Adam J Santanasto1, Mary K Wojczynski2, Ryan K Cvejkus1, Shiow Lin2, Lihua Wang2, Bharat Thyagarajan3, Kaare Christensen4, Nicole Schupf5, Mary F Feitosa2, Ping An2, Joseph M Zmuda1. 1. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania, USA. 2. Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA. 3. Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, USA. 4. The Danish Aging Research Center, Epidemiology Unit, Institute of Public Health, University of Southern Denmark, Odense, Denmark. 5. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA.
Abstract
BACKGROUND: Gait speed is a powerful indicator of health with aging. Potential genetic contributions to gait speed and its decline with aging are not well defined. We determined the heritability of and potential genetic regions underlying change in gait speed using longitudinal data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30-110 years; 45% men). METHODS: Gait speed was measured over 4 m at baseline and follow-up (7 ± 1 years). Quantitative trait linkage analyses were completed using pedigree-based maximum likelihood methods with logarithm of the odds (LOD) scores greater than 3.0, indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height, and field center. RESULTS: At baseline, 26.9% of individuals had "slow" gait speed less than 1.0 m/s (mean: 1.1 ± 0.2 m/s) and gait speed declined at a rate of -0.02 ± 0.03 m/s per year (p < .0001). Baseline and change in gait speed were significantly heritable (h2 = 0.24-0.32, p < .05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a significant locus for change in gait speed on chromosome 16p (LOD = 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Association analyses on chromosome 16 showed that the strongest variant resides within the ADCY9 gene. CONCLUSION: Further analysis of the chromosome 16 region, and ADCY9 gene, may yield new insight on the biology of mobility decline with aging.
BACKGROUND: Gait speed is a powerful indicator of health with aging. Potential genetic contributions to gait speed and its decline with aging are not well defined. We determined the heritability of and potential genetic regions underlying change in gait speed using longitudinal data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30-110 years; 45% men). METHODS: Gait speed was measured over 4 m at baseline and follow-up (7 ± 1 years). Quantitative trait linkage analyses were completed using pedigree-based maximum likelihood methods with logarithm of the odds (LOD) scores greater than 3.0, indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height, and field center. RESULTS: At baseline, 26.9% of individuals had "slow" gait speed less than 1.0 m/s (mean: 1.1 ± 0.2 m/s) and gait speed declined at a rate of -0.02 ± 0.03 m/s per year (p < .0001). Baseline and change in gait speed were significantly heritable (h2 = 0.24-0.32, p < .05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a significant locus for change in gait speed on chromosome 16p (LOD = 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Association analyses on chromosome 16 showed that the strongest variant resides within the ADCY9 gene. CONCLUSION: Further analysis of the chromosome 16 region, and ADCY9 gene, may yield new insight on the biology of mobility decline with aging.
Authors: W Jack Rejeski; Peter H Brubaker; David C Goff; Lucille B Bearon; Jacquelyn W McClelland; Michael G Perri; Walter T Ambrosius Journal: Arch Intern Med Date: 2011-01-24
