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Kiel, Douglas

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Kiel

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Douglas

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Kiel, Douglas
Author's Publications: search.filters.isAuthorOfPublication.37a27286-e840-41d2-a716-9cadc8b8e700

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    The complex genetics of gait speed: genome-wide meta-analysis approach
    (Impact Journals LLC, 2017) Ben-Avraham, Dan; Karasik, David; Verghese, Joe; Lunetta, Kathryn L.; Smith, Jennifer A.; Eicher, John D.; Vered, Rotem; Deelen, Joris; Arnold, Alice M.; Buchman, Aron S.; Tanaka, Toshiko; Faul, Jessica D.; Nethander, Maria; Fornage, Myriam; Adams, Hieab H.; Matteini, Amy M.; Callisaya, Michele L.; Smith, Albert V.; Yu, Lei; De Jager, Philip; Evans, Denis A.; Gudnason, Vilmundur; Hofman, Albert; Pattie, Alison; Corley, Janie; Launer, Lenore J.; Knopman, Davis S.; Parimi, Neeta; Turner, Stephen T.; Bandinelli, Stefania; Beekman, Marian; Gutman, Danielle; Sharvit, Lital; Mooijaart, Simon P.; Liewald, David C.; Houwing-Duistermaat, Jeanine J.; Ohlsson, Claes; Moed, Matthijs; Verlinden, Vincent J.; Mellström, Dan; van der Geest, Jos N.; Karlsson, Magnus; Hernandez, Dena; McWhirter, Rebekah; Liu, Yongmei; Thomson, Russell; Tranah, Gregory J.; Uitterlinden, Andre G.; Weir, David R.; Zhao, Wei; Starr, John M.; Johnson, Andrew D.; Ikram, M. Arfan; Bennett, David A.; Cummings, Steven R.; Deary, Ian J.; Harris, Tamara B.; Kardia, Sharon L. R.; Mosley, Thomas H.; Srikanth, Velandai K.; Windham, Beverly G.; Newman, Ann B.; Walston, Jeremy D.; Davies, Gail; Evans, Daniel S.; Slagboom, Eline P.; Ferrucci, Luigi; Kiel, Douglas; Murabito, Joanne M.; Atzmon, Gil
    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.
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    Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels
    (Nature Publishing Group UK, 2018) Jiang, Xia; O’Reilly, Paul F.; Aschard, Hugues; Hsu, Yi-Hsiang; Richards, J. Brent; Dupuis, Josée; Ingelsson, Erik; Karasik, David; Pilz, Stefan; Berry, Diane; Kestenbaum, Bryan; Zheng, Jusheng; Luan, Jianan; Sofianopoulou, Eleni; Streeten, Elizabeth A.; Albanes, Demetrius; Lutsey, Pamela L.; Yao, Lu; Tang, Weihong; Econs, Michael J.; Wallaschofski, Henri; Völzke, Henry; Zhou, Ang; Power, Chris; McCarthy, Mark I.; Michos, Erin D.; Boerwinkle, Eric; Weinstein, Stephanie J.; Freedman, Neal D.; Huang, Wen-Yi; Van Schoor, Natasja M.; van der Velde, Nathalie; Groot, Lisette C. P. G. M. de; Enneman, Anke; Cupples, L. Adrienne; Booth, Sarah L.; Vasan, Ramachandran S.; Liu, Ching-Ti; Zhou, Yanhua; Ripatti, Samuli; Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias; Eriksson, Johan G.; Shea, M. Kyla; Houston, Denise K.; Kritchevsky, Stephen B.; Liu, Yongmei; Lohman, Kurt K.; Ferrucci, Luigi; Peacock, Munro; Gieger, Christian; Beekman, Marian; Slagboom, Eline; Deelen, Joris; Heemst, Diana van; Kleber, Marcus E.; März, Winfried; de Boer, Ian H.; Wood, Alexis C.; Rotter, Jerome I.; Rich, Stephen S.; Robinson-Cohen, Cassianne; den Heijer, Martin; Jarvelin, Marjo-Riitta; Cavadino, Alana; Joshi, Peter K.; Wilson, James F.; Hayward, Caroline; Lind, Lars; Michaëlsson, Karl; Trompet, Stella; Zillikens, M. Carola; Uitterlinden, Andre G.; Rivadeneira, Fernando; Broer, Linda; Zgaga, Lina; Campbell, Harry; Theodoratou, Evropi; Farrington, Susan M.; Timofeeva, Maria; Dunlop, Malcolm G.; Valdes, Ana M.; Tikkanen, Emmi; Lehtimäki, Terho; Lyytikäinen, Leo-Pekka; Kähönen, Mika; Raitakari, Olli T.; Mikkilä, Vera; Ikram, M. Arfan; Sattar, Naveed; Jukema, J. Wouter; Wareham, Nicholas J.; Langenberg, Claudia; Forouhi, Nita G.; Gundersen, Thomas E.; Khaw, Kay-Tee; Butterworth, Adam S.; Danesh, John; Spector, Timothy; Wang, Thomas J.; Hyppönen, Elina; Kraft, Phillip; Kiel, Douglas
    Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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    GWAS of epigenetic aging rates in blood reveals a critical role for TERT
