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1. Exploring the genetics of airflow limitation in lung function across the lifespan – a polygenic risk score study

Author

Hernandez-Pacheco, Natalia, Kilanowski, Anna, Kumar, Ashish, Curtin, John A., Olvera, Núria, Kress, Sara, Bertels, Xander, Lahousse, Lies, Bhatta, Laxmi, Granell, Raquel, Marí, Sergi, Bilbao, Jose Ramon, Sun, Yidan, Tingskov Pedersen, Casper-Emil, Karramass, Tarik, Thiering, Elisabeth, Dardani, Christina, Kebede Merid, Simon, Wang, Gang, Hallberg, Jenny, Koch, Sarah, Garcia-Aymerich, Judith, Esplugues, Ana, Torrent, Maties, Ibarluzea, Jesus, Lowe, Lesley, Simpson, Angela, Gehring, Ulrike, Vermeulen, Roel C.H., Roberts, Graham, Bergström, Anna, Vonk, Judith M., Felix, Janine F., Duijts, Liesbeth, Bønnelykke, Klaus, Timpson, Nic, Brusselle, Guy, Brumpton, Ben M., Langhammer, Arnulf, Turner, Stephen, Holloway, John W., Arshad, Syed Hasan, Ullah, Anhar, Custovic, Adnan, Cullinan, Paul, Murray, Clare S., van den Berge, Maarten, Kull, Inger, Schikowski, Tamara, Wedzicha, Jadwiga A., Koppelman, Gerard, Faner, Rosa, Agustí, Àlvar, Standl, Marie, and Melén, Erik

Published
2024
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6. The Emergence of Networks in Human Genome Epidemiology: "Challenges and Opportunities"

Author

Seminara, Daniela, Khoury, Muin J., O'Brien, Thomas R., Manolio, Teri, Gwinn, Marta L., Little, Julian, Higgins, Julian P. T., Bernstein, Jonine L., Boffetta, Paolo, Bondy, Melissa, Bray, Molly S., Brenchley, Paul E., Buffler, Patricia A., Casas, Juan Pablo, Chokkalingam, Anand P., Danesh, John, Smith, George Davey, Dolan, Siobhan, Duncan, Ross, Gruis, Nelleke A., Hashibe, Mia, Hunter, David, Jarvelin, Marjo-Riitta, Malmer, Beatrice, Maraganore, Demetrius M., Newton-Bishop, Julia A., Riboli, Elio, Salanti, Georgia, Taioli, Emanuela, Timpson, Nic, Uitterlinden, André G., Vineis, Paolo, Wareham, Nick, Winn, Deborah M., Zimmern, Ron, and Ioannidis, John P. A.

Published
2007
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8. Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology

Author

Smith, George Davey, Lawlor, Debbie A., Harbord, Roger, Timpson, Nic, Day, Ian, and Ebrahim, Shah

Abstract

Introduction Observational epidemiology has had notable successes, but also high-profile failures, in that it has identified many modifiable exposures apparently increasing or decreasing disease risk that have been revealed by [...], Background In conventional epidemiology confounding of the exposure of interest with lifestyle or socioeconomic factors, and reverse causation whereby disease status influences exposure rather than vice versa, may invalidate causal interpretations of observed associations. Conversely, genetic variants should not be related to the confounding factors that distort associations in conventional observational epidemiological studies. Furthermore, disease onset will not influence genotype. Therefore, it has been suggested that genetic variants that are known to be associated with a modifiable (nongenetic) risk factor can be used to help determine the causal effect of this modifiable risk factor on disease outcomes. This approach, mendelian randomization, is increasingly being applied within epidemiological studies. However, there is debate about the underlying premise that associations between genotypes and disease outcomes are not confounded by other risk factors. We examined the extent to which genetic variants, on the one hand, and nongenetic environmental exposures or phenotypic characteristics on the other, tend to be associated with each other, to assess the degree of confounding that would exist in conventional epidemiological studies compared with mendelian randomization studies. Methods and Findings We estimated pairwise correlations between nongenetic baseline variables and genetic variables in a cross-sectional study comparing the number of correlations that were statistically significant at the 5%, 1%, and 0.01% level (α = 0.05, 0.01, and 0.0001, respectively) with the number expected by chance if all variables were in fact uncorrelated, using a two-sided binomial exact test. We demonstrate that behavioural, socioeconomic, and physiological factors are strongly interrelated, with 45% of all possible pairwise associations between 96 nongenetic characteristics (n = 4,560 correlations) being significant at the p < 0.01 level (the ratio of observed to expected significant associations was 45; p-value for difference between observed and expected < 0.000001). Similar findings were observed for other levels of significance. In contrast, genetic variants showed no greater association with each other, or with the 96 behavioural, socioeconomic, and physiological factors, than would be expected by chance. Conclusions These data illustrate why observational studies have produced misleading claims regarding potentially causal factors for disease. The findings demonstrate the potential power of a methodology that utilizes genetic variants as indicators of exposure level when studying environmentally modifiable risk factors.