Authors: Dmitry Shungin; Thomas W Winkler; Damien C Croteau-Chonka; Teresa Ferreira; Adam E Locke; Reedik Mägi; Rona J Strawbridge; Tune H Pers; Krista Fischer; Anne E Justice; Tsegaselassie Workalemahu; Joseph M W Wu; Martin L Buchkovich; Nancy L Heard-Costa; Tamara S Roman; Alexander W Drong; Ci Song; Stefan Gustafsson; Felix R Day; Tonu Esko; Tove Fall; Zoltán Kutalik; Jian'an Luan; Joshua C Randall; André Scherag; Sailaja Vedantam; Andrew R Wood; Jin Chen; Rudolf Fehrmann; Juha Karjalainen; Bratati Kahali; Ching-Ti Liu; Ellen M Schmidt; Devin Absher; Najaf Amin; Denise Anderson; Marian Beekman; Jennifer L Bragg-Gresham; Steven Buyske; Ayse Demirkan; Georg B Ehret; Mary F Feitosa; Anuj Goel; Anne U Jackson; Toby Johnson; Marcus E Kleber; Kati Kristiansson; Massimo Mangino; Irene Mateo Leach; Carolina Medina-Gomez; Cameron D Palmer; Dorota Pasko; Sonali Pechlivanis; Marjolein J Peters; Inga Prokopenko; Alena Stančáková; Yun Ju Sung; Toshiko Tanaka; Alexander Teumer; Jana V Van Vliet-Ostaptchouk; Loïc Yengo; Weihua Zhang; Eva Albrecht; Johan Ärnlöv; Gillian M Arscott; Stefania Bandinelli; Amy Barrett; Claire Bellis; Amanda J Bennett; Christian Berne; Matthias Blüher; Stefan Böhringer; Fabrice Bonnet; Yvonne Böttcher; Marcel Bruinenberg; Delia B Carba; Ida H Caspersen; Robert Clarke; E Warwick Daw; Joris Deelen; Ewa Deelman; Graciela Delgado; Alex Sf Doney; Niina Eklund; Michael R Erdos; Karol Estrada; Elodie Eury; Nele Friedrich; Melissa E Garcia; Vilmantas Giedraitis; Bruna Gigante; Alan S Go; Alain Golay; Harald Grallert; Tanja B Grammer; Jürgen Gräßler; Jagvir Grewal; Christopher J Groves; Toomas Haller; Goran Hallmans; Catharina A Hartman; Maija Hassinen; Caroline Hayward; Kauko Heikkilä; Karl-Heinz Herzig; Quinta Helmer; Hans L Hillege; Oddgeir Holmen; Steven C Hunt; Aaron Isaacs; Till Ittermann; Alan L James; Ingegerd Johansson; Thorhildur Juliusdottir; Ioanna-Panagiota Kalafati; Leena Kinnunen; Wolfgang Koenig; Ishminder K Kooner; Wolfgang Kratzer; Claudia Lamina; Karin Leander; Nanette R Lee; Peter Lichtner; Lars Lind; Jaana Lindström; Stéphane Lobbens; Mattias Lorentzon; François Mach; Patrik Ke Magnusson; Anubha Mahajan; Wendy L McArdle; Cristina Menni; Sigrun Merger; Evelin Mihailov; Lili Milani; Rebecca Mills; Alireza Moayyeri; Keri L Monda; Simon P Mooijaart; Thomas W Mühleisen; Antonella Mulas; Gabriele Müller; Martina Müller-Nurasyid; Ramaiah Nagaraja; Michael A Nalls; Narisu Narisu; Nicola Glorioso; Ilja M Nolte; Matthias Olden; Nigel W Rayner; Frida Renstrom; Janina S Ried; Neil R Robertson; Lynda M Rose; Serena Sanna; Hubert Scharnagl; Salome Scholtens; Bengt Sennblad; Thomas Seufferlein; Colleen M Sitlani; Albert Vernon Smith; Kathleen Stirrups; Heather M Stringham; Johan Sundström; Morris A Swertz; Amy J Swift; Ann-Christine Syvänen; Bamidele O Tayo; Barbara Thorand; Gudmar Thorleifsson; Andreas Tomaschitz; Chiara Troffa; Floor Va van Oort; Niek Verweij; Judith M Vonk; Lindsay L Waite; Roman Wennauer; Tom Wilsgaard; Mary K Wojczynski; Andrew Wong; Qunyuan Zhang; Jing Hua Zhao; Eoin P Brennan; Murim Choi; Per Eriksson; Lasse Folkersen; Anders Franco-Cereceda; Ali G Gharavi; Åsa K Hedman; Marie-France Hivert; Jinyan Huang; Stavroula Kanoni; Fredrik Karpe; Sarah Keildson; Krzysztof Kiryluk; Liming Liang; Richard P Lifton; Baoshan Ma; Amy J McKnight; Ruth McPherson; Andres Metspalu; Josine L Min; Miriam F Moffatt; Grant W Montgomery; Joanne M Murabito; George Nicholson; Dale R Nyholt; Christian Olsson; John Rb Perry; Eva Reinmaa; Rany M Salem; Niina Sandholm; Eric E Schadt; Robert A Scott; Lisette Stolk; Edgar E Vallejo; Harm-Jan Westra; Krina T Zondervan; Philippe Amouyel; Dominique Arveiler; Stephan Jl Bakker; John Beilby; Richard N Bergman; John Blangero; Morris J Brown; Michel Burnier; Harry Campbell; Aravinda Chakravarti; Peter S Chines; Simone Claudi-Boehm; Francis S Collins; Dana C Crawford; John Danesh; Ulf de Faire; Eco Jc de Geus; Marcus Dörr; Raimund Erbel; Johan G Eriksson; Martin Farrall; Ele Ferrannini; Jean Ferrières; Nita G Forouhi; Terrence Forrester; Oscar H Franco; Ron T Gansevoort; Christian Gieger; Vilmundur Gudnason; Christopher A Haiman; Tamara B Harris; Andrew T Hattersley; Markku Heliövaara; Andrew A Hicks; Aroon D Hingorani; Wolfgang Hoffmann; Albert Hofman; Georg Homuth; Steve E Humphries; Elina Hyppönen; Thomas Illig; Marjo-Riitta Jarvelin; Berit Johansen; Pekka Jousilahti; Antti M Jula; Jaakko Kaprio; Frank Kee; Sirkka M Keinanen-Kiukaanniemi; Jaspal S Kooner; Charles Kooperberg; Peter Kovacs; Aldi T Kraja; Meena Kumari; Kari Kuulasmaa; Johanna Kuusisto; Timo A Lakka; Claudia Langenberg; Loic Le Marchand; Terho Lehtimäki; Valeriya Lyssenko; Satu Männistö; André Marette; Tara C Matise; Colin A McKenzie; Barbara McKnight; Arthur W Musk; Stefan Möhlenkamp; Andrew D Morris; Mari Nelis; Claes Ohlsson; Albertine J Oldehinkel; Ken K Ong; Lyle J Palmer; Brenda W Penninx; Annette Peters; Peter P Pramstaller; Olli T Raitakari; Tuomo Rankinen; D C Rao; Treva K Rice; Paul M Ridker; Marylyn D Ritchie; Igor Rudan; Veikko Salomaa; Nilesh J Samani; Jouko Saramies; Mark A Sarzynski; Peter Eh Schwarz; Alan R Shuldiner; Jan A Staessen; Valgerdur Steinthorsdottir; Ronald P Stolk; Konstantin Strauch; Anke Tönjes; Angelo Tremblay; Elena Tremoli; Marie-Claude Vohl; Uwe Völker; Peter Vollenweider; James F Wilson; Jacqueline C Witteman; Linda S Adair; Murielle Bochud; Bernhard O Boehm; Stefan R Bornstein; Claude Bouchard; Stéphane Cauchi; Mark J Caulfield; John C Chambers; Daniel I Chasman; Richard S Cooper; George Dedoussis; Luigi Ferrucci; Philippe Froguel; Hans-Jörgen Grabe; Anders Hamsten; Jennie Hui; Kristian Hveem; Karl-Heinz Jöckel; Mika Kivimaki; Diana Kuh; Markku Laakso; Yongmei Liu; Winfried März; Patricia B Munroe; Inger Njølstad; Ben A Oostra; Colin Na Palmer; Nancy L Pedersen; Markus Perola; Louis Pérusse; Ulrike Peters; Chris Power; Thomas Quertermous; Rainer Rauramaa; Fernando Rivadeneira; Timo E Saaristo; Danish Saleheen; Juha Sinisalo; P Eline Slagboom; Harold Snieder; Tim D Spector; Kari Stefansson; Michael Stumvoll; Jaakko Tuomilehto; André G Uitterlinden; Matti Uusitupa; Pim van der Harst; Giovanni Veronesi; Mark Walker; Nicholas J Wareham; Hugh Watkins; H-Erich Wichmann; Goncalo R Abecasis; Themistocles L Assimes; Sonja I Berndt; Michael Boehnke; Ingrid B Borecki; Panos Deloukas; Lude Franke; Timothy M Frayling; Leif C Groop; David J Hunter; Robert C Kaplan; Jeffrey R O'Connell; Lu Qi; David Schlessinger; David P Strachan; Unnur Thorsteinsdottir; Cornelia M van Duijn; Cristen J Willer; Peter M Visscher; Jian Yang; Joel N Hirschhorn; M Carola Zillikens; Mark I McCarthy; Elizabeth K Speliotes; Kari E North; Caroline S Fox; Inês Barroso; Paul W Franks; Erik Ingelsson; Iris M Heid; Ruth Jf Loos; L Adrienne Cupples; Andrew P Morris; Cecilia M Lindgren; Karen L Mohlke Journal: Nature Date: 2015-02-12 Impact factor: 49.962
