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4. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty

Author

Duckett, Katie, Williamson, Alice, Kincaid, John, Rainbow, Kara, Lam, Brian, Corbin, Laura J, Martin, Hilary C., Eberhardt, Ruth Y., Huang, Qin Qin, Hurles, Matthew, Brauner, Raja, Delaney, Angela, McElreavey, Ken, Hall, Janet, Hirschhorn, Joel N, Palmert, Mark, Seminara, Stephanie, Banerjee, Indi, Perry, John R B, Timpson, Nicholas John, Clayton, Peter, Chan, Yee-Ming, Ong, Ken K, and O'Rahilly, Stephen

Subjects
ALSPAC
Abstract

ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Published
2023
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8. Participant acceptability of ‘digital footprint’ data collection strategies:evidence from the index participants of the ALSPAC birth cohort study

Author

Boyd, Andy, Shiells, Kate, Di Cara, Nina, Skatova, Anya, Davis, Oliver S.P., Haworth , Claire M A, Skinner, Andrew L, Thomas, Richard G, Tanner, Alastair, Macleod, John A A, and Timpson, Nicholas John

Subjects
Participant Acceptability, Longitudinal Research, Digital Footprints, ALSPAC, Cohort Study
Abstract

Executive Summary• ALSPAC have identified that digital footprint records offer new research utility andare developing a strategy for incorporating these data into the study databank;• It is imperative that this novel use of participant data is understood and acceptable in order to successfully establish linkage to these data whilst maintaining trust in thewider study;• ALSPAC are testing participant views and expectations through qualitative researchwith participant groups to inform the design of our digital footprint strategy;• The evidence collected to date suggests that participants are initially unfamiliar withthe rationale for using these forms of data in the ALSPAC research programme, andare unsure as to what benefits this can bring;• While some of these data are already in the public domain (e.g. twitter posts, airpollution measures), there is a perception that this is a substantial change in thestudies data collection strategy;• Some participants consider that some forms of digital footprint data are moresensitive than others: with information on detailed online and transactionalbehaviours considered particularly sensitive, as are precise location information,bank records and medical records;• Participants consider that maintaining confidentiality, receiving clear informationabout any proposed data use and having mechanisms to retain control over the useof their data are important safeguards when considering requests to use these data;• Once the value and benefits are made clear, and subject to safeguard controls beingin place, then many – but not all – participants suggest they would be accepting ofthis use of their records;• The use of digital footprint records will introduce ethical challenges, but the majorityof these challenges align with existing ethical issues and can be accommodatedwithin existing study frameworks

Published
2022

10. Bias from questionnaire invitation and response in COVID-19 research:an example using ALSPAC [version 1; peer review: awaiting peer review]

Author

Fernandez-Sanles, Alba, Smith, Daniel, Clayton, Gemma L, Northstone, Kate, Carter, Alice R, Millard, Louise A C, Borges, Maria C, Timpson, Nicholas John, Tilling, Kate M, Griffith, Gareth J, and Lawlor, Deborah A

Subjects
Selection bias, Questionnaire response, Missing data, COVID-19 risk factors, Questionnaire invitation, COVID-19, Covid19, ALSPAC, Longitudinal study
Abstract

Background: Longitudinal studies are crucial for identifying potential risk factors for infection with, and consequences of, COVID-19, but relationships can be biased if they are associated with invitation and response to data collection. We describe factors relating to questionnaire invitation and response in COVID-19 questionnaire data collection in a multigenerational birth cohort (the Avon Longitudinal Study of Parents and Children, ALSPAC). Methods: We analysed online questionnaires completed between the beginning of the pandemic and easing of the first UK lockdown by participants with valid email addresses who had not actively disengaged from the study. We assessed associations of pre-pandemic sociodemographic, behavioural, anthropometric and health-related factors with: i) being sent a questionnaire; ii) returning a questionnaire; and iii) item response (for specific questions). Analyses were conducted in three cohorts: the index children born in the early 1990s (now young adults; 41 variables assessed), their mothers (35 variables) and the mothers’ partners (27 variables). Results: Of 14,849 young adults, 41% were sent a questionnaire, of whom 57% returned one. Item response was >95%. In this cohort, 78% of factors were associated with being sent a questionnaire, 56% with returning one, and, as an example of item response, 20% with keyworker status response. For instance, children from mothers educated to degree-level had greater odds of being sent a questionnaire (OR=5.59; 95% CI=4.87-6.41), returning one (OR=1.60; 95% CI=1.31-1.95), and responding to items (e.g., keyworker status OR=1.65; 95% CI=0.88-3.04), relative to children from mothers with fewer qualifications. Invitation and response rates and associations were similar in all cohorts. Conclusions: These results highlight the importance of considering potential biases due to non-response when using longitudinal studies in COVID-19 research and interpreting results. We recommend researchers report response rates and factors associated with invitation and response in all COVID-19 observational research studies, which can inform sensitivity analyses.

Published
2021
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14. The Avon Longitudinal Study of Parents and Children - A resource for COVID-19 research: Generation 2 questionnaire data capture May-July 2020

Author

Smith, Daniel, primary, Northstone, Kate, additional, Bowring, Claire, additional, Wells, Nicholas, additional, Crawford, Michael, additional, Pearson, Rebecca M., additional, Thomas, Amy, additional, Brooks-Pollock, Ellen, additional, Lawlor, Deborah A., additional, and Timpson, Nicholas John, additional

Published
2021
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15. The Avon Longitudinal Study of Parents and Children - A resource for COVID-19 research:Generation 2 questionnaire data capture May-July 2020

Author

Smith, Daniel, Northstone, Kate, Bowring, Claire E, Wells, Nicholas S, Crawford, Mike, Pearson, Rebecca M, Thomas, Amy, Brooks Pollock, Ellen, Lawlor, Debbie A, and Timpson, Nicholas John

Subjects
Coronavirus, Mental Health, Cross-generation, COVID-19, Contact Patterns, ALSPAC, Children of the 90s
Abstract

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 from the Bristol area (UK). ALSPAC has followed these women, their partners (Generation 0; G0) and their offspring (Generation 1; G1) ever since. From 2012, ALSPAC has identified G1 participants who were pregnant (or their partner was) or had become parents, and enrolled them, their partners, and children in the ALSPAC-Generation 2 (ALSPAC-G2) study, providing a unique multigenerationalcohort. At present, approximately 1,100 G2 children (excluding those in utero) from 810 G1 participants have been enrolled.In response to the COVID-19 pandemic, ALSPAC rapidly deployed two online questionnaires; one during the initial lockdown phase in 2020 (9th April-15th May), and another when national lockdown restrictions were eased (26th May-5th July). As part of this second questionnaire, G1 parents completed a questionnaire about each of their G2 children. This covered: parental reports of children’s feelings and behaviour since lockdown, school attendance, contact patterns, and health. A total of 289 G1 participants completed this questionnaire on behalf of 411 G2 children.This COVID-19 G2 questionnaire data can be combined with prepandemic ALSPAC-G2 data, plus ALSPAC-G1 and -G0 data, to understand how children’s health and behaviour has been affected by the pandemic and its management. Data from this questionnaire will be complemented with linkage to health records and results of biological testing as they become available. Prospective studies are necessary to understand the impact of this pandemic on children’s health and development, yet few relevant studies exist; this resource will aid these efforts.Data has been released as: 1) a freely-available dataset containing participant responses with key sociodemographic variables; and 2) an ALSPAC-held dataset which can be combined with existing ALSPAC data, enabling bespoke research across all areas supported by the study.