Published
2007

9. Obesity and cancer: Mendelian randomization approach utilizing the FTO genotype

Author

Brennan, Paul, McKay, James, Moore, Lee, Zaridze, David, Mukeria, Anush, Szeszenia-Dabrowska, Neonilia, Lissowska, Jolanta, Rudnai, Peter, Fabianova, Eleonora, Mates, Dana, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Chow, Wong-Ho, Rothman, Nathaniel, Chabrier, Amélie, Gaborieau, Valérie, Timpson, Nic, Hung, Rayjean J, and Smith, George Davey

Published
2009

13. An assessment of the portability of ancestry informative markers between human populations

Author

Stoneking Mark, Myles Sean, and Timpson Nic

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Recent work has shown that population stratification can have confounding effects on genetic association studies and statistical methods have been developed to correct for these effects. Subsets of markers that are highly-differentiated between populations, ancestry-informative markers (AIMs), have been used to correct for population stratification. Often AIMs are discovered in one set of populations and then employed in a different set of populations. The underlying assumption in these cases is that the population under study has the same substructure as the population in which the AIMs were discovered. The present study assesses this assumption and evaluates the portability between worldwide populations of 10 SNPs found to be highly-differentiated within Britain (BritAIMs). Methods We genotyped 10 BritAIMs in ~1000 individuals from 53 populations worldwide. We assessed the degree to which these 10 BritAIMs capture population stratification in other groups of populations by use of the Fst statistic. We used Fst values from 2750 random markers typed in the same set of individuals as an empirical distribution to which the Fst values of the 10 BritAIMs were compared. Results Allele frequency differences between continental groups for the BritAIMs are not unusually high. This is also the case for comparisons within continental groups distantly related to Britain. However, two BritAIMs show high Fst between European populations and two BritAIMs show high Fst between populations from the Middle East. Overall the median Fst across all BritAIMs is not unusually high compared to the empirical distribution. Conclusion We find that BritAIMs are generally not useful to distinguish between continental groups or within continental groups distantly related to Britain. Moreover, our analyses suggest that the portability of AIMs across geographical scales (e.g. between Europe and Britain) can be limited and should therefore be taken into consideration in the design and interpretation of genetic association studies.

Published
2009
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14. Worldwide population differentiation at disease-associated SNPs

Author

Barrett Jeffrey, Davison Dan, Myles Sean, Stoneking Mark, and Timpson Nic

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Recent genome-wide association (GWA) studies have provided compelling evidence of association between genetic variants and common complex diseases. These studies have made use of cases and controls almost exclusively from populations of European ancestry and little is known about the frequency of risk alleles in other populations. The present study addresses the transferability of disease associations across human populations by examining levels of population differentiation at disease-associated single nucleotide polymorphisms (SNPs). Methods We genotyped ~1000 individuals from 53 populations worldwide at 25 SNPs which show robust association with 6 complex human diseases (Crohn's disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, coronary artery disease and obesity). Allele frequency differences between populations for these SNPs were measured using Fst. The Fst values for the disease-associated SNPs were compared to Fst values from 2750 random SNPs typed in the same set of individuals. Results On average, disease SNPs are not significantly more differentiated between populations than random SNPs in the genome. Risk allele frequencies, however, do show substantial variation across human populations and may contribute to differences in disease prevalence between populations. We demonstrate that, in some cases, risk allele frequency differences are unusually high compared to random SNPs and may be due to the action of local (i.e. geographically-restricted) positive natural selection. Moreover, some risk alleles were absent or fixed in a population, which implies that risk alleles identified in one population do not necessarily account for disease prevalence in all human populations. Conclusion Although differences in risk allele frequencies between human populations are not unusually large and are thus likely not due to positive local selection, there is substantial variation in risk allele frequencies between populations which may account for differences in disease prevalence between human populations.