Authors: Mariaelisa Graff; Robert A Scott; Anne E Justice; Kristin L Young; Mary F Feitosa; Llilda Barata; Thomas W Winkler; Audrey Y Chu; Anubha Mahajan; David Hadley; Luting Xue; Tsegaselassie Workalemahu; Nancy L Heard-Costa; Marcel den Hoed; Tarunveer S Ahluwalia; Qibin Qi; Julius S Ngwa; Frida Renström; Lydia Quaye; John D Eicher; James E Hayes; Marilyn Cornelis; Zoltan Kutalik; Elise Lim; Jian'an Luan; Jennifer E Huffman; Weihua Zhang; Wei Zhao; Paula J Griffin; Toomas Haller; Shafqat Ahmad; Pedro M Marques-Vidal; Stephanie Bien; Loic Yengo; Alexander Teumer; Albert Vernon Smith; Meena Kumari; Marie Neergaard Harder; Johanne Marie Justesen; Marcus E Kleber; Mette Hollensted; Kurt Lohman; Natalia V Rivera; John B Whitfield; Jing Hua Zhao; Heather M Stringham; Leo-Pekka Lyytikäinen; Charlotte Huppertz; Gonneke Willemsen; Wouter J Peyrot; Ying Wu; Kati Kristiansson; Ayse Demirkan; Myriam Fornage; Maija Hassinen; Lawrence F Bielak; Gemma Cadby; Toshiko Tanaka; Reedik Mägi; Peter J van der Most; Anne U Jackson; Jennifer L Bragg-Gresham; Veronique Vitart; Jonathan Marten; Pau Navarro; Claire Bellis; Dorota Pasko; Åsa Johansson; Søren Snitker; Yu-Ching Cheng; Joel Eriksson; Unhee Lim; Mette Aadahl; Linda S Adair; Najaf Amin; Beverley Balkau; Juha Auvinen; John Beilby; Richard N Bergman; Sven Bergmann; Alain G Bertoni; John Blangero; Amélie Bonnefond; Lori L Bonnycastle; Judith B Borja; Søren Brage; Fabio Busonero; Steve Buyske; Harry Campbell; Peter S Chines; Francis S Collins; Tanguy Corre; George Davey Smith; Graciela E Delgado; Nicole Dueker; Marcus Dörr; Tapani Ebeling; Gudny Eiriksdottir; Tõnu Esko; Jessica D Faul; Mao Fu; Kristine Færch; Christian Gieger; Sven Gläser; Jian Gong; Penny Gordon-Larsen; Harald Grallert; Tanja B Grammer; Niels Grarup; Gerard van Grootheest; Kennet Harald; Nicholas D Hastie; Aki S Havulinna; Dena Hernandez; Lucia Hindorff; Lynne J Hocking; Oddgeir L Holmens; Christina Holzapfel; Jouke Jan Hottenga; Jie Huang; Tao Huang; Jennie Hui; Cornelia Huth; Nina Hutri-Kähönen; Alan L James; John-Olov Jansson; Min A Jhun; Markus Juonala; Leena Kinnunen; Heikki A Koistinen; Ivana Kolcic; Pirjo Komulainen; Johanna Kuusisto; Kirsti Kvaløy; Mika Kähönen; Timo A Lakka; Lenore J Launer; Benjamin Lehne; Cecilia M Lindgren; Mattias Lorentzon; Robert Luben; Michel Marre; Yuri Milaneschi; Keri L Monda; Grant W Montgomery; Marleen H M De Moor; Antonella Mulas; Martina Müller-Nurasyid; A W Musk; Reija Männikkö; Satu Männistö; Narisu Narisu; Matthias Nauck; Jennifer A Nettleton; Ilja M Nolte; Albertine J Oldehinkel; Matthias Olden; Ken K Ong; Sandosh Padmanabhan; Lavinia Paternoster; Jeremiah Perez; Markus Perola; Annette Peters; Ulrike Peters; Patricia A Peyser; Inga Prokopenko; Hannu Puolijoki; Olli T Raitakari; Tuomo Rankinen; Laura J Rasmussen-Torvik; Rajesh Rawal; Paul M Ridker; Lynda M Rose; Igor Rudan; Cinzia Sarti; Mark A Sarzynski; Kai Savonen; William R Scott; Serena Sanna; Alan R Shuldiner; Steve Sidney; Günther Silbernagel; Blair H Smith; Jennifer A Smith; Harold Snieder; Alena Stančáková; Barbara Sternfeld; Amy J Swift; Tuija Tammelin; Sian-Tsung Tan; Barbara Thorand; Dorothée Thuillier; Liesbeth Vandenput; Henrik Vestergaard; Jana V van Vliet-Ostaptchouk; Marie-Claude Vohl; Uwe Völker; Gérard Waeber; Mark Walker; Sarah Wild; Andrew Wong; Alan F Wright; M Carola Zillikens; Niha Zubair; Christopher A Haiman; Loic Lemarchand; Ulf Gyllensten; Claes Ohlsson; Albert Hofman; Fernando Rivadeneira; André G Uitterlinden; Louis Pérusse; James F Wilson; Caroline Hayward; Ozren Polasek; Francesco Cucca; Kristian