a}inen, Tuomas O and Klopp, Norman and Kloth, Jacqueline S L and Koller, Daniel L and Kooner, Jaspal S and Kraus, William E and Kritchevsky, Stephen and Kutalik, Zolt{\'a}n and Kuulasmaa, Teemu and Kuusisto, Johanna and Laakso, Markku and Lahti, Jari and Lang, Thomas and Langdahl, Bente L and Lerch, Markus M and Lewis, Joshua R and Lill, Christina and Lind, Lars and Lindgren, Cecilia and Liu, Yongmei and Livshits, Gregory and Ljunggren, Osten and Loos, Ruth J F and Lorentzon, Mattias and Luan, Jian{\textquoteright}an and Luben, Robert N and Malkin, Ida and McGuigan, Fiona E and Medina-G{\'o}mez, Carolina and Meitinger, Thomas and Melhus, H{\r a}kan and Mellstr{\"o}m, Dan and Micha{\"e}lsson, Karl and Mitchell, Braxton D and Morris, Andrew P and Mosekilde, Leif and Nethander, Maria and Newman, Anne B and O{\textquoteright}Connell, Jeffery R and Oostra, Ben A and Orwoll, Eric S and Palotie, Aarno and Peacock, Munro and Perola, Markus and Peters, Annette and Prince, Richard L and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Ralston, Stuart H and Ripatti, Samuli and Rivadeneira, Fernando and Robbins, John A and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Satterfield, Suzanne and Schipf, Sabine and Shin, Chan Soo and Smith, Albert V and Smith, Shad B and Soranzo, Nicole and Spector, Timothy D and Stan{\v c}{\'a}kov{\'a}, Alena and Stefansson, Kari and Steinhagen-Thiessen, Elisabeth and Stolk, Lisette and Streeten, Elizabeth A and Styrkarsdottir, Unnur and Swart, Karin M A and Thompson, Patricia and Thomson, Cynthia A and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tikkanen, Emmi and Tranah, Gregory J and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and van Schoor, Natasja M and Vandenput, Liesbeth and Vollenweider, Peter and V{\"o}lzke, Henry and Wactawski-Wende, Jean and Walker, Mark and J Wareham, Nicholas and Waterworth, Dawn and Weedon, Michael N and Wichmann, H-Erich and Widen, Elisabeth and Williams, Frances M K and Wilson, James F and Wright, Nicole C and Yerges-Armstrong, Laura M and Yu, Lei and Zhang, Weihua and Zhao, Jing Hua and Zhou, Yanhua and Nielson, Carrie M and Harris, Tamara B and Demissie, Serkalem and Kiel, Douglas P and Ohlsson, Claes} } @article {8989, title = {What Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {76}, year = {2021}, month = {2021 09 13}, pages = {e321-e327}, abstract = {

BACKGROUND: Cut-points to define slow walking speed have largely been derived from expert opinion.

METHODS: Study participants (13 589 men and 5043 women aged >=65years) had walking speed (m/s) measured over 4-6 m (mean {\textpm} SD: 1.20 {\textpm} 0.27 m/s in men and 0.94 {\textpm} 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6\% men, 26.4\% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.

RESULTS: Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2\%) with walking speed >=0.75 m/s, which we labeled as "fast"; 478 (9.5\%) as "intermediate" (walking speed >=0.62 m/s but <0.75 m/s); and 421 (8.3\%) as "slow" (walking speed <0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6\%) with walking speed >=1.00 m/s ("very fast"); 2901 (21.3\%) as "fast" (walking speed >=0.74 m/s but <1.00 m/s); 497 (3.7\%) as "intermediate" (walking speed >=0.57 m/s but <0.74 m/s); and 190 (1.4\%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11\% for men and 19\% for women) and highest in the "slow" (60.5\% in men and 71.0\% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.

CONCLUSIONS: Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

}, keywords = {Aged, Female, Gait, Humans, Independent Living, Male, Mobility Limitation, Sarcopenia, Walking, Walking Speed}, issn = {1758-535X}, doi = {10.1093/gerona/glab183}, author = {Cawthon, Peggy M and Patel, Sheena M and Kritchevsky, Stephen B and Newman, Anne B and Santanasto, Adam and Kiel, Douglas P and Travison, Thomas G and Lane, Nancy and Cummings, Steven R and Orwoll, Eric S and Duchowny, Kate A and Kwok, Timothy and Hirani, Vasant and Schousboe, John and Karlsson, Magnus K and Mellstr{\"o}m, Dan and Ohlsson, Claes and Ljunggren, Osten and Xue, Qian-Li and Shardell, Michelle and Jordan, Joanne M and Pencina, Karol M and Fielding, Roger A and Magaziner, Jay and Correa-de-Araujo, Rosaly and Bhasin, Shalender and Manini, Todd M} } @article {9481, title = {Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-like-3, and Risk of Heart Failure in Elders.}, journal = {J Gerontol A Biol Sci Med Sci}, year = {2023}, month = {2023 Aug 25}, abstract = {

BACKGROUND: Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8.

METHODS: We tested the hypothesis that GDF-11 and GDF-8, and their major antagonists follistatin and follistatin-like (FSTL)-3, are associated with incident heart failure (HF) and its subtypes in elders. Based on validation experiments, we used liquid chromatography tandem mass spectrometry to measure total serum GDF-11 and GDF-8, along with follistatin and follistatin-like (FSTL)-3 by immunoassay, in two longitudinal cohorts of older adults.

RESULTS: In 2,599 participants (age 75.2{\textpm}4.3) followed for 10.8{\textpm}5.6 years, 721 HF events occurred. After adjustment, neither GDF-11 (HR per doubling: 0.93 [0.67, 1.30]) nor GDF-8 (HR: 1.02 per doubling [0.83, 1.27]) was associated with incident HF or its subtypes. Positive associations with HF were detected for follistatin (HR: 1.15 [1.00, 1.32]) and FLST-3 (HR: 1.38 [1.03, 1.85]), and with HF with preserved ejection fraction for FSTL-3 (HR: 1.77 [1.03, 3.02]). (All HRs per doubling of biomarker.) FSTL-3 associations with HF appeared stronger at higher follistatin levels and vice versa, and also for men, Blacks and lower kidney function.

CONCLUSIONS: Among older adults, serum follistatin and FSTL-3, but not GDF-11 or GDF-8, were associated with incident HF. These findings do not support the concept that low serum levels of total GDF-11 or GDF-8 contribute to HF late in life, but do implicate transforming growth factor-βsuperfamily pathways as potential therapeutic targets.

}, issn = {1758-535X}, doi = {10.1093/gerona/glad206}, author = {Kizer, Jorge R and Patel, Sheena and Ganz, Peter and Newman, Anne B and Bhasin, Shalender and Lee, Se-Jin and Cawthon, Peggy M and LeBrasseur, Nathan and Shah, Sanjiv J and Psaty, Bruce M and Tracy, Russell P and Cummings, Steven R} }