Published
2008
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15. Physical Inactivity and Sleep Inefficiency Accentuate the Genetic Risk of Obesity

Author

WOOD, ANDREW R., primary, JONES, SAMUEL E., additional, RICHMOND, REBECCA, additional, AHMAD, SHAFQAT, additional, YAGHOOTKAR, HANIEH, additional, BEAUMONT, ROBERT, additional, RUTH, KATHERINE S., additional, TUKE, MARCUS, additional, MURRAY, ANNA, additional, FREATHY, RACHEL M., additional, SMITH, GEORGE DAVEY, additional, LEE, I-MIN, additional, TIMPSON, NIC, additional, CHASMAN, DANIEL, additional, KUTALIK, ZOLTAN, additional, WEEDON, MICHAEL N., additional, TYRRELL, JESSICA, additional, and FRAYLING, TIMOTHY M., additional

Published
2018
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16. Physical Inactivity and Sleep Inefficiency Accentuate the Genetic Risk of Obesity

Author

WOOD, ANDREW R., JONES, SAMUEL E., RICHMOND, REBECCA, AHMAD, SHAFQAT, YAGHOOTKAR, HANIEH, BEAUMONT, ROBERT, RUTH, KATHERINE S., TUKE, MARCUS, MURRAY, ANNA, FREATHY, RACHEL M., SMITH, GEORGE DAVEY, LEE, I-MIN, TIMPSON, NIC, CHASMAN, DANIEL, KUTALIK, ZOLTAN, WEEDON, MICHAEL N., TYRRELL, JESSICA, FRAYLING, TIMOTHY M., WOOD, ANDREW R., JONES, SAMUEL E., RICHMOND, REBECCA, AHMAD, SHAFQAT, YAGHOOTKAR, HANIEH, BEAUMONT, ROBERT, RUTH, KATHERINE S., TUKE, MARCUS, MURRAY, ANNA, FREATHY, RACHEL M., SMITH, GEORGE DAVEY, LEE, I-MIN, TIMPSON, NIC, CHASMAN, DANIEL, KUTALIK, ZOLTAN, WEEDON, MICHAEL N., TYRRELL, JESSICA, and FRAYLING, TIMOTHY M.

Published
2018
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17. Truncation of POC1A associated with short stature and extreme insulin resistance

Author

Chen, Jian Hua, Segni, Maria, Payne, Felicity, Huang-Doran, Isabel, Sleigh, Alison, Adams, Claire, Durbin, Richard, Muddyman, Dawn, Soranzo, Nicole, Timpson, Nic, Spector, Tim, Richards, Bren, Palotie, Aarno, Owen, Michael, Barrett, Jeff, Geschwind, Daniel, Hurles, Matt, Fitzpatrick, David, Barroso, Inês, Farooqi, Sadaf, Zeggini, Eleftheria, Kaye, Jane, Kennedy, Karen, McCarthy, Shane, Stalker, Jim, Langford, Cordelia, Keane, Thomas, Savage, David B., O’Rahilly, Stephen, and Semple, Robert K.

Subjects
Adult, Dyslipidaemia, Molecular Sequence Data, Mitosis, Cell Cycle Proteins, Dwarfism, Spindle Apparatus, Article, POC1A, Humans, Protein Isoforms, Amino Acid Sequence, Frameshift Mutation, Centrioles, Centrosome, Primary cilium, Diabetes, Cell Cycle, Facies, Proteins, Insulin resistance, Centriole, centriole, centrosome, diabetes, dyslipidaemia, insulin resistance, primary cilium, short stature, skeletal dysplasia, Body Height, Fatty Liver, Short stature, Cytoskeletal Proteins, Skeletal dysplasia, Female, Insulin Resistance, Sequence Alignment
Abstract

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health.