    (Nature Publishing Group UK, 2018) Lu, Ake T.; Xue, Luting; Salfati, Elias L.; Chen, Brian H.; Ferrucci, Luigi; Levy, Daniel; Joehanes, Roby; Murabito, Joanne M.; Kiel, Douglas; Tsai, Pei-Chien; Yet, Idil; Bell, Jordana T.; Mangino, Massimo; Tanaka, Toshiko; McRae, Allan F.; Marioni, Riccardo E.; Visscher, Peter M.; Wray, Naomi R.; Deary, Ian J.; Levine, Morgan E.; Quach, Austin; Assimes, Themistocles; Tsao, Philip S.; Absher, Devin; Stewart, James D.; Li, Yun; Reiner, Alex P.; Hou, Lifang; Baccarelli, Andrea A.; Whitsel, Eric A.; Aviv, Abraham; Cardona, Alexia; Day, Felix R.; Wareham, Nicholas J.; Perry, John R. B.; Ong, Ken K.; Raj, Kenneth; Lunetta, Kathryn L.; Horvath, Steve
    DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10−11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
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    Correction: The complex genetics of gait speed: genome-wide meta-analysis approach
    (Impact Journals LLC, 2017) Ben-Avraham, Dan; Karasik, David; Verghese, Joe; Lunetta, Kathryn L.; Smith, Jennifer A.; Eicher, John D.; Vered, Rotem; Deelen, Joris; Arnold, Alice M.; Buchman, Aron S.; Tanaka, Toshiko; Faul, Jessica D.; Nethander, Maria; Fornage, Myriam; Adams, Hieab H.; Matteini, Amy M.; Callisaya, Michele L.; Smith, Albert V.; Yu, Lei; De Jager, Philip; Evans, Denis A.; Gudnason, Vilmundur; Hofman, Albert; Pattie, Alison; Corley, Janie; Launer, Lenore J.; Knopman, Davis S.; Parimi, Neeta; Turner, Stephen T.; Bandinelli, Stefania; Beekman, Marian; Gutman, Danielle; Sharvit, Lital; Mooijaart, Simon P.; Liewald, David C.; Houwing-Duistermaat, Jeanine J.; Ohlsson, Claes; Moed, Matthijs; Verlinden, Vincent J.; Mellström, Dan; van der Geest, Jos N.; Karlsson, Magnus; Hernandez, Dena; McWhirter, Rebekah; Liu, Yongmei; Thomson, Russell; Tranah, Gregory J.; Uitterlinden, Andre G.; Weir, David R.; Zhao, Wei; Starr, John M.; Johnson, Andrew D.; Ikram, M. Arfan; Bennett, David A.; Cummings, Steven R.; Deary, Ian J.; Harris, Tamara B.; Kardia, Sharon L. R.; Mosley, Thomas H.; Srikanth, Velandai K.; Windham, Beverly G.; Newman, Ann B.; Walston, Jeremy D.; Davies, Gail; Evans, Daniel S.; Slagboom, Eline P.; Ferrucci, Luigi; Kiel, Douglas; Murabito, Joanne M.; Atzmon, Gil
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    Evaluation of a new approach to compute intervertebral disc height measurements from lateral radiographic views of the spine
    (Springer Nature, 2016) Allaire, Brett T.; DePaolis Kaluza, M. Clara; Bruno, Alexander G.; Samelson, Elizabeth; Kiel, Douglas; Anderson, Dennis; Bouxsein, Mary
    Purpose Current standard methods to quantify disc height, namely distortion compensated Roentgen analysis (DCRA), have been mostly utilized in the lumbar and cervical spine and have strict exclusion criteria. Specifically, discs adjacent to a vertebral fracture are excluded from measurement, thus limiting the use of DCRA in studies that include older populations with a high prevalence of vertebral fractures. Thus, we developed and tested a modified DCRA algorithm that does not depend on vertebral shape. Methods Participants included 1186 men and women from the Framingham Heart Study Offspring and Third Generation Multidetector CT Study. Lateral CT scout images were used to place 6 morphometry points around each vertebra at 13 vertebral levels in each participant. Disc heights were calculated utilizing these morphometry points using DCRA methodology and our modified version of DCRA, which requires information from fewer morphometry points than the standard DCRA. Results Modified DCRA and standard DCRA measures of disc height are highly correlated, with concordance correlation coefficients above 0.999. Both measures demonstrate good inter- and intra-operator reproducibility. 13.9 % of available disc heights were not evaluable or excluded using the standard DCRA algorithm, while only 3.3 % of disc heights were not evaluable using our modified DCRA algorithm. Conclusions Using our modified DCRA algorithm, it is not necessary to exclude vertebrae with fracture or other deformity from disc height measurements as in the standard DCRA. Modified DCRA also yields identical measurements to the standard DCRA. Thus, the use of modified DCRA for quantitative assessment of disc height will lead to less missing data without any loss of accuracy, making it a preferred alternative to the current standard methodology.