Hveem; Catharina A Hartman; Anke Tönjes; Stefania Bandinelli; Lyle J Palmer; Sharon L R Kardia; Rainer Rauramaa; Thorkild I A Sørensen; Jaakko Tuomilehto; Veikko Salomaa; Brenda W J H Penninx; Eco J C de Geus; Dorret I Boomsma; Terho Lehtimäki; Massimo Mangino; Markku Laakso; Claude Bouchard; Nicholas G Martin; Diana Kuh; Yongmei Liu; Allan Linneberg; Winfried März; Konstantin Strauch; Mika Kivimäki; Tamara B Harris; Vilmundur Gudnason; Henry Völzke; Lu Qi; Marjo-Riitta Järvelin; John C Chambers; Jaspal S Kooner; Philippe Froguel; Charles Kooperberg; Peter Vollenweider; Göran Hallmans; Torben Hansen; Oluf Pedersen; Andres Metspalu; Nicholas J Wareham; Claudia Langenberg; David R Weir; David J Porteous; Eric Boerwinkle; Daniel I Chasman; Gonçalo R Abecasis; Inês Barroso; Mark I McCarthy; Timothy M Frayling; Jeffrey R O'Connell; Cornelia M van Duijn; Michael Boehnke; Iris M Heid; Karen L Mohlke; David P Strachan; Caroline S Fox; Ching-Ti Liu; Joel N Hirschhorn; Robert J Klein; Andrew D Johnson; Ingrid B Borecki; Paul W Franks; Kari E North; L Adrienne Cupples; Ruth J F Loos; Tuomas O Kilpeläinen Journal: PLoS Genet Date: 2017-04-27 Impact factor: 5.917
Authors: Annalisa Buniello; Jacqueline A L MacArthur; Maria Cerezo; Laura W Harris; James Hayhurst; Cinzia Malangone; Aoife McMahon; Joannella Morales; Edward Mountjoy; Elliot Sollis; Daniel Suveges; Olga Vrousgou; Patricia L Whetzel; Ridwan Amode; Jose A Guillen; Harpreet S Riat; Stephen J Trevanion; Peggy Hall; Heather Junkins; Paul Flicek; Tony Burdett; Lucia A Hindorff; Fiona Cunningham; Helen Parkinson Journal: Nucleic Acids Res Date: 2019-01-08 Impact factor: 16.971
Authors: María Soler Artigas; Louise V Wain; Suzanne Miller; Abdul Kader Kheirallah; Jennifer E Huffman; Ioanna Ntalla; Nick Shrine; Ma'en Obeidat; Holly Trochet; Wendy L McArdle; Alexessander Couto Alves; Jennie Hui; Jing Hua Zhao; Peter K Joshi; Alexander Teumer; Eva Albrecht; Medea Imboden; Rajesh Rawal; Lorna M Lopez; Jonathan Marten; Stefan Enroth; Ida Surakka; Ozren Polasek; Leo-Pekka Lyytikäinen; Raquel Granell; Pirro G Hysi; Claudia Flexeder; Anubha Mahajan; John Beilby; Yohan Bossé; Corry-Anke Brandsma; Harry Campbell; Christian Gieger; Sven Gläser; Juan R González; Harald Grallert; Chris J Hammond; Sarah E Harris; Anna-Liisa Hartikainen; Markku Heliövaara; John Henderson; Lynne Hocking; Momoko Horikoshi; Nina Hutri-Kähönen; Erik Ingelsson; Åsa Johansson; John P Kemp; Ivana Kolcic; Ashish Kumar; Lars Lind; Erik Melén; Arthur W Musk; Pau Navarro; David C Nickle; Sandosh Padmanabhan; Olli T Raitakari; Janina S Ried; Samuli Ripatti; Holger Schulz; Robert A Scott; Don D Sin; John M Starr; Ana Viñuela; Henry Völzke; Sarah H Wild; Alan F Wright; Tatijana Zemunik; Deborah L Jarvis; Tim D Spector; David M Evans; Terho Lehtimäki; Veronique Vitart; Mika Kähönen; Ulf Gyllensten; Igor Rudan; Ian J Deary; Stefan Karrasch; Nicole M Probst-Hensch; Joachim Heinrich; Beate Stubbe; James F Wilson; Nicholas J Wareham; Alan L James; Andrew P Morris; Marjo-Riitta Jarvelin; Caroline Hayward; Ian Sayers; David P Strachan; Ian P Hall; Martin D Tobin Journal: Nat Commun Date: 2015-12-04 Impact factor: 14.919
Authors: Christopher Hübel; Héléna A Gaspar; Jonathan R I Coleman; Hilary Finucane; Kirstin L Purves; Ken B Hanscombe; Inga Prokopenko; Mariaelisa Graff; Julius S Ngwa; Tsegaselassie Workalemahu; Paul F O'Reilly; Cynthia M Bulik; Gerome Breen Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2018-12-28 Impact factor: 3.568