Published
2015
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18. Genome-Wide Meta-Analysis of Cotinine Levels in Cigarette Smokers Identifies Locus at 4q13.2

Author

Ware, Jennifer J., primary, Chen, Xiangning, additional, Vink, Jacqueline, additional, Loukola, Anu, additional, Minica, Camelia, additional, Pool, Rene, additional, Milaneschi, Yuri, additional, Mangino, Massimo, additional, Menni, Cristina, additional, Chen, Jingchun, additional, Peterson, Roseann E., additional, Auro, Kirsi, additional, Lyytikäinen, Leo-Pekka, additional, Wedenoja, Juho, additional, Stiby, Alexander I., additional, Hemani, Gibran, additional, Willemsen, Gonneke, additional, Hottenga, Jouke Jan, additional, Korhonen, Tellervo, additional, Heliövaara, Markku, additional, Perola, Markus, additional, Rose, Richard J., additional, Paternoster, Lavinia, additional, Timpson, Nic, additional, Wassenaar, Catherine A., additional, Zhu, Andy Z. X., additional, Davey Smith, George, additional, T. Raitakari, Olli, additional, Lehtimäki, Terho, additional, Kähönen, Mika, additional, Koskinen, Seppo, additional, Spector, Timothy, additional, Penninx, Brenda W. J. H., additional, Salomaa, Veikko, additional, Boomsma, Dorret I., additional, Tyndale, Rachel F., additional, Kaprio, Jaakko, additional, and Munafò, Marcus R., additional

Published
2016
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19. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Author

Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Daly, Allan, Danecek, Petr, Smith, George Davey, Day-Williams, Aaron, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lee, Irene, Li, Rui, Li, Yingrui, Ryan, Liu, Lönnqvist, Jouko, Lopes, Margarida, MacArthur, Daniel G., Massimo, Mangino, Marchini, Jonathan, Maslen, John, McCarthy, Shane, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, O’Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy, Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Perry, John, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, Zheng, Hou-Feng, Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Daly, Allan, Danecek, Petr, Smith, George Davey, Day-Williams, Aaron, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lee, Irene, Li, Rui, Li, Yingrui, Ryan, Liu, Lönnqvist, Jouko, Lopes, Margarida, MacArthur, Daniel G., Massimo, Mangino, Marchini, Jonathan, Maslen, John, McCarthy, Shane, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, O’Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy, Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Perry, John, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, and Zheng, Hou-Feng

Abstract

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.

Published
2015

22. Can a genotype for lactase persistence be used as a tool to assess the relationship between renal cell carcinoma and milk drinking? Pitfalls in the application of Mendelian randomization

Author

Timpson, Nic, Brennan, Paul, Gaborieau, Valérie, Moore, Lee, Zaridze, David, Matveev, Vsevolod, Szeszenia-Dabrowska, Neonilia, Lissowska, Jolanta, Fabianova, Eleonora, Mates, Dana, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Chow, Wong-Ho, Rothman, Nathaniel, Boffetta, Paolo, Harbord, Roger, and Davey Smith, George

Subjects
Adult, Male, Genotype, Lactose, Mendelian Randomization Analysis, Middle Aged, Prognosis, Article, Kidney Neoplasms, Young Adult, Milk, Risk Factors, Case-Control Studies, Animals, Humans, Female, Carcinoma, Renal Cell, Aged, Lactase
Abstract

Increased risk of renal cell carcinoma (RCC) with milk consumption has been reported from observational studies. Whether this represents a causal association or is a result of confounding or bias is unclear. We assessed the potential for using genetic variation in lactase persistence as a tool for the study of this relationship.Using a large, hospital-based case-control study, we used observational, phenotypic, and genetic data to determine whether the MCM6 -13910 C/T(rs4988235) variant may be used as a nonconfounded and unbiased marker for milk consumption.Consumption of milk during adulthood was associated with increased risk of RCC [odds ratio (OR), 1.35; 95% confidence interval (95% CI), 1.03-1.76; P=0.03]. Among controls, consumption of milk was associated with the lactase persistence genotype at rs4988235 (OR, 2.39; 95% CI, 1.81-3.15; P=6.9x10(-10)); however, the same genotype was not associated with RCC (OR, 1.01; 95% CI, 0.83-1.22; P=0.9). In controls, milk consumption was associated with confounding factors, including smoking and educational attainment, whereas genotypes at rs4988235 showed negligible association with confounding factors.The absence of an association between the MCM6 genotype and RCC suggests that observational associations between milk consumption and RCC may be due to confounding or bias.Although these data suggest that associations between milk consumption and RCC may be spurious, if the association between genotype and behavioral exposure is weak, then the power of this test may be low. The nature of intermediate risk factor instrumentation is an important consideration in the undertaking and interpretation of this type of causal analysis experiment.

Published
2010

23. Managing clinically significant findings in research: The UK10K example

Author

Kaye, Jane, Hurles, Matthew, Griffin, Heather, Grewal, Jasjote, Bobrow, Martin, Timpson, Nic, Smee, Carol, Bolton, Patrick, Durbin, Richard, Dyke, Stephanie, Fitzpatrick, David, Kennedy, Karen, Kent, Alastair, Muddyman, Dawn, Muntoni, Francesco, Raymond, Lucy F., Semple, Robert, Spector, Tim, Kaye, Jane, Hurles, Matthew, Griffin, Heather, Grewal, Jasjote, Bobrow, Martin, Timpson, Nic, Smee, Carol, Bolton, Patrick, Durbin, Richard, Dyke, Stephanie, Fitzpatrick, David, Kennedy, Karen, Kent, Alastair, Muddyman, Dawn, Muntoni, Francesco, Raymond, Lucy F., Semple, Robert, and Spector, Tim

Abstract

Recent advances in sequencing technology allow data on the human genome to be generated more quickly and in greater detail than ever before. Such detail includes findings that may be of significance to the health of the research participant involved. Although research studies generally do not feed back information on clinically significant findings (CSFs) to participants, this stance is increasingly being questioned. There may be difficulties and risks in feeding clinically significant information back to research participants, however, the UK10K consortium sought to address these by creating a detailed management pathway. This was not intended to create any obligation upon the researchers to feed back any CSFs they discovered. Instead, it provides a mechanism to ensure that any such findings can be passed on to the participant where appropriate. This paper describes this mechanism and the specific criteria, which must be fulfilled in order for a finding and participant to qualify for feedback. This mechanism could be used by future research consortia, and may also assist in the development of sound principles for dealing with CSFs. © 2014 Macmillan Publishers Limited All rights reserved.

Published
2014

25. A road map for efficient and reliable human genome epidemiology

Author

Ioannidis, John P A, Gwinn, Marta, Little, Julian, Higgins, Julian P T, Bernstein, Jonine L, Boffetta, Paolo, Bondy, Melissa, Bray, Molly S, Brenchley, Paul E, Buffler, Patricia A, Casas, Juan Pablo, Chokkalingam, Anand, Danesh, John, Smith, George Davey, Dolan, Siobhan, Duncan, Ross, Gruis, Nelleke A, Hartge, Patricia, Hashibe, Mia, Hunter, David J, Jarvelin, Marjo-Riitta, Malmer, Beatrice, Maraganore, Demetrius M, Newton-Bishop, Julia A, O'Brien, Thomas R, Petersen, Gloria, Riboli, Elio, Salanti, Georgia, Seminara, Daniela, Smeeth, Liam, Taioli, Emanuela, Timpson, Nic, Uitterlinden, Andre G, Vineis, Paolo, Wareham, Nick, Winn, Deborah M, Zimmern, Ron, Khoury, Muin J, Ioannidis, John P A, Gwinn, Marta, Little, Julian, Higgins, Julian P T, Bernstein, Jonine L, Boffetta, Paolo, Bondy, Melissa, Bray, Molly S, Brenchley, Paul E, Buffler, Patricia A, Casas, Juan Pablo, Chokkalingam, Anand, Danesh, John, Smith, George Davey, Dolan, Siobhan, Duncan, Ross, Gruis, Nelleke A, Hartge, Patricia, Hashibe, Mia, Hunter, David J, Jarvelin, Marjo-Riitta, Malmer, Beatrice, Maraganore, Demetrius M, Newton-Bishop, Julia A, O'Brien, Thomas R, Petersen, Gloria, Riboli, Elio, Salanti, Georgia, Seminara, Daniela, Smeeth, Liam, Taioli, Emanuela, Timpson, Nic, Uitterlinden, Andre G, Vineis, Paolo, Wareham, Nick, Winn, Deborah M, Zimmern, Ron, and Khoury, Muin J