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    Heritability of Thoracic Spine Curvature and Genetic Correlations With Other Spine Traits: The Framingham Study
    (Wiley, 2016) Yau, Michelle; Demissie, Serkalem; Zhou, Yanhua; Anderson, Dennis; Lorbergs, Amanda L; Kiel, Douglas; Allaire, Brett T; Yang, Laiji; Cupples, L Adrienne; Travison, Thomas; Bouxsein, Mary; Karasik, David; Samelson, Elizabeth
    Hyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co-occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T4–T12 kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (math formulaG, –0.46; 95% CI, –0.67 to –0.26), vertebral fracture (math formulaG, 0.39; 95% CI, 0.18 to 0.61), vBMD (math formulaG, –0.23; 95% CI, –0.41 to –0.04), and paraspinal muscle density (math formulaG, –0.22; 95% CI, –0.48 to 0.03). Genetic correlations between kyphosis angle and disc height narrowing (math formulaG, 0.17; 95% CI, –0.05 to 0.38) and facet joint OA (math formulaG, 0.05; 95% CI, –0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age-related spine traits including trunk muscle size, vertebral fracture, and bone mineral density.
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    Epigenome‐wide Association of DNA Methylation in Whole Blood With Bone Mineral Density
    (John Wiley and Sons Inc., 2017) Morris, John A; Tsai, Pei‐Chien; Joehanes, Roby; Zheng, Jie; Trajanoska, Katerina; Soerensen, Mette; Forgetta, Vincenzo; Castillo‐Fernandez, Juan Edgar; Frost, Morten; Spector, Tim D; Christensen, Kaare; Christiansen, Lene; Rivadeneira, Fernando; Tobias, Jonathan H; Evans, David M; Kiel, Douglas; Hsu, Yi‐Hsiang; Richards, J Brent; Bell, Jordana T
    ABSTRACT Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome‐wide association study (EWAS) of BMD. We undertook a large‐scale BMD EWAS using the Infinium HumanMethylation450 array to measure site‐specific DNA methylation in up to 5515 European‐descent individuals (NDiscovery = 4614, NValidation = 901). We associated methylation at multiple cytosine‐phosphate‐guanine (CpG) sites with dual‐energy X‐ray absorptiometry (DXA)‐derived femoral neck and lumbar spine BMD. We performed sex‐combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false‐discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females (p = 7.9 × 10−11) and 4614 females and males (p = 3.0 × 10−8). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females (p = 0.64) and 901 males and females (p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large‐effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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    The associations between QCT-based vertebral bone measurements and prevalent vertebral fractures depend on the spinal locations of both bone measurement and fracture
    (Springer Nature, 2013) Anderson, Dennis; Demissie, S.; Allaire, B. T.; Bruno, A. G.; Kopperdahl, D. L.; Keaveny, T. M.; Kiel, Douglas; Bouxsein, Mary
    Summary—We examined how spinal location affects the relationships between quantitative computed tomography (QCT)-based bone measurements and prevalent vertebral fractures. Upper spine (T4–T10) fractures appear to be more strongly related to bone measures than lower spine (T11–L4) fractures, while lower spine measurements are at least as strongly related to fractures as upper spine measurements. Introduction—Vertebral fracture (VF), a common injury in older adults, is most prevalent in the mid-thoracic (T7–T8) and thoracolumbar (T12–L1) areas of the spine. However, measurements of bone mineral density (BMD) are typically made in the lumbar spine. It