Published
2020
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16. Novel loci for childhood body mass index and shared heritability with adult 2 cardiometabolic traits

Author

Vogelezang, Suzanne, Stergiakouli, Evie, Timpson, Nicholas John, Freathy, Rachel M, Davey Smith, George, Felix, Janine F, and al., et

Subjects
nutritional and metabolic diseases
Abstract

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values

Published
2020
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17. The Avon Longitudinal Study of Parents and Children - A resource for COVID-19 research: Generation 2 questionnaire data capture May-July 2020

Author

Smith, Daniel, primary, Northstone, Kate, additional, Bowring, Claire, additional, Wells, Nicholas, additional, Crawford, Michael, additional, Pearson, Rebecca M., additional, Thomas, Amy, additional, Brooks-Pollock, Ellen, additional, Lawlor, Deborah A., additional, and Timpson, Nicholas John, additional

Published
2020
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19. Determinants of intima-media thickness in the young:The Avon Longitudinal Study of Parents and Children (ALSPAC)

Author

Chiesa, Scott T, Charakida, Marietta, Georgiopoulos, George, Dangardt, Frida, Wade, Kaitlin H, Rapala, Alicja, Bhowruth, Devina, Nguyen, Helen, Muthurangu, Vivek, Shroff, Rukshana, Davey Smith, George, Lawlor, Debbie A, Sattar, Naveed, Timpson, Nicholas John, Hughes, Alun, and Deanfield, John E

Subjects
Fat-free mass, systolic blood pressure, cardiovascular system, cardiovascular diseases, ALSPAC, intima-media thickness
Abstract

Objectives: To characterize the determinants of cIMT in a large (n>4000) longitudinal cohort of healthy young people aged 9-21 years. Background: Greater carotid intima-media thickness (cIMT) is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. Methods: Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (age 9-17) and cross-sectional (age 17 and 21) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 allowed investigation of the distinct layers (i.e. intima or media) which may underlie observed differences. Results: Fat-free mass (FFM) and systolic blood pressure (SBP) were the only modifiable risk factors positively associated with cIMT (e.g. mean difference in cIMT per 1-SD increase in FFM at age 17 [95% CI] = 0.007mm [0.004,0.010]; p

Published
2019
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26. Body mass index:Has epidemiology started to break down causal contributions to health and disease?

Author

Corbin, Laura J and Timpson, Nicholas John

Subjects
obesity, causal analyses, Mendelian randomization, body mass index, epidemiology
Abstract

ObjectivesTo review progress in understanding the methods and results concerning the causal contribution of body mass index (BMI) to health and disease.MethodsIn the context of conventional evidence focused on the relationship between BMI and health, this review considers current literature on the common, population-based, genetic contribution to BMI and how this has fed into the developing field of applied epidemiology.ResultsTechnological and analytical developments have driven considerable success in identifying genetic variants relevant to BMI. This has enabled the implementation of Mendelian randomization to address questions of causality. The product of this work has been the implication of BMI as a causal agent in a host of health outcomes. Further breakdown of causal pathways by integration with other “omics” technologies promises to deliver additional benefit.ConclusionsGaps remain in our understanding of BMI as a risk factor for health and disease, and while promising, applied genetic epidemiology should be considered alongside alternative methods for assessing the impact of BMI on health. Potential limitations, relating to inappropriate or nonspecific measures of obesity and the improper use of genetic instruments, will need to be explored and incorporated into future research aiming to dissect BMI as a risk factor.

Published
2016
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27. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia:The CREAM Consortium

Author

Fan, Qiao, Pourcain, Beaté St, Evans, David, Timpson, Nicholas John, McMahon, George, and Guggenheim, Jeremy A

Abstract

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Published
2016
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28. GARFIELD classifies disease-relevant genomic features through integration of functional annotations with association signals

Author

Iotchkova, Valentina, Ritchie, Graham R. S., Geihs, Matthias, Morganella, Sandro, Min, Josine L., Walter, Klaudia, Timpson, Nicholas John, Dunham, Ian, Birney, Ewan, and Soranzo, Nicole

Abstract

Loci discovered by genome-wide association studies predominantly map outside protein-coding genes. The interpretation of the functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking by which to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Here we propose a novel approach that leverages genome-wide association studies’ findings with regulatory or functional annotations to classify features relevant to a phenotype of interest. Within our framework, we account for major sources of confounding not offered by current methods. We further assess enrichment of genome-wide association studies for 19 traits within Encyclopedia of DNA Elements- and Roadmap-derived regulatory regions. We characterize unique enrichment patterns for traits and annotations driving novel biological insights. The method is implemented in standalone software and an R package, to facilitate its application by the research community.

Published
2019
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29. Corrigendum: Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Author

Heid, Iris M, Jackson, Anne U, Randall, Joshua C, Winkler, Thomas W, Qi, Lu, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Zillikens, M Carola, Speliotes, Elizabeth K, Mägi, Reedik, Workalemahu, Tsegaselassie, White, Charles C, Bouatia-Naji, Nabila, Harris, Tamara B, Berndt, Sonja I, Ingelsson, Erik, Willer, Cristen J, Weedon, Michael N, Luan, Jian'an, Vedantam, Sailaja, Esko, Tõnu, Kilpeläinen, Tuomas O, Kutalik, Zoltán, Li, Shengxu, Monda, Keri L, Dixon, Anna L, Holmes, Christopher C, Kaplan, Lee M, Liang, Liming, Min, Josine L, Moffatt, Miriam F, Molony, Cliona, Nicholson, George, Schadt, Eric E, Zondervan, Krina T, Feitosa, Mary F, Ferreira, Teresa, Allen, Hana Lango, Weyant, Robert J, Wheeler, Eleanor, Wood, Andrew R, Estrada, Karol, Goddard, Michael E, Lettre, Guillaume, Mangino, Massimo, Nyholt, Dale R, Purcell, Shaun, Vernon Smith, Albert, Visscher, Peter M, Yang, Jian, McCarroll, Steven A, Nemesh, James, Voight, Benjamin F, Absher, Devin, Amin, Najaf, Aspelund, Thor, Coin, Lachlan, Glazer, Nicole L, Hayward, Caroline, Heard-Costa, Nancy L, Hottenga, Jouke-Jan, Johansson, Asa, Johnson, Toby, Kaakinen, Marika, Kapur, Karen, Ketkar, Shamika, Knowles, Joshua W, Kraft, Peter, Kraja, Aldi T, Lamina, Claudia, Leitzmann, Michael F, McKnight, Barbara, Morris, Andrew P, Ong, Ken K, Perry, John R B, Peters, Marjolein J, Polasek, Ozren, Prokopenko, Inga, Rayner, Nigel W, Ripatti, Samuli, Rivadeneira, Fernando, Robertson, Neil R, Sanna, Serena, Sovio, Ulla, Surakka, Ida, Teumer, Alexander, van Wingerden, Sophie, Vitart, Veronique, Zhao, Jing Hua, Cavalcanti-Proença, Christine, Chines, Peter S, Fisher, Eva, Kulzer, Jennifer R, Lecoeur, Cecile, Narisu, Narisu, Sandholt, Camilla, Scott, Laura J, Silander, Kaisa, Stark, Klaus, Tammesoo, Mari-Liis, Teslovich, Tanya M, Timpson, Nicholas John, Watanabe, Richard M, Welch, Ryan, Chasman, Daniel I, Cooper, Matthew N, Jansson, John-Olov, Kettunen, Johannes, Lawrence, Robert W, Pellikka, Niina, Perola, Markus, Vandenput, Liesbeth, Alavere, Helene, Almgren, Peter, Atwood, Larry D, Bennett, Amanda J, Biffar, Reiner, Bonnycastle, Lori L, Bornstein, Stefan R, Buchanan, Thomas A, Campbell, Harry, Day, Ian N M, Dei, Mariano, Dörr, Marcus, Elliott, Paul, Erdos, Michael R, Eriksson, Johan G, Freimer, Nelson B, Fu, Mao, Gaget, Stefan, Geus, Eco J C, Gjesing, Anette P, Grallert, Harald, Gräßler, Jürgen, Groves, Christopher J, Guiducci, Candace, Hartikainen, Anna-Liisa, Hassanali, Neelam, Havulinna, Aki S, Herzig, Karl-Heinz, Hicks, Andrew A, Hui, Jennie, Igl, Wilmar, Jousilahti, Pekka, Jula, Antti, Kajantie, Eero, Kinnunen, Leena, Kolcic, Ivana, Koskinen, Seppo, Kovacs, Peter, Kroemer, Heyo K, Krzelj, Vjekoslav, Kuusisto, Johanna, Kvaloy, Kirsti, Laitinen, Jaana, Lantieri, Olivier, Lathrop, G Mark, Lokki, Marja-Liisa, Luben, Robert N, Ludwig, Barbara, McArdle, Wendy L, McCarthy, Anne, Morken, Mario A, Nelis, Mari, Neville, Matt J, Paré, Guillaume, Parker, Alex N, Peden, John F, Pichler, Irene, Pietiläinen, Kirsi H, Platou, Carl G P, Pouta, Anneli, Ridderstråle, Martin, Samani, Nilesh J, Saramies, Jouko, Sinisalo, Juha, Smit, Jan H, Strawbridge, Rona J, Stringham, Heather M, Swift, Amy J, Teder-Laving, Maris, Thomson, Brian, Usala, Gianluca, van Meurs, Joyce B J, van Ommen, Gert-Jan, Vatin, Vincent, Volpato, Claudia B, Wallaschofski, Henri, Walters, G Bragi, Widen, Elisabeth, Wild, Sarah H, Willemsen, Gonneke, Witte, Daniel R, Zgaga, Lina, Zitting, Paavo, Beilby, John P, James, Alan L, Kähönen, Mika, Lehtimäki, Terho, Nieminen, Markku S, Ohlsson, Claes, Palmer, Lyle J, Raitakari, Olli, Ridker, Paul M, Stumvoll, Michael, Tönjes, Anke, Viikari, Jorma, Balkau, Beverley, Ben-Shlomo, Yoav, Bergman, Richard N, Boeing, Heiner, Smith, George Davey, Ebrahim, Shah, Froguel, Philippe, Hansen, Torben, Hengstenberg, Christian, Hveem, Kristian, Isomaa, Bo, Jørgensen, Torben, Karpe, Fredrik, Khaw, Kay-Tee, Laakso, Markku, Lawlor, Debbie A, Marre, Michel, Meitinger, Thomas, Metspalu, Andres, Midthjell, Kristian, Pedersen, Oluf, Salomaa, Veikko, Schwarz, Peter E H, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Valle, Timo T, Wareham, Nicholas J, Arnold, Alice M, Beckmann, Jacques S, Bergmann, Sven, Boerwinkle, Eric, Boomsma, Dorret I, Caulfield, Mark J, Collins, Francis S, Eiriksdottir, Gudny, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Hattersley, Andrew T, Hofman, Albert, Hu, Frank B, Illig, Thomas, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Kao, W H Linda, Kaprio, Jaakko, Launer, Lenore J, Munroe, Patricia B, Oostra, Ben, Penninx, Brenda W, Pramstaller, Peter P, Psaty, Bruce M, Quertermous, Thomas, Rissanen, Aila, Rudan, Igor, Shuldiner, Alan R, Soranzo, Nicole, Spector, Timothy D, Syvanen, Ann-Christine, Uda, Manuela, Uitterlinden, André, Völzke, Henry, Vollenweider, Peter, Wilson, James F, Witteman, Jacqueline C, Wright, Alan F, Abecasis, Gonçalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Groop, Leif C, Haritunians, Talin, Hunter, David J, Kaplan, Robert C, North, Kari E, O'Connell, Jeffrey R, Peltonen, Leena, Schlessinger, David, Strachan, David P, Hirschhorn, Joel N, Assimes, Themistocles L, Wichmann, H-Erich, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Stefansson, Kari, Cupples, L Adrienne, Loos, Ruth J F, Barroso, Inês, McCarthy, Mark I, Fox, Caroline S, Mohlke, Karen L, Lindgren, Cecilia M, Heid, Iris M, Jackson, Anne U, Randall, Joshua C, Winkler, Thomas W, Qi, Lu, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Zillikens, M Carola, Speliotes, Elizabeth K, Mägi, Reedik, Workalemahu, Tsegaselassie, White, Charles C, Bouatia-Naji, Nabila, Harris, Tamara B, Berndt, Sonja I, Ingelsson, Erik, Willer, Cristen J, Weedon, Michael N, Luan, Jian'an, Vedantam, Sailaja, Esko, Tõnu, Kilpeläinen, Tuomas O, Kutalik, Zoltán, Li, Shengxu, Monda, Keri L, Dixon, Anna L, Holmes, Christopher C, Kaplan, Lee M, Liang, Liming, Min, Josine L, Moffatt, Miriam F, Molony, Cliona, Nicholson, George, Schadt, Eric E, Zondervan, Krina T, Feitosa, Mary F, Ferreira, Teresa, Allen, Hana Lango, Weyant, Robert J, Wheeler, Eleanor, Wood, Andrew R, Estrada, Karol, Goddard, Michael E, Lettre, Guillaume, Mangino, Massimo, Nyholt, Dale R, Purcell, Shaun, Vernon Smith, Albert, Visscher, Peter M, Yang, Jian, McCarroll, Steven A, Nemesh, James, Voight, Benjamin F, Absher, Devin, Amin, Najaf, Aspelund, Thor, Coin, Lachlan, Glazer, Nicole L, Hayward, Caroline, Heard-Costa, Nancy L, Hottenga, Jouke-Jan, Johansson, Asa, Johnson, Toby, Kaakinen, Marika, Kapur, Karen, Ketkar, Shamika, Knowles, Joshua W, Kraft, Peter, Kraja, Aldi T, Lamina, Claudia, Leitzmann, Michael F, McKnight, Barbara, Morris, Andrew P, Ong, Ken K, Perry, John R B, Peters, Marjolein J, Polasek, Ozren, Prokopenko, Inga, Rayner, Nigel W, Ripatti, Samuli, Rivadeneira, Fernando, Robertson, Neil R, Sanna, Serena, Sovio, Ulla, Surakka, Ida, Teumer, Alexander, van Wingerden, Sophie, Vitart, Veronique, Zhao, Jing Hua, Cavalcanti-Proença, Christine, Chines, Peter S, Fisher, Eva, Kulzer, Jennifer R, Lecoeur, Cecile, Narisu, Narisu, Sandholt, Camilla, Scott, Laura J, Silander, Kaisa, Stark, Klaus, Tammesoo, Mari-Liis, Teslovich, Tanya M, Timpson, Nicholas John, Watanabe, Richard M, Welch, Ryan, Chasman, Daniel I, Cooper, Matthew N, Jansson, John-Olov, Kettunen, Johannes, Lawrence, Robert W, Pellikka, Niina, Perola, Markus, Vandenput, Liesbeth, Alavere, Helene, Almgren, Peter, Atwood, Larry D, Bennett, Amanda J, Biffar, Reiner, Bonnycastle, Lori L, Bornstein, Stefan R, Buchanan, Thomas A, Campbell, Harry, Day, Ian N M, Dei, Mariano, Dörr, Marcus, Elliott, Paul, Erdos, Michael R, Eriksson, Johan G, Freimer, Nelson B, Fu, Mao, Gaget, Stefan, Geus, Eco J C, Gjesing, Anette P, Grallert, Harald, Gräßler, Jürgen, Groves, Christopher J, Guiducci, Candace, Hartikainen, Anna-Liisa, Hassanali, Neelam, Havulinna, Aki S, Herzig, Karl-Heinz, Hicks, Andrew A, Hui, Jennie, Igl, Wilmar, Jousilahti, Pekka, Jula, Antti, Kajantie, Eero, Kinnunen, Leena, Kolcic, Ivana, Koskinen, Seppo, Kovacs, Peter, Kroemer, Heyo K, Krzelj, Vjekoslav, Kuusisto, Johanna, Kvaloy, Kirsti, Laitinen, Jaana, Lantieri, Olivier, Lathrop, G Mark, Lokki, Marja-Liisa, Luben, Robert N, Ludwig, Barbara, McArdle, Wendy L, McCarthy, Anne, Morken, Mario A, Nelis, Mari, Neville, Matt J, Paré, Guillaume, Parker, Alex N, Peden, John F, Pichler, Irene, Pietiläinen, Kirsi H, Platou, Carl G P, Pouta, Anneli, Ridderstråle, Martin, Samani, Nilesh J, Saramies, Jouko, Sinisalo, Juha, Smit, Jan H, Strawbridge, Rona J, Stringham, Heather M, Swift, Amy J, Teder-Laving, Maris, Thomson, Brian, Usala, Gianluca, van Meurs, Joyce B J, van Ommen, Gert-Jan, Vatin, Vincent, Volpato, Claudia B, Wallaschofski, Henri, Walters, G Bragi, Widen, Elisabeth, Wild, Sarah H, Willemsen, Gonneke, Witte, Daniel R, Zgaga, Lina, Zitting, Paavo, Beilby, John P, James, Alan L, Kähönen, Mika, Lehtimäki, Terho, Nieminen, Markku S, Ohlsson, Claes, Palmer, Lyle J, Raitakari, Olli, Ridker, Paul M, Stumvoll, Michael, Tönjes, Anke, Viikari, Jorma, Balkau, Beverley, Ben-Shlomo, Yoav, Bergman, Richard N, Boeing, Heiner, Smith, George Davey, Ebrahim, Shah, Froguel, Philippe, Hansen, Torben, Hengstenberg, Christian, Hveem, Kristian, Isomaa, Bo, Jørgensen, Torben, Karpe, Fredrik, Khaw, Kay-Tee, Laakso, Markku, Lawlor, Debbie A, Marre, Michel, Meitinger, Thomas, Metspalu, Andres, Midthjell, Kristian, Pedersen, Oluf, Salomaa, Veikko, Schwarz, Peter E H, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Valle, Timo T, Wareham, Nicholas J, Arnold, Alice M, Beckmann, Jacques S, Bergmann, Sven, Boerwinkle, Eric, Boomsma, Dorret I, Caulfield, Mark J, Collins, Francis S, Eiriksdottir, Gudny, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Hattersley, Andrew T, Hofman, Albert, Hu, Frank B, Illig, Thomas, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Kao, W H Linda, Kaprio, Jaakko, Launer, Lenore J, Munroe, Patricia B, Oostra, Ben, Penninx, Brenda W, Pramstaller, Peter P, Psaty, Bruce M, Quertermous, Thomas, Rissanen, Aila, Rudan, Igor, Shuldiner, Alan R, Soranzo, Nicole, Spector, Timothy D, Syvanen, Ann-Christine, Uda, Manuela, Uitterlinden, André, Völzke, Henry, Vollenweider, Peter, Wilson, James F, Witteman, Jacqueline C, Wright, Alan F, Abecasis, Gonçalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Groop, Leif C, Haritunians, Talin, Hunter, David J, Kaplan, Robert C, North, Kari E, O'Connell, Jeffrey R, Peltonen, Leena, Schlessinger, David, Strachan, David P, Hirschhorn, Joel N, Assimes, Themistocles L, Wichmann, H-Erich, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Stefansson, Kari, Cupples, L Adrienne, Loos, Ruth J F, Barroso, Inês, McCarthy, Mark I, Fox, Caroline S, Mohlke, Karen L, and Lindgren, Cecilia M

Published
2011

30. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Author

Heid, Iris M, Jackson, Anne U, Randall, Joshua C, Winkler, Thomas W, Qi, Lu, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Zillikens, M Carola, Speliotes, Elizabeth K, Mägi, Reedik, Workalemahu, Tsegaselassie, White, Charles C, Bouatia-Naji, Nabila, Harris, Tamara B, Berndt, Sonja I, Ingelsson, Erik, Willer, Cristen J, Weedon, Michael N, Luan, Jian'an, Vedantam, Sailaja, Esko, Tõnu, Kilpeläinen, Tuomas O, Kutalik, Zoltán, Li, Shengxu, Monda, Keri L, Dixon, Anna L, Holmes, Christopher C, Kaplan, Lee M, Liang, Liming, Min, Josine L, Moffatt, Miriam F, Molony, Cliona, Nicholson, George, Schadt, Eric E, Zondervan, Krina T, Feitosa, Mary F, Ferreira, Teresa, Allen, Hana Lango, Weyant, Robert J, Wheeler, Eleanor, Wood, Andrew R, Estrada, Karol, Goddard, Michael E, Lettre, Guillaume, Mangino, Massimo, Nyholt, Dale R, Purcell, Shaun, Smith, Albert Vernon, Visscher, Peter M, Yang, Jian, McCarroll, Steven A, Nemesh, James, Voight, Benjamin F, Absher, Devin, Amin, Najaf, Aspelund, Thor, Coin, Lachlan, Glazer, Nicole L, Hayward, Caroline, Heard-Costa, Nancy L, Hottenga, Jouke-Jan, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kapur, Karen, Ketkar, Shamika, Knowles, Joshua W, Kraft, Peter, Kraja, Aldi T, Lamina, Claudia, Leitzmann, Michael F, McKnight, Barbara, Morris, Andrew P, Ong, Ken K, Perry, John R B, Peters, Marjolein J, Polasek, Ozren, Prokopenko, Inga, Rayner, Nigel W, Ripatti, Samuli, Rivadeneira, Fernando, Robertson, Neil R, Sanna, Serena, Sovio, Ulla, Surakka, Ida, Teumer, Alexander, van Wingerden, Sophie, Vitart, Veronique, Zhao, Jing Hua, Cavalcanti-Proença, Christine, Chines, Peter S, Fisher, Eva, Kulzer, Jennifer R, Lecoeur, Cecile, Narisu, Narisu, Sandholt, Camilla, Scott, Laura J, Silander, Kaisa, Stark, Klaus, Tammesoo, Mari-Liis, Teslovich, Tanya M, Timpson, Nicholas John, Watanabe, Richard M, Welch, Ryan, Chasman, Daniel I, Cooper, Matthew N, Jansson, John-Olov, Kettunen, Johannes, Lawrence, Robert W, Pellikka, Niina, Perola, Markus, Vandenput, Liesbeth, Alavere, Helene, Almgren, Peter, Atwood, Larry D, Bennett, Amanda J, Biffar, Reiner, Bonnycastle, Lori L, Bornstein, Stefan R, Buchanan, Thomas A, Campbell, Harry, Day, Ian N M, Dei, Mariano, Dörr, Marcus, Elliott, Paul, Erdos, Michael R, Eriksson, Johan G, Freimer, Nelson B, Fu, Mao, Gaget, Stefan, Geus, Eco J C, Gjesing, Anette P, Grallert, Harald, Grässler, Jürgen, Groves, Christopher J, Guiducci, Candace, Hartikainen, Anna-Liisa, Hassanali, Neelam, Havulinna, Aki S, Herzig, Karl-Heinz, Hicks, Andrew A, Hui, Jennie, Igl, Wilmar, Jousilahti, Pekka, Jula, Antti, Kajantie, Eero, Kinnunen, Leena, Kolcic, Ivana, Koskinen, Seppo, Kovacs, Peter, Kroemer, Heyo K, Krzelj, Vjekoslav, Kuusisto, Johanna, Kvaloy, Kirsti, Laitinen, Jaana, Lantieri, Olivier, Lathrop, G Mark, Lokki, Marja-Liisa, Luben, Robert N, Ludwig, Barbara, McArdle, Wendy L, McCarthy, Anne, Morken, Mario A, Nelis, Mari, Neville, Matt J, Paré, Guillaume, Parker, Alex N, Peden, John F, Pichler, Irene, Pietiläinen, Kirsi H, Platou, Carl G P, Pouta, Anneli, Ridderstråle, Martin, Samani, Nilesh J, Saramies, Jouko, Sinisalo, Juha, Smit, Jan H, Strawbridge, Rona J, Stringham, Heather M, Swift, Amy J, Teder-Laving, Maris, Thomson, Brian, Usala, Gianluca, van Meurs, Joyce B J, van Ommen, Gert-Jan, Vatin, Vincent, Volpato, Claudia B, Wallaschofski, Henri, Walters, G Bragi, Widen, Elisabeth, Wild, Sarah H, Willemsen, Gonneke, Witte, Daniel R, Zgaga, Lina, Zitting, Paavo, Beilby, John P, James, Alan L, Kähönen, Mika, Lehtimäki, Terho, Nieminen, Markku S, Ohlsson, Claes, Palmer, Lyle J, Raitakari, Olli, Ridker, Paul M, Stumvoll, Michael, Tönjes, Anke, Viikari, Jorma, Balkau, Beverley, Ben-Shlomo, Yoav, Bergman, Richard N, Boeing, Heiner, Smith, George Davey, Ebrahim, Shah, Froguel, Philippe, Hansen, Torben, Hengstenberg, Christian, Hveem, Kristian, Isomaa, Bo, Jørgensen, Torben, Karpe, Fredrik, Khaw, Kay-Tee, Laakso, Markku, Lawlor, Debbie A, Marre, Michel, Meitinger, Thomas, Metspalu, Andres, Midthjell, Kristian, Pedersen, Oluf, Salomaa, Veikko, Schwarz, Peter E H, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Valle, Timo T, Wareham, Nicholas J, Arnold, Alice M, Beckmann, Jacques S, Bergmann, Sven, Boerwinkle, Eric, Boomsma, Dorret I, Caulfield, Mark J, Collins, Francis S, Eiriksdottir, Gudny, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Hattersley, Andrew T, Hofman, Albert, Hu, Frank B, Illig, Thomas, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Kao, W H Linda, Kaprio, Jaakko, Launer, Lenore J, Munroe, Patricia B, Oostra, Ben, Penninx, Brenda W, Pramstaller, Peter P, Psaty, Bruce M, Quertermous, Thomas, Rissanen, Aila, Rudan, Igor, Shuldiner, Alan R, Soranzo, Nicole, Spector, Timothy D, Syvänen, Ann-Christine, Uda, Manuela, Uitterlinden, André, Völzke, Henry, Vollenweider, Peter, Wilson, James F, Witteman, Jacqueline C, Wright, Alan F, Abecasis, Gonçalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Groop, Leif C, Haritunians, Talin, Hunter, David J, Kaplan, Robert C, North, Kari E, O'Connell, Jeffrey R, Peltonen, Leena, Schlessinger, David, Strachan, David P, Hirschhorn, Joel N, Assimes, Themistocles L, Wichmann, H-Erich, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Stefansson, Kari, Cupples, L Adrienne, Loos, Ruth J F, Barroso, Inês, McCarthy, Mark I, Fox, Caroline S, Mohlke, Karen L, Lindgren, Cecilia M, Heid, Iris M, Jackson, Anne U, Randall, Joshua C, Winkler, Thomas W, Qi, Lu, Steinthorsdottir, Valgerdur, Thorleifsson, Gudmar, Zillikens, M Carola, Speliotes, Elizabeth K, Mägi, Reedik, Workalemahu, Tsegaselassie, White, Charles C, Bouatia-Naji, Nabila, Harris, Tamara B, Berndt, Sonja I, Ingelsson, Erik, Willer, Cristen J, Weedon, Michael N, Luan, Jian'an, Vedantam, Sailaja, Esko, Tõnu, Kilpeläinen, Tuomas O, Kutalik, Zoltán, Li, Shengxu, Monda, Keri L, Dixon, Anna L, Holmes, Christopher C, Kaplan, Lee M, Liang, Liming, Min, Josine L, Moffatt, Miriam F, Molony, Cliona, Nicholson, George, Schadt, Eric E, Zondervan, Krina T, Feitosa, Mary F, Ferreira, Teresa, Allen, Hana Lango, Weyant, Robert J, Wheeler, Eleanor, Wood, Andrew R, Estrada, Karol, Goddard, Michael E, Lettre, Guillaume, Mangino, Massimo, Nyholt, Dale R, Purcell, Shaun, Smith, Albert Vernon, Visscher, Peter M, Yang, Jian, McCarroll, Steven A, Nemesh, James, Voight, Benjamin F, Absher, Devin, Amin, Najaf, Aspelund, Thor, Coin, Lachlan, Glazer, Nicole L, Hayward, Caroline, Heard-Costa, Nancy L, Hottenga, Jouke-Jan, Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kapur, Karen, Ketkar, Shamika, Knowles, Joshua W, Kraft, Peter, Kraja, Aldi T, Lamina, Claudia, Leitzmann, Michael F, McKnight, Barbara, Morris, Andrew P, Ong, Ken K, Perry, John R B, Peters, Marjolein J, Polasek, Ozren, Prokopenko, Inga, Rayner, Nigel W, Ripatti, Samuli, Rivadeneira, Fernando, Robertson, Neil R, Sanna, Serena, Sovio, Ulla, Surakka, Ida, Teumer, Alexander, van Wingerden, Sophie, Vitart, Veronique, Zhao, Jing Hua, Cavalcanti-Proença, Christine, Chines, Peter S, Fisher, Eva, Kulzer, Jennifer R, Lecoeur, Cecile, Narisu, Narisu, Sandholt, Camilla, Scott, Laura J, Silander, Kaisa, Stark, Klaus, Tammesoo, Mari-Liis, Teslovich, Tanya M, Timpson, Nicholas John, Watanabe, Richard M, Welch, Ryan, Chasman, Daniel I, Cooper, Matthew N, Jansson, John-Olov, Kettunen, Johannes, Lawrence, Robert W, Pellikka, Niina, Perola, Markus, Vandenput, Liesbeth, Alavere, Helene, Almgren, Peter, Atwood, Larry D, Bennett, Amanda J, Biffar, Reiner, Bonnycastle, Lori L, Bornstein, Stefan R, Buchanan, Thomas A, Campbell, Harry, Day, Ian N M, Dei, Mariano, Dörr, Marcus, Elliott, Paul, Erdos, Michael R, Eriksson, Johan G, Freimer, Nelson B, Fu, Mao, Gaget, Stefan, Geus, Eco J C, Gjesing, Anette P, Grallert, Harald, Grässler, Jürgen, Groves, Christopher J, Guiducci, Candace, Hartikainen, Anna-Liisa, Hassanali, Neelam, Havulinna, Aki S, Herzig, Karl-Heinz, Hicks, Andrew A, Hui, Jennie, Igl, Wilmar, Jousilahti, Pekka, Jula, Antti, Kajantie, Eero, Kinnunen, Leena, Kolcic, Ivana, Koskinen, Seppo, Kovacs, Peter, Kroemer, Heyo K, Krzelj, Vjekoslav, Kuusisto, Johanna, Kvaloy, Kirsti, Laitinen, Jaana, Lantieri, Olivier, Lathrop, G Mark, Lokki, Marja-Liisa, Luben, Robert N, Ludwig, Barbara, McArdle, Wendy L, McCarthy, Anne, Morken, Mario A, Nelis, Mari, Neville, Matt J, Paré, Guillaume, Parker, Alex N, Peden, John F, Pichler, Irene, Pietiläinen, Kirsi H, Platou, Carl G P, Pouta, Anneli, Ridderstråle, Martin, Samani, Nilesh J, Saramies, Jouko, Sinisalo, Juha, Smit, Jan H, Strawbridge, Rona J, Stringham, Heather M, Swift, Amy J, Teder-Laving, Maris, Thomson, Brian, Usala, Gianluca, van Meurs, Joyce B J, van Ommen, Gert-Jan, Vatin, Vincent, Volpato, Claudia B, Wallaschofski, Henri, Walters, G Bragi, Widen, Elisabeth, Wild, Sarah H, Willemsen, Gonneke, Witte, Daniel R, Zgaga, Lina, Zitting, Paavo, Beilby, John P, James, Alan L, Kähönen, Mika, Lehtimäki, Terho, Nieminen, Markku S, Ohlsson, Claes, Palmer, Lyle J, Raitakari, Olli, Ridker, Paul M, Stumvoll, Michael, Tönjes, Anke, Viikari, Jorma, Balkau, Beverley, Ben-Shlomo, Yoav, Bergman, Richard N, Boeing, Heiner, Smith, George Davey, Ebrahim, Shah, Froguel, Philippe, Hansen, Torben, Hengstenberg, Christian, Hveem, Kristian, Isomaa, Bo, Jørgensen, Torben, Karpe, Fredrik, Khaw, Kay-Tee, Laakso, Markku, Lawlor, Debbie A, Marre, Michel, Meitinger, Thomas, Metspalu, Andres, Midthjell, Kristian, Pedersen, Oluf, Salomaa, Veikko, Schwarz, Peter E H, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Valle, Timo T, Wareham, Nicholas J, Arnold, Alice M, Beckmann, Jacques S, Bergmann, Sven, Boerwinkle, Eric, Boomsma, Dorret I, Caulfield, Mark J, Collins, Francis S, Eiriksdottir, Gudny, Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Hattersley, Andrew T, Hofman, Albert, Hu, Frank B, Illig, Thomas, Iribarren, Carlos, Jarvelin, Marjo-Riitta, Kao, W H Linda, Kaprio, Jaakko, Launer, Lenore J, Munroe, Patricia B, Oostra, Ben, Penninx, Brenda W, Pramstaller, Peter P, Psaty, Bruce M, Quertermous, Thomas, Rissanen, Aila, Rudan, Igor, Shuldiner, Alan R, Soranzo, Nicole, Spector, Timothy D, Syvänen, Ann-Christine, Uda, Manuela, Uitterlinden, André, Völzke, Henry, Vollenweider, Peter, Wilson, James F, Witteman, Jacqueline C, Wright, Alan F, Abecasis, Gonçalo R, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Frayling, Timothy M, Groop, Leif C, Haritunians, Talin, Hunter, David J, Kaplan, Robert C, North, Kari E, O'Connell, Jeffrey R, Peltonen, Leena, Schlessinger, David, Strachan, David P, Hirschhorn, Joel N, Assimes, Themistocles L, Wichmann, H-Erich, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Stefansson, Kari, Cupples, L Adrienne, Loos, Ruth J F, Barroso, Inês, McCarthy, Mark I, Fox, Caroline S, Mohlke, Karen L, and Lindgren, Cecilia M

Abstract

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions., Group Author(s): MAGIC

Published
2010
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31. Erratum: Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Author

Heid, Iris M, primary, Jackson, Anne U, additional, Randall, Joshua C, additional, Winkler, Thomas W, additional, Qi, Lu, additional, Steinthorsdottir, Valgerdur, additional, Thorleifsson, Gudmar, additional, Zillikens, M Carola, additional, Speliotes, Elizabeth K, additional, Mägi, Reedik, additional, Workalemahu, Tsegaselassie, additional, White, Charles C, additional, Bouatia-Naji, Nabila, additional, Harris, Tamara B, additional, Berndt, Sonja I, additional, Ingelsson, Erik, additional, Willer, Cristen J, additional, Weedon, Michael N, additional, Luan, Jian'an, additional, Vedantam, Sailaja, additional, Esko, Tõnu, additional, Kilpeläinen, Tuomas O, additional, Kutalik, Zoltán, additional, Li, Shengxu, additional, Monda, Keri L, additional, Dixon, Anna L, additional, Holmes, Christopher C, additional, Kaplan, Lee M, additional, Liang, Liming, additional, Min, Josine L, additional, Moffatt, Miriam F, additional, Molony, Cliona, additional, Nicholson, George, additional, Schadt, Eric E, additional, Zondervan, Krina T, additional, Feitosa, Mary F, additional, Ferreira, Teresa, additional, Allen, Hana Lango, additional, Weyant, Robert J, additional, Wheeler, Eleanor, additional, Wood, Andrew R, additional, Estrada, Karol, additional, Goddard, Michael E, additional, Lettre, Guillaume, additional, Mangino, Massimo, additional, Nyholt, Dale R, additional, Purcell, Shaun, additional, Vernon Smith, Albert, additional, Visscher, Peter M, additional, Yang, Jian, additional, McCarroll, Steven A, additional, Nemesh, James, additional, Voight, Benjamin F, additional, Absher, Devin, additional, Amin, Najaf, additional, Aspelund, Thor, additional, Coin, Lachlan, additional, Glazer, Nicole L, additional, Hayward, Caroline, additional, Heard-Costa, Nancy L, additional, Hottenga, Jouke-Jan, additional, Johansson, Åsa, additional, Johnson, Toby, additional, Kaakinen, Marika, additional, Kapur, Karen, additional, Ketkar, Shamika, additional, Knowles, Joshua W, additional, Kraft, Peter, additional, Kraja, Aldi T, additional, Lamina, Claudia, additional, Leitzmann, Michael F, additional, McKnight, Barbara, additional, Morris, Andrew P, additional, Ong, Ken K, additional, Perry, John R B, additional, Peters, Marjolein J, additional, Polasek, Ozren, additional, Prokopenko, Inga, additional, Rayner, Nigel W, additional, Ripatti, Samuli, additional, Rivadeneira, Fernando, additional, Robertson, Neil R, additional, Sanna, Serena, additional, Sovio, Ulla, additional, Surakka, Ida, additional, Teumer, Alexander, additional, van Wingerden, Sophie, additional, Vitart, Veronique, additional, Zhao, Jing Hua, additional, Cavalcanti-Proença, Christine, additional, Chines, Peter S, additional, Fisher, Eva, additional, Kulzer, Jennifer R, additional, Lecoeur, Cecile, additional, Narisu, Narisu, additional, Sandholt, Camilla, additional, Scott, Laura J, additional, Silander, Kaisa, additional, Stark, Klaus, additional, Tammesoo, Mari-Liis, additional, Teslovich, Tanya M, additional, Timpson, Nicholas John, additional, Watanabe, Richard M, additional, Welch, Ryan, additional, Chasman, Daniel I, additional, Cooper, Matthew N, additional, Jansson, John-Olov, additional, Kettunen, Johannes, additional, Lawrence, Robert W, additional, Pellikka, Niina, additional, Perola, Markus, additional, Vandenput, Liesbeth, additional, Alavere, Helene, additional, Almgren, Peter, additional, Atwood, Larry D, additional, Bennett, Amanda J, additional, Biffar, Reiner, additional, Bonnycastle, Lori L, additional, Bornstein, Stefan R, additional, Buchanan, Thomas A, additional, Campbell, Harry, additional, Day, Ian N M, additional, Dei, Mariano, additional, Dörr, Marcus, additional, Elliott, Paul, additional, Erdos, Michael R, additional, Eriksson, Johan G, additional, Freimer, Nelson B, additional, Fu, Mao, additional, Gaget, Stefan, additional, Geus, Eco J C, additional, Gjesing, Anette P, additional, Grallert, Harald, additional, Gräßler, Jürgen, additional, Groves, Christopher J, additional, Guiducci, Candace, additional, Hartikainen, Anna-Liisa, additional, Hassanali, Neelam, additional, Havulinna, Aki S, additional, Herzig, Karl-Heinz, additional, Hicks, Andrew A, additional, Hui, Jennie, additional, Igl, Wilmar, additional, Jousilahti, Pekka, additional, Jula, Antti, additional, Kajantie, Eero, additional, Kinnunen, Leena, additional, Kolcic, Ivana, additional, Koskinen, Seppo, additional, Kovacs, Peter, additional, Kroemer, Heyo K, additional, Krzelj, Vjekoslav, additional, Kuusisto, Johanna, additional, Kvaloy, Kirsti, additional, Laitinen, Jaana, additional, Lantieri, Olivier, additional, Lathrop, G Mark, additional, Lokki, Marja-Liisa, additional, Luben, Robert N, additional, Ludwig, Barbara, additional, McArdle, Wendy L, additional, McCarthy, Anne, additional, Morken, Mario A, additional, Nelis, Mari, additional, Neville, Matt J, additional, Paré, Guillaume, additional, Parker, Alex N, additional, Peden, John F, additional, Pichler, Irene, additional, Pietiläinen, Kirsi H, additional, Platou, Carl G P, additional, Pouta, Anneli, additional, Ridderstråle, Martin, additional, Samani, Nilesh J, additional, Saramies, Jouko, additional, Sinisalo, Juha, additional, Smit, Jan H, additional, Strawbridge, Rona J, additional, Stringham, Heather M, additional, Swift, Amy J, additional, Teder-Laving, Maris, additional, Thomson, Brian, additional, Usala, Gianluca, additional, van Meurs, Joyce B J, additional, van Ommen, Gert-Jan, additional, Vatin, Vincent, additional, Volpato, Claudia B, additional, Wallaschofski, Henri, additional, Walters, G Bragi, additional, Widen, Elisabeth, additional, Wild, Sarah H, additional, Willemsen, Gonneke, additional, Witte, Daniel R, additional, Zgaga, Lina, additional, Zitting, Paavo, additional, Beilby, John P, additional, James, Alan L, additional, Kähönen, Mika, additional, Lehtimäki, Terho, additional, Nieminen, Markku S, additional, Ohlsson, Claes, additional, Palmer, Lyle J, additional, Raitakari, Olli, additional, Ridker, Paul M, additional, Stumvoll, Michael, additional, Tönjes, Anke, additional, Viikari, Jorma, additional, Balkau, Beverley, additional, Ben-Shlomo, Yoav, additional, Bergman, Richard N, additional, Boeing, Heiner, additional, Smith, George Davey, additional, Ebrahim, Shah, additional, Froguel, Philippe, additional, Hansen, Torben, additional, Hengstenberg, Christian, additional, Hveem, Kristian, additional, Isomaa, Bo, additional, Jørgensen, Torben, additional, Karpe, Fredrik, additional, Khaw, Kay-Tee, additional, Laakso, Markku, additional, Lawlor, Debbie A, additional, Marre, Michel, additional, Meitinger, Thomas, additional, Metspalu, Andres, additional, Midthjell, Kristian, additional, Pedersen, Oluf, additional, Salomaa, Veikko, additional, Schwarz, Peter E H, additional, Tuomi, Tiinamaija, additional, Tuomilehto, Jaakko, additional, Valle, Timo T, additional, Wareham, Nicholas J, additional, Arnold, Alice M, additional, Beckmann, Jacques S, additional, Bergmann, Sven, additional, Boerwinkle, Eric, additional, Boomsma, Dorret I, additional, Caulfield, Mark J, additional, Collins, Francis S, additional, Eiriksdottir, Gudny, additional, Gudnason, Vilmundur, additional, Gyllensten, Ulf, additional, Hamsten, Anders, additional, Hattersley, Andrew T, additional, Hofman, Albert, additional, Hu, Frank B, additional, Illig, Thomas, additional, Iribarren, Carlos, additional, Jarvelin, Marjo-Riitta, additional, Kao, W H Linda, additional, Kaprio, Jaakko, additional, Launer, Lenore J, additional, Munroe, Patricia B, additional, Oostra, Ben, additional, Penninx, Brenda W, additional, Pramstaller, Peter P, additional, Psaty, Bruce M, additional, Quertermous, Thomas, additional, Rissanen, Aila, additional, Rudan, Igor, additional, Shuldiner, Alan R, additional, Soranzo, Nicole, additional, Spector, Timothy D, additional, Syvanen, Ann-Christine, additional, Uda, Manuela, additional, Uitterlinden, André, additional, Völzke, Henry, additional, Vollenweider, Peter, additional, Wilson, James F, additional, Witteman, Jacqueline C, additional, Wright, Alan F, additional, Abecasis, Gonçalo R, additional, Boehnke, Michael, additional, Borecki, Ingrid B, additional, Deloukas, Panos, additional, Frayling, Timothy M, additional, Groop, Leif C, additional, Haritunians, Talin, additional, Hunter, David J, additional, Kaplan, Robert C, additional, North, Kari E, additional, O'Connell, Jeffrey R, additional, Peltonen, Leena, additional, Schlessinger, David, additional, Strachan, David P, additional, Hirschhorn, Joel N, additional, Assimes, Themistocles L, additional, Wichmann, H-Erich, additional, Thorsteinsdottir, Unnur, additional, van Duijn, Cornelia M, additional, Stefansson, Kari, additional, Cupples, L Adrienne, additional, Loos, Ruth J F, additional, Barroso, Inês, additional, McCarthy, Mark I, additional, Fox, Caroline S, additional, Mohlke, Karen L, additional, and Lindgren, Cecilia M, additional

Published
2011
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32. NETVIEW: A High-Definition Network-Visualization Approach to Detect Fine-Scale Population Structures from Genome-Wide Patterns of Variation.

Author

Neuditschko, Markus, Khatkar, Mehar S., Raadsma, Herman W., and Timpson, Nicholas John

Subjects
SINGLE nucleotide polymorphisms, GENOMES, BIOMARKERS, GENETICS, GENEALOGY, PHENOTYPES
Abstract

High-throughput sequencing and single nucleotide polymorphism (SNP) genotyping can be used to infer complex population structures. Fine-scale population structure analysis tracing individual ancestry remains one of the major challenges. Based on network theory and recent advances in SNP chip technology, we investigated an unsupervised network clustering method called Super Paramagnetic Clustering (SPC). When applied to whole-genome marker data it identifies the natural divisions of groups of individuals into population clusters without use of prior ancestry information. Furthermore, we optimised an analysis pipeline called NETVIEW, a high-definition network visualization, starting with computation of genetic distance, followed clustering using SPC and finally visualization of clusters with CYTOSCAPE.We compared NETVIEW against commonly used methodologies including Principal Component Analyses (PCA) and a model- based algorithm, ADMIXTURE, on whole-genome-wide SNP data derived from three previously described data sets: simulated (2.5 million SNPs, 5 populations), human (1.4 million SNPs, 11 populations) and cattle (32,653 SNPs, 19 populations). We demonstrate that individuals can be effectively allocated to their correct population whilst simultaneously revealing fine- scale structure within the populations. Analyzing the human HapMap populations, we identified unexpected genetic relatedness among individuals, and population stratification within the Indian, African and Mexican samples. In the cattle data set, we correctly assigned all individuals to their respective breeds and detected fine-scale population sub-structures reflecting different sample origins and phenotypes. The NETVIEW pipeline is computationally extremely efficient and can be easily applied on large-scale genome-wide data sets to assign individuals to particular populations and to reproduce fine- scale population structures without prior knowledge of individual ancestry. NETVIEW can be used on any data from which a genetic relationship/distance between individuals can be calculated. [ABSTRACT FROM AUTHOR]

Published
2012
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33. A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels.

Author

Richards, J. Brent, Waterworth, Dawn, O'Rahilly, Stephen, Hivert, Marie-France, Loos, Ruth J. F., Perry, John R. B., Tanaka, Toshiko, Timpson, Nicholas John, Semple, Robert K., Soranzo, Nicole, Kijoung Song, Rocha, Nuno, Grundberg, Elin, Dupuis, Josée, Florez, Jose C., Langenberg, Claudia, Prokopenko, Inga, Saxena, Richa, Sladek, Robert, and Aulchenko, Yurii

Subjects
GENOMES, FAT cells, DIABETES, NUCLEOTIDES, GENETIC polymorphisms, PROTEINS
Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P⩽5×10-8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P⩽0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10-19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10-8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10-6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10-6, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk. [ABSTRACT FROM AUTHOR]

Published
2009
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34. A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

Author

Waterworth, Dawn, O'Rahilly, Stephen, Hivert, Marie-France, Loos, Ruth J. F., Tanaka, Toshiko, Timpson, Nicholas John, Semple, Robert K., Soranzo, Nicole, Song, Kijoung, Rocha, Nuno, Grundberg, Elin, Dupuis, Josée, Langenberg, Claudia, Prokopenko, Inga, Sladek, Robert, Aulchenko, Yurii, Waeber, Gerard, Erdmann, Jeanette, Burnett, Mary-Susan, Sattar, Naveed, Devaney, Joseph, Willenborg, Christina, Hingorani, Aroon, Witteman, Jaquelin C. M., Vollenweider, Peter, Glaser, Beate, Hengstenberg, Christian, Ferrucci, Luigi, Melzer, David, Stark, Klaus, Deanfield, John, Winogradow, Janina, Grassl, Martina, Hall, Alistair S., Egan, Josephine M., Ricketts, Sally L., König, Inke R., Reinhard, Wibke, Grundy, Scott, Wichmann, H-Erich, Barter, Phil, Mahley, Robert, Kesaniemi, Y. Antero, Rader, Daniel J., Reilly, Muredach P., Stewart, Alexandre F. R., Van Duijn, Cornelia M., Schunkert, Heribert, Burling, Keith, Deloukas, Panos, Pastinen, Tomi, Samani, Nilesh J., McPherson, Ruth, Davey Smith, George, Frayling, Timothy M., Wareham, Nicholas J., Mooser, Vincent, Spector, Tim D., Richards, J. Brent, Florez, Jose Carlos, Perry, John R.B., Saxena, Richa, Evans, David, Meigs, James Benjamin, Thompson, John R., and Epstein, Stephen E.

Subjects
cardiovascular disorders, congenital heart disease, diabetes and endocrinology, obesity, type 2 diabetes, genetics and genomics, genetics of disease
Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Published
2009
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35. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author

Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF

Abstract

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Published
2024
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36. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.

Author

Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, Thorleifsson G, Zillikens MC, Speliotes EK, Mägi R, Workalemahu T, White CC, Bouatia-Naji N, Harris TB, Berndt SI, Ingelsson E, Willer CJ, Weedon MN, Luan J, Vedantam S, Esko T, Kilpeläinen TO, Kutalik Z, Li S, Monda KL, Dixon AL, Holmes CC, Kaplan LM, Liang L, Min JL, Moffatt MF, Molony C, Nicholson G, Schadt EE, Zondervan KT, Feitosa MF, Ferreira T, Lango Allen H, Weyant RJ, Wheeler E, Wood AR, Estrada K, Goddard ME, Lettre G, Mangino M, Nyholt DR, Purcell S, Smith AV, Visscher PM, Yang J, McCarroll SA, Nemesh J, Voight BF, Absher D, Amin N, Aspelund T, Coin L, Glazer NL, Hayward C, Heard-Costa NL, Hottenga JJ, Johansson A, Johnson T, Kaakinen M, Kapur K, Ketkar S, Knowles JW, Kraft P, Kraja AT, Lamina C, Leitzmann MF, McKnight B, Morris AP, Ong KK, Perry JR, Peters MJ, Polasek O, Prokopenko I, Rayner NW, Ripatti S, Rivadeneira F, Robertson NR, Sanna S, Sovio U, Surakka I, Teumer A, van Wingerden S, Vitart V, Zhao JH, Cavalcanti-Proença C, Chines PS, Fisher E, Kulzer JR, Lecoeur C, Narisu N, Sandholt C, Scott LJ, Silander K, Stark K, Tammesoo ML, Teslovich TM, Timpson NJ, Watanabe RM, Welch R, Chasman DI, Cooper MN, Jansson JO, Kettunen J, Lawrence RW, Pellikka N, Perola M, Vandenput L, Alavere H, Almgren P, Atwood LD, Bennett AJ, Biffar R, Bonnycastle LL, Bornstein SR, Buchanan TA, Campbell H, Day IN, Dei M, Dörr M, Elliott P, Erdos MR, Eriksson JG, Freimer NB, Fu M, Gaget S, Geus EJ, Gjesing AP, Grallert H, Grässler J, Groves CJ, Guiducci C, Hartikainen AL, Hassanali N, Havulinna AS, Herzig KH, Hicks AA, Hui J, Igl W, Jousilahti P, Jula A, Kajantie E, Kinnunen L, Kolcic I, Koskinen S, Kovacs P, Kroemer HK, Krzelj V, Kuusisto J, Kvaloy K, Laitinen J, Lantieri O, Lathrop GM, Lokki ML, Luben RN, Ludwig B, McArdle WL, McCarthy A, Morken MA, Nelis M, Neville MJ, Paré G, Parker AN, Peden JF, Pichler I, Pietiläinen KH, Platou CG, Pouta A, Ridderstråle M, Samani NJ, Saramies J, Sinisalo J, Smit JH, Strawbridge RJ, Stringham HM, Swift AJ, Teder-Laving M, Thomson B, Usala G, van Meurs JB, van Ommen GJ, Vatin V, Volpato CB, Wallaschofski H, Walters GB, Widen E, Wild SH, Willemsen G, Witte DR, Zgaga L, Zitting P, Beilby JP, James AL, Kähönen M, Lehtimäki T, Nieminen MS, Ohlsson C, Palmer LJ, Raitakari O, Ridker PM, Stumvoll M, Tönjes A, Viikari J, Balkau B, Ben-Shlomo Y, Bergman RN, Boeing H, Smith GD, Ebrahim S, Froguel P, Hansen T, Hengstenberg C, Hveem K, Isomaa B, Jørgensen T, Karpe F, Khaw KT, Laakso M, Lawlor DA, Marre M, Meitinger T, Metspalu A, Midthjell K, Pedersen O, Salomaa V, Schwarz PE, Tuomi T, Tuomilehto J, Valle TT, Wareham NJ, Arnold AM, Beckmann JS, Bergmann S, Boerwinkle E, Boomsma DI, Caulfield MJ, Collins FS, Eiriksdottir G, Gudnason V, Gyllensten U, Hamsten A, Hattersley AT, Hofman A, Hu FB, Illig T, Iribarren C, Jarvelin MR, Kao WH, Kaprio J, Launer LJ, Munroe PB, Oostra B, Penninx BW, Pramstaller PP, Psaty BM, Quertermous T, Rissanen A, Rudan I, Shuldiner AR, Soranzo N, Spector TD, Syvanen AC, Uda M, Uitterlinden A, Völzke H, Vollenweider P, Wilson JF, Witteman JC, Wright AF, Abecasis GR, Boehnke M, Borecki IB, Deloukas P, Frayling TM, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, North KE, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, Hirschhorn JN, Assimes TL, Wichmann HE, Thorsteinsdottir U, van Duijn CM, Stefansson K, Cupples LA, Loos RJ, Barroso I, McCarthy MI, Fox CS, Mohlke KL, and Lindgren CM

Subjects
Adipose Tissue anatomy & histology, Age Factors, Chromosome Mapping, Female, Genome, Human, Humans, Male, Meta-Analysis as Topic, Sex Characteristics, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Waist-Hip Ratio
Abstract

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

Published
2010
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