Published
2006

28. The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

Author

Lawlor, Debbie A., primary, Harbord, Roger M., additional, Timpson, Nic J., additional, Lowe, Gordon D. O., additional, Rumley, Ann, additional, Gaunt, Tom R., additional, Baker, Ian, additional, Yarnell, John W. G., additional, Kivimäki, Mika, additional, Kumari, Meena, additional, Norman, Paul E., additional, Jamrozik, Konrad, additional, Hankey, Graeme J., additional, Almeida, Osvaldo P., additional, Flicker, Leon, additional, Warrington, Nicole, additional, Marmot, Michael G., additional, Ben-Shlomo, Yoav, additional, Palmer, Lyle J., additional, Day, Ian N. M., additional, Ebrahim, Shah, additional, and Smith, George Davey, additional

Published
2008
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32. A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol.

Author

Ware, Jennifer J., Timpson, Nic, Smith, George Davey, and Munafò, Marcus R.

Subjects
*CIGARETTE smokers, *NICOTINE, *TOBACCO, *GENETIC polymorphisms, *MOLECULAR genetics
Abstract

Background Genome-wide association studies have revealed an association between several loci in the nicotinic acetylcholine receptor gene cluster CHRNA5-A3-B4 and daily cigarette consumption. Recent studies have sought to refine this phenotype, and have shown that a locus within this cluster, marked primarily by rs1051730 and rs16969968, is also associated with levels of cotinine, the primary metabolite of nicotine. This association remains after adjustment for self-reported smoking, which suggests that even amongst people who smoke the same number of cigarettes there is still genetically-influenced variation in nicotine consumption. This is likely to be due to differences in smoking topography, that is, how a cigarette is smoked (e.g., volume of smoke inhaled per puff, number of puffs taken per cigarette). The aim of this study is to determine potential mediation of the relationship between the rs1051730 locus and cotinine levels by smoking topography. Methods/design Adopting a recall-by-genotype design, we will recruit 200 adults from the Avon Longitudinal Study of Parents and Children on the basis of minor or major homozygote status at rs1051730 (100 in each genotype group). All participants will be current, daily smokers. Our primary study outcome measures will be measures of smoking topography: total volume of smoke (ml) inhaled per cigarette, total volume of smoke (ml) inhaled over of the course of one day, and salivary cotinine level (ng/ml). Discussion This study will extend our understanding of the biological basis of inter-individual variability in heaviness of smoking, and therefore in exposure to smoking-related toxins. The novel recall-by-genotype approach we will use is efficient, maximising statistical power, and enables the collection of extremely precise phenotypic data that are impractical to collect in a larger sample. The methods described within this protocol also hold the potential for wider application in the field of molecular genetics. [ABSTRACT FROM AUTHOR]

Published
2014
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33. Lactase persistence-related genetic variant: population substructure and health outcomes.

Author

Smith, George Davey, Lawlor, Debbie A., Timpson, Nic J., Baban, Jamil, Kiessling, Matt, Day, Ian N. M., and Ebrahim, Shah

Subjects
LACTASE persistence, GENOTYPE-environment interaction, HUMAN genetics, LIFESTYLES, DISEASE risk factors, PUBLIC health
Abstract

Lactase persistence is an autosomal-dominant trait that is common in European-derived populations. A basic tendency for lactase persistence to increase from the southeast to the northwest across European populations has been noted, but such trends within countries have not been extensively studied. We genotyped the C/T−13910 variant (rs4988235) that constitutes the putatively causal allele for lactase persistence (T allele representing persistence) in a general population sample of 3344 women aged 60–79 years from 23 towns across Britain. We found an overall frequency of 0.253 for the C (lactase non-persistence) allele, but with considerable gradients of decreasing frequency from the south to the north and from the east to the west of Britain for this allele. Daily sunlight was positively related to C (non-persistence) allele prevalence. However, sunlight exposure and latitude are strongly correlated, and it was not possible to identify which is the primary factor statistically underlying the distribution of lactase persistence. The C/T−13910 variant (rs4988235) was not related to drinking milk or bone health (although drinking milk itself was protective of bone health), and was essentially unrelated to a wide range of other lifestyle, health and demographic characteristics. One exception was general health being rated as being poor or fair, for which there was an odds ratio of 1.38 (1.04, 1.84) for women homozygous for the C allele; on adjustment for latitude and longitude of place of birth, this attenuated to 1.19 (0.87, 1.64). The lactase persistence variant could contribute to the examination of data for the existence of, and then statistical control for, population substructure in genetic association studies.European Journal of Human Genetics (2009) 17, 357–367; doi:10.1038/ejhg.2008.156; published online 17 September 2008 [ABSTRACT FROM AUTHOR]

Published
2009
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34. TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Author

Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Daly, Allan, Danecek, Petr, Smith, George Davey, Day-Williams, Aaron, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lee, Irene, Li, Rui, Li, Yingrui, Ryan, Liu, Lönnqvist, Jouko, Lopes, Margarida, MacArthur, Daniel G., Massimo, Mangino, Marchini, Jonathan, Maslen, John, McCarthy, Shane, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, O’Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy, Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Perry, John, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, Zheng, Hou-Feng, Schmidts, Miriam, Hou, Yuqing, Cortés, Claudio R., Mans, Dorus A., Huber, Celine, Boldt, Karsten, Patel, Mitali, van Reeuwijk, Jeroen, Plaza, Jean-Marc, van Beersum, Sylvia E. C., Yap, Zhi Min, Letteboer, Stef J. F., Taylor, S. Paige, Herridge, Warren, Johnson, Colin A., Scambler, Peter J., Ueffing, Marius, Kayserili, Hulya, Krakow, Deborah, King, Stephen M., Beales, Philip L., Al-Gazali, Lihadh, Wicking, Carol, Cormier-Daire, Valerie, Roepman, Ronald, Mitchison, Hannah M., Witman, George B., Al-Turki, Saeed, Anderson, Carl, Anney, Richard, Antony, Dinu, Asimit, Jennifer, Ayub, Mohammad, Barrett, Jeff, Barroso, Inês, Bentham, Jamie, Bhattacharya, Shoumo, Blackwood, Douglas, Bobrow, Martin, Bochukova, Elena, Bolton, Patrick, Boustred, Chris, Breen, Gerome, Brion, Marie-Jo, Brown, Andrew, Calissano, Mattia, Carss, Keren, Chatterjee, Krishna, Chen, Lu, Cirak, Sebhattin, Clapham, Peter, Clement, Gail, Coates, Guy, Collier, David, Cosgrove, Catherine, Cox, Tony, Craddock, Nick, Crooks, Lucy, Curran, Sarah, Daly, Allan, Danecek, Petr, Smith, George Davey, Day-Williams, Aaron, Day, Ian, Durbin, Richard, Edkins, Sarah, Ellis, Peter, Evans, David, Farooqi, I. Sadaf, Fatemifar, Ghazaleh, Fitzpatrick, David, Flicek, Paul, Floyd, Jamie, Foley, A. Reghan, Franklin, Chris, Futema, Marta, Gallagher, Louise, Gaunt, Tom, Geschwind, Daniel, Greenwood, Celia, Grozeva, Detelina, Guo, Xiaosen, Gurling, Hugh, Hart, Deborah, Hendricks, Audrey, Holmans, Peter, Huang, Jie, Humphries, Steve E., Hurles, Matt, Hysi, Pirro, Jackson, David, Jamshidi, Yalda, Jewell, David, Chris, Joyce, Kaye, Jane, Keane, Thomas, Kemp, John, Kennedy, Karen, Kent, Alastair, Kolb-Kokocinski, Anja, Lachance, Genevieve, Langford, Cordelia, Lee, Irene, Li, Rui, Li, Yingrui, Ryan, Liu, Lönnqvist, Jouko, Lopes, Margarida, MacArthur, Daniel G., Massimo, Mangino, Marchini, Jonathan, Maslen, John, McCarthy, Shane, McGuffin, Peter, McIntosh, Andrew, McKechanie, Andrew, McQuillin, Andrew, Memari, Yasin, Metrustry, Sarah, Min, Josine, Moayyeri, Alireza, Morris, James, Muddyman, Dawn, Muntoni, Francesco, Northstone, Kate, O’Donovan, Michael, O’Rahilly, Stephen, Onoufriadis, Alexandros, Oualkacha, Karim, Owen, Michael, Palotie, Aarno, Panoutsopoulou, Kalliope, Parker, Victoria, Parr, Jeremy, Paternoster, Lavinia, Paunio, Tiina, Payne, Felicity, Perry, John, Pietilainen, Olli, Plagnol, Vincent, Quail, Michael A., Quaye, Lydia, Raymond, Lucy, Rehnström, Karola, Brent Richards, J., Ring, Sue, Ritchie, Graham R S, Savage, David B., Schoenmakers, Nadia, Semple, Robert K., Serra, Eva, Shihab, Hashem, Shin, So-Youn, Skuse, David, Small, Kerrin, Smee, Carol, Soler, Artigas María, Soranzo, Nicole, Southam, Lorraine, Spector, Tim, St Pourcain, Beate, St. Clair, David, Stalker, Jim, Surdulescu, Gabriela, Suvisaari, Jaana, Tachmazidou, Ioanna, Tian, Jing, Timpson, Nic, Tobin, Martin, Valdes, Ana, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Wain, Louise, Walter, Klaudia, Wang, Jun, Ward, Kirsten, Wheeler, Ellie, Whittall, Ros, Williams, Hywel, Williamson, Kathy, Wilson, Scott G., Wong, Kim, Whyte, Tamieka, ChangJiang, Xu, Zeggini, Eleftheria, Zhang, Feng, and Zheng, Hou-Feng

Abstract

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.

37. Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality.

Author

Davey Smith G, Lawlor DA, Harbord R, Timpson N, Rumley A, Lowe GD, Day IN, and Ebrahim S

Subjects
Aged, Blood Pressure, Cross-Sectional Studies, Female, Genotype, Humans, Hypertension blood, Incidence, Middle Aged, Polymorphism, Genetic, Prevalence, Risk Factors, C-Reactive Protein genetics, C-Reactive Protein metabolism, Hypertension epidemiology, Hypertension genetics
Abstract

Background: C-reactive protein (CRP) has repeatedly been associated with blood pressure and prevalent and incident hypertension, but whether a causal link exists is uncertain., Methods and Results: We assessed the cross-sectional relations of CRP to systolic blood pressure, pulse pressure, and prevalent hypertension in a representative sample of >3500 British women aged 60 to 79 years. For both outcomes, substantial associations were observed. However, these associations were greatly attenuated by adjustment for a wide range of confounding factors acting over the life course. We further investigated causality using a Mendelian randomization approach by examining the association of the 1059G/C polymorphism in the human CRP gene with CRP and with blood pressure, pulse pressure, and hypertension. The polymorphism was associated with a robust difference in CRP, and the expectation would be for higher blood pressure and pulse pressure and greater prevalence of hypertension among those carrying the genetic variant associated with higher CRP levels. This was not observed, and the predicted causal effects of CRP on blood pressure, pulse pressure, and hypertension using instrumental variables methods were close to 0, although with wide CIs., Conclusions: CRP levels are associated with blood pressure, pulse pressure, and hypertension, but adjustment for life course confounding and a Mendelian randomization approach suggest the elevated CRP levels do not lead to elevated blood pressure.

Published
2005
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