is not clear how the associations between bone measurements and VFs are affected by the spinal locations of both bone measurements and VF. Methods—A community-based case–control study includes 40 cases with moderate or severe prevalent VF and 80 age- and sex-matched controls. Measures of vertebral BMD, strength (estimated by finite element analysis), and factor of risk (load:strength ratio) were determined based on QCT scans at the L3 and T10 vertebrae. Associations were determined between bone measures and prevalent VF occurring at any location, in the upper spine (T4–T10), or in the lower spine (T11–L4). Results—Prevalent VF at any location was significantly associated with bone measures, with odds ratios (ORs) generally higher for measurements made at L3 (ORs=1.9–3.9) than at T10 (ORs=1.5–2.4). Upper spine fracture was associated with these measures at both T10 and L3 (ORs=1.9–8.2), while lower spine fracture was less strongly associated (ORs=1.0–2.4) and only reached significance for volumetric BMD measures at L3. Conclusions—Closer proximity between the locations of bone measures and prevalent VF does not strengthen associations between bone measures and fracture. Furthermore, VF etiology may vary by region, with VFs in the upper spine more strongly related to skeletal fragility.
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    Dynamic Parameters of Balance Which Correlate to Elderly Persons with a History of Falls
    (Public Library of Science, 2013) Muir, Jesse W.; Kiel, Douglas; Hannan, Marian; Magaziner, Jay; Rubin, Clinton T.
    Poor balance in older persons contributes to a rise in fall risk and serious injury, yet no consensus has developed on which measures of postural sway can identify those at greatest risk of falling. Postural sway was measured in 161 elderly individuals (81.8y±7.4), 24 of which had at least one self-reported fall in the prior six months, and compared to sway measured in 37 young adults (34.9y±7.1). Center of pressure (COP) was measured during 4 minutes of quiet stance with eyes opened. In the elderly with fall history, all measures but one were worse than those taken from young adults (e.g., maximal COP velocity was 2.7× greater in fallers than young adults; p<0.05), while three measures of balance were significantly worse in fallers as compared to older persons with no recent fall history (COP Displacement, Short Term Diffusion Coefficient, and Critical Displacement). Variance of elderly subjects' COP measures from the young adult cohort were weighted to establish a balance score (“B-score”) algorithm designed to distinguish subjects with a fall history from those more sure on their feet. Relative to a young adult B-score of zero, elderly “non-fallers” had a B-score of 0.334, compared to 0.645 for those with a fall history (p<0.001). A weighted amalgam of postural sway elements may identify individuals at greatest risk of falling, allowing interventions to target those with greatest need of attention.
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    Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits
    (American Diabetes Association, 2012) Billings, Liana K.; Hsu, Yi-Hsiang; Ackerman, Rachel J.; Dupuis, Josée; Voight, Benjamin F.; Rasmussen-Torvik, Laura J.; Hercberg, Serge; Lathrop, Mark; Barnes, Daniel; Langenberg, Claudia; Hui, Jennie; Fu, Mao; Bouatia-Naji, Nabila; Lecoeur, Cecile; An, Ping; Magnusson, Patrik K.; Surakka, Ida; Ripatti, Samuli; Christiansen, Lene; Dalgård, Christine; Folkersen, Lasse; Grundberg, Elin; Eriksson, Per; Kaprio, Jaakko; Ohm Kyvik, Kirsten; Pedersen, Nancy L.; Borecki, Ingrid B.; Province, Michael A.; Balkau, Beverley; Froguel, Philippe; Shuldiner, Alan R.; Palmer, Lyle J.; Wareham, Nick; Meneton, Pierre; Johnson, Toby; Pankow, James S.; Karasik, David; Meigs, James; Kiel, Douglas; Florez, Jose
    Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r2 > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post–oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations.