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2.  Lessons from Mackenzie that still resonate 
doi:10.3399/bjgp13X664423
PMCID: PMC3582972  PMID: 23561780
3.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y. | Willems, Sara M. | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A. | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E. | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J. | Grarup, Niels | Ehm, Margaret G. | Li, Li | Baldridge, Abigail S. | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F. | Garcia, Melissa E. | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A. | Layton, Jill C. | Li, Man | Zhao, Jing Hua | Meidtner, Karina | Morrison, Alanna C. | Nalls, Mike A. | Peters, Marjolein J. | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V. | Southam, Lorraine | Stoiber, Marcus H. | Strawbridge, Rona J. | Taylor, Kent D. | Varga, Tibor V. | Allin, Kristine H. | Amin, Najaf | Aponte, Jennifer L. | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A. | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W. | Burns, Sean M. | Chen, Yuning | Chen, Yii-Der I. | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B. | Eiriksdottir, Gudny | Escher, Stefan A. | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | III, William A. Goddard | Goel, Anuj | Gottesman, Omri | Grove, Megan L. | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K. | Jensen, Richard A. | Jørgensen, Marit E. | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C. | Kirkpatrick, Andrea | Kraja, Aldi T. | Kuusisto, Johanna | Lange, Ethan M. | Lee, I.T. | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M. | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M. | Matchan, Angela | McKean, Roberta | McLeod, Olga | Metcalf, Ginger A. | Mohlke, Karen L. | Muzny, Donna M. | Ntalla, Ioanna | Palmer, Nicholette D. | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W. | Renström, Frida | Rice, Ken | Sala, Cinzia F. | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A. | Soranzo, Nicole | Speliotes, Elizabeth K. | Stahl, Eli A. | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R. | Zengini, Eleni | Becker, Diane M. | Bis, Joshua C. | Brown, James B. | Cupples, L. Adrienne | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J. | Lorenzo, Carlos | Mathias, Rasika A. | Norris, Jill M. | Peloso, Gina M. | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E. | Boeing, Heiner | Bottinger, Erwin P. | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H. | Franks, Paul W. | Gibbs, Richard A. | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B. | Hattersley, Andrew T. | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J. | Levy, Daniel | Oostra, Ben A. | O'Donnell, Christopher J. | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S. | Polasek, Ozren | Province, Michael A. | Rich, Stephen S. | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B. | Smith, Blair H. | Uitterlinden, André G. | Walker, Mark | Watkins, Hugh | Wong, Tien Y. | Zeggini, Eleftheria | Scotland, Generation | Laakso, Markku | Borecki, Ingrid B. | Chasman, Daniel I. | Pedersen, Oluf | Psaty, Bruce M. | Tai, E. Shyong | van Duijn, Cornelia M. | Wareham, Nicholas J. | Waterworth, Dawn M. | Boerwinkle, Eric | Kao, WH Linda | Florez, Jose C. | Loos, Ruth J.F. | Wilson, James G. | Frayling, Timothy M. | Siscovick, David S. | Dupuis, Josée | Rotter, Jerome I. | Meigs, James B. | Scott, Robert A. | Goodarzi, Mark O.
Nature communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol L−1, p=3.4×10−12), T2D risk (OR[95%CI]=0.86[0.76-0.96], p=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose−1, p=0.048), but higher 2-h glucose (β=0.16±0.05 mmol L−1, p=4.3×10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8×10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol L−1, p=1.3×10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
5.  What's in a name? 
PMCID: PMC2034166  PMID: 17263923
6.  Genetic epidemiology and primary care 
Large-scale, population-based studies of genetic epidemiology are under way or planned in several countries, including the UK. The results will have many implications for GPs and their patients. Primary care has much to contribute to this research, and basing genetic epidemiology studies in primary care will confer several advantages. These include enhanced public engagement, building on the personal relationships and trust that are at the core of primary care practice; methodological factors that will strengthen study design; and the potential of linkage of multiple datasets and between networks of research practices. Essential development work with primary care professionals and the public is, however, required for this to happen, and, if undertaken, this work will have the additional important benefit of increasing the uptake of new knowledge into general practice.
PMCID: PMC1828265  PMID: 16536962
epidemiology; genetics; primary care; public engagement
7.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
8.  Pharmacist-led management of chronic pain in primary care: costs and benefits in a pilot randomised controlled trial 
BMJ Open  2015;5(4):e006874.
Objectives
To explore differences in mean costs (from a UK National Health Service perspective) and effects of pharmacist-led management of chronic pain in primary care evaluated in a pilot randomised controlled trial (RCT), and to estimate optimal sample size for a definitive RCT.
Design
Regression analysis of costs and effects, using intention-to-treat and expected value of sample information analysis (EVSI).
Setting
Six general practices: Grampian (3); East Anglia (3).
Participants
125 patients with complete resource use and short form-six-dimension questionnaire (SF-6D) data at baseline, 3 months and 6 months.
Interventions
Patients were randomised to either pharmacist medication review with face-to-face pharmacist prescribing or pharmacist medication review with feedback to general practitioner or treatment as usual (TAU).
Main outcome measures
Differences in mean total costs and effects measured as quality-adjusted life years (QALYs) at 6 months and EVSI for sample size calculation.
Results
Unadjusted total mean costs per patient were £452 for prescribing (SD: £466), £570 for review (SD: £527) and £668 for TAU (SD: £1333). After controlling for baseline costs, the adjusted mean cost differences per patient relative to TAU were £77 for prescribing (95% CI −82 to 237) and £54 for review (95% CI −103 to 212). Unadjusted mean QALYs were 0.3213 for prescribing (SD: 0.0659), 0.3161 for review (SD: 0.0684) and 0.3079 for TAU (SD: 0.0606). Relative to TAU, the adjusted mean differences were 0.0069 for prescribing (95% CI −0.0091 to 0.0229) and 0.0097 for review (95% CI −0.0054 to 0.0248). The EVSI suggested the optimal future trial size was between 460 and 690, and between 540 and 780 patients per arm using a threshold of £30 000 and £20 000 per QALY gained, respectively.
Conclusions
Compared with TAU, pharmacist-led interventions for chronic pain appear more costly and provide similar QALYs. However, these estimates are imprecise due to the small size of the pilot trial. The EVSI indicates that a larger trial is necessary to obtain more precise estimates of differences in mean effects and costs between treatment groups.
Trial registration number
ISRCTN06131530.
doi:10.1136/bmjopen-2014-006874
PMCID: PMC4390732  PMID: 25833666
HEALTH ECONOMICS; PAIN MANAGEMENT; PRIMARY CARE
9.  A study of National Health Service management of chronic osteoarthritis and low back pain 
Aim
To describe treatment and referral patterns and National Health Service resource use in patients with chronic pain associated with low back pain or osteoarthritis, from a Primary Care perspective.
Background
Osteoarthritis and low back pain are the two commonest debilitating causes of chronic pain, with high health and social costs, and particularly important in primary care. Understanding current practice and resource use in their management will inform health service and educational requirements and the design and optimisation of future care.
Method
Multi-centre, retrospective, descriptive study of adults (⩾18 years) with chronic pain arising from low back pain or osteoarthritis, identified through primary care records. Five general practices in Scotland, England (two), Northern Ireland and Wales. All patients with a diagnosis of low back pain or osteoarthritis made on or before 01/09/2006 who had received three or more prescriptions for pain medication were identified and a sub-sample randomly selected then consented to an in-depth review of their medical records (n=264). Data on management of chronic pain were collected retrospectively from patients’ records for three years from diagnosis (‘newly diagnosed’ patients) or for the most recent three years (‘established’ patients).
Findings
Patients received a wide variety of pain medications with no overall common prescribing pattern. GP visits represented the majority of the resource use and ‘newly diagnosed’ patients were significantly more likely to visit their GP for pain management than ‘established’ patients. Although ‘newly diagnosed’ patients had more referrals outside the GP practice, the number of visits to secondary care for pain management was similar for both groups.
Conclusion
This retrospective study confirmed the complexity of managing these causes of chronic pain and the associated high resource use. It provides an in-depth picture of prescribing and referral patterns and of resource use.
doi:10.1017/S1463423614000140
PMCID: PMC4356172  PMID: 24674890
analgesic prescribing; low back pain; osteoarthritis; pain; primary healthcare; referral and consultations
10.  Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 
Wessel, Jennifer | Chu, Audrey Y | Willems, Sara M | Wang, Shuai | Yaghootkar, Hanieh | Brody, Jennifer A | Dauriz, Marco | Hivert, Marie-France | Raghavan, Sridharan | Lipovich, Leonard | Hidalgo, Bertha | Fox, Keolu | Huffman, Jennifer E | An, Ping | Lu, Yingchang | Rasmussen-Torvik, Laura J | Grarup, Niels | Ehm, Margaret G | Li, Li | Baldridge, Abigail S | Stančáková, Alena | Abrol, Ravinder | Besse, Céline | Boland, Anne | Bork-Jensen, Jette | Fornage, Myriam | Freitag, Daniel F | Garcia, Melissa E | Guo, Xiuqing | Hara, Kazuo | Isaacs, Aaron | Jakobsdottir, Johanna | Lange, Leslie A | Layton, Jill C | Li, Man | Hua Zhao, Jing | Meidtner, Karina | Morrison, Alanna C | Nalls, Mike A | Peters, Marjolein J | Sabater-Lleal, Maria | Schurmann, Claudia | Silveira, Angela | Smith, Albert V | Southam, Lorraine | Stoiber, Marcus H | Strawbridge, Rona J | Taylor, Kent D | Varga, Tibor V | Allin, Kristine H | Amin, Najaf | Aponte, Jennifer L | Aung, Tin | Barbieri, Caterina | Bihlmeyer, Nathan A | Boehnke, Michael | Bombieri, Cristina | Bowden, Donald W | Burns, Sean M | Chen, Yuning | Chen, Yii-DerI | Cheng, Ching-Yu | Correa, Adolfo | Czajkowski, Jacek | Dehghan, Abbas | Ehret, Georg B | Eiriksdottir, Gudny | Escher, Stefan A | Farmaki, Aliki-Eleni | Frånberg, Mattias | Gambaro, Giovanni | Giulianini, Franco | Goddard, William A | Goel, Anuj | Gottesman, Omri | Grove, Megan L | Gustafsson, Stefan | Hai, Yang | Hallmans, Göran | Heo, Jiyoung | Hoffmann, Per | Ikram, Mohammad K | Jensen, Richard A | Jørgensen, Marit E | Jørgensen, Torben | Karaleftheri, Maria | Khor, Chiea C | Kirkpatrick, Andrea | Kraja, Aldi T | Kuusisto, Johanna | Lange, Ethan M | Lee, I T | Lee, Wen-Jane | Leong, Aaron | Liao, Jiemin | Liu, Chunyu | Liu, Yongmei | Lindgren, Cecilia M | Linneberg, Allan | Malerba, Giovanni | Mamakou, Vasiliki | Marouli, Eirini | Maruthur, Nisa M | Matchan, Angela | McKean-Cowdin, Roberta | McLeod, Olga | Metcalf, Ginger A | Mohlke, Karen L | Muzny, Donna M | Ntalla, Ioanna | Palmer, Nicholette D | Pasko, Dorota | Peter, Andreas | Rayner, Nigel W | Renström, Frida | Rice, Ken | Sala, Cinzia F | Sennblad, Bengt | Serafetinidis, Ioannis | Smith, Jennifer A | Soranzo, Nicole | Speliotes, Elizabeth K | Stahl, Eli A | Stirrups, Kathleen | Tentolouris, Nikos | Thanopoulou, Anastasia | Torres, Mina | Traglia, Michela | Tsafantakis, Emmanouil | Javad, Sundas | Yanek, Lisa R | Zengini, Eleni | Becker, Diane M | Bis, Joshua C | Brown, James B | Adrienne Cupples, L | Hansen, Torben | Ingelsson, Erik | Karter, Andrew J | Lorenzo, Carlos | Mathias, Rasika A | Norris, Jill M | Peloso, Gina M | Sheu, Wayne H.-H. | Toniolo, Daniela | Vaidya, Dhananjay | Varma, Rohit | Wagenknecht, Lynne E | Boeing, Heiner | Bottinger, Erwin P | Dedoussis, George | Deloukas, Panos | Ferrannini, Ele | Franco, Oscar H | Franks, Paul W | Gibbs, Richard A | Gudnason, Vilmundur | Hamsten, Anders | Harris, Tamara B | Hattersley, Andrew T | Hayward, Caroline | Hofman, Albert | Jansson, Jan-Håkan | Langenberg, Claudia | Launer, Lenore J | Levy, Daniel | Oostra, Ben A | O'Donnell, Christopher J | O'Rahilly, Stephen | Padmanabhan, Sandosh | Pankow, James S | Polasek, Ozren | Province, Michael A | Rich, Stephen S | Ridker, Paul M | Rudan, Igor | Schulze, Matthias B | Smith, Blair H | Uitterlinden, André G | Walker, Mark | Watkins, Hugh | Wong, Tien Y | Zeggini, Eleftheria | Laakso, Markku | Borecki, Ingrid B | Chasman, Daniel I | Pedersen, Oluf | Psaty, Bruce M | Shyong Tai, E | van Duijn, Cornelia M | Wareham, Nicholas J | Waterworth, Dawn M | Boerwinkle, Eric | Linda Kao, W H | Florez, Jose C | Loos, Ruth J.F. | Wilson, James G | Frayling, Timothy M | Siscovick, David S | Dupuis, Josée | Rotter, Jerome I | Meigs, James B | Scott, Robert A | Goodarzi, Mark O
Nature Communications  2015;6:5897.
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits.
doi:10.1038/ncomms6897
PMCID: PMC4311266  PMID: 25631608
11.  Mosaic structural variation in children with developmental disorders 
Human Molecular Genetics  2015;24(10):2733-2745.
Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.
doi:10.1093/hmg/ddv033
PMCID: PMC4406290  PMID: 25634561
12.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
14.  Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers 
PLoS Genetics  2014;10(12):e1004799.
We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00×10−10), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38×10−5). An interaction test confirmed that these estimates differed from each other (P = 4.95×10−13). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.
Author Summary
We found that a single nucleotide polymorphism in the CHRNA5-A3-B4 gene cluster, which is known to influence smoking heaviness, is associated with lower body mass index (BMI) in current smokers, but higher BMI in never smokers. This difference in effects suggests that the variant influences BMI both via pathways other than smoking, and via the weight-reducing effects of smoking, in opposite directions. The overall effect on BMI would therefore be undetectable in an unstratified genome-wide association study, indicating that novel associations may be obscured by hidden population sub-structure.
doi:10.1371/journal.pgen.1004799
PMCID: PMC4256159  PMID: 25474695
15.  Estimating the burden of disease in chronic pain with and without neuropathic characteristics: Does the choice between the EQ-5D and SF-6D matter? 
Pain  2014;155(10):1996-2004.
Summary
Chronic pain with neuropathic characteristics is associated with significantly lower EQ-5D and Short Form 6D health utilities scores, with 17% reporting health states “worse than death”.
The EQ-5D and Short Form (SF)12 are widely used generic health-related quality of life (HRQoL) questionnaires. They can be used to derive health utility index scores, on a scale where 0 is equivalent to death and 1 represents full health, with scores less than zero representing states “worse than death.” We compared EQ-5D or SF-6D health utility index scores in patients with no chronic pain, and chronic pain with and without neuropathic characteristics (NC), and to explore their discriminant ability for pain severity. Self-reported health and chronic pain status was collected as part of a UK general population survey (n = 4451). We found moderate agreement between individual dimensions of EQ-5D and SF-6D, with most highly correlated dimensions found for mental health and anxiety/depression, role limitations and usual activities, and pain and pain/discomfort. Overall 43% reported full health on the EQ-5D, compared with only 4.2% on the SF-6D. There were significant differences in mean utilities for chronic pain with NC (EQ-5D 0.47 vs SF-6D 0.62) and especially for severe pain (EQ-5D 0.33 vs SF-6D 0.58). On the EQ-5D, 17% of those with chronic pain with NC and 3% without NC scored “worse than death,” a state which is not possible using the SF-6D. Health utilities derived from EQ-5D and SF-12/36 can discriminate between group differences for chronic pain with and without NC and greater pain severity. However, the instruments generate widely differing HRQoL scores for the same patient groups. The choice between using the EQ-5D or SF-6D matters greatly when estimating the burden of disease.
doi:10.1016/j.pain.2014.07.001
PMCID: PMC4220009  PMID: 25020004
Chronic pain; EQ-5D; Health-related quality of life; Health utilities; Neuropathic pain; SF-6D; S-LANSS
16.  “I Try and Smile, I Try and Be Cheery, I Try Not to Be Pushy. I Try to Say ‘I'm Here for Help’ but I Leave Feeling… Worried”: A Qualitative Study of Perceptions of Interactions with Health Professionals by Community-Based Older Adults with Chronic Pain 
PLoS ONE  2014;9(9):e105450.
Background
Over 50% of community-dwelling older adults experience chronic pain, which threatens their quality of life. Of importance to their pain management is older people's interaction with health professionals that, if unsatisfactory, may impair the outcome.
Aims
To add to the limited research specific to older people living with chronic pain in the community, we explored how they perceive their experiences of interacting with health professionals, seeking factors that might optimise these interactions.
Methods
Purposive sampling was used to recruit men and women >65 years with self-reported musculoskeletal chronic pain. Qualitative individual interviews and one group interview were undertaken with 23 participants. Data were transcribed verbatim and underwent Framework Analysis.
Results
Three themes were identified. Seeking help illustrates issues around why older people in the community may or may not seek help for chronic pain, and highlights the potential involvement of social comparison. Importance of diagnosis illustrates the desire for professional validation of their condition and an aversion to vague explanations based on the person's age. Being listened to and being heard illustrates the importance of empathic communication and understanding expectations, with due respect for the person's age.
Conclusions
In common with people of all ages, an effective partnership between an older person in pain and health professionals is essential if pain is to be reported, appropriately assessed and managed, because of the subjective nature of pain and its treatment responses. For older people with pain, perception about their age, by both parties in the partnership, is an additional factor that can unnecessarily interfere with the effectiveness of this partnership. Health professionals should engage with older adults to clarify their expectations about pain and its management, which may be influenced by perceptions about age; and to encourage expression of their concerns, which may also be affected by perceptions about age.
doi:10.1371/journal.pone.0105450
PMCID: PMC4154857  PMID: 25187952
17.  Systematically searching for and assessing the literature for self-management of chronic pain: a lay users’ perspective 
BMC Geriatrics  2014;14:86.
Background
The Engaging with older adults in the development of strategies for the self management of chronic pain (EOPIC) study aims to design and develop self management strategies to enable older adults to manage their own pain. Involving older adults in research into chronic pain management will better enable the identification and development of strategies that are more appropriate for their use, but how can perspectives really be utilised to the best possible outcomes?
Method
Seven older adults were recruited through a local advertising campaign to take part. We also invited participants from the local pain services, individuals who had been involved in earlier phase of the EOPIC study and a previous ESRC funded project. The group undertook library training and research skills training to facilitate searching of the literature and identified sources of material. A grading tool was developed using perceived essential criteria identified by the older adults and material was graded according to the criteria within this scale.
Results
Fifty-seven resources from over twenty-eight sources were identified. These materials were identified as being easily accessible, readable and relevant. Many of the web based materials were not always easy to find or readily available so they were excluded by the participants. All but one were UK based. Forty-four items were identified as meeting the key criteria for inclusion in the study. This included five key categories as follows; books, internet, magazines, leaflets, CD’s/Tapes.
Conclusion
This project was able to identify a number of exemplars of self management material along with some general rules regarding the categories identified. We must point out that the materials identified were not age specific, were often locally developed and would need to be adapted to older adults with chronic pain. For copyright issues we have not included them in this paper. The key message is really related to the format rather than the content. However, the group acknowledge that these may vary according to the requirements of each individual older adult and therefore recommend the development of a leaflet to help others in their search for resources. This leaflet has been developed as part of Phase IV of the EOPIC study.
doi:10.1186/1471-2318-14-86
PMCID: PMC4118203  PMID: 25064208
Older adults; Literature for self-management of chronic pain; Strategies for managing chronic pain; Involving older adults in research
18.  Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study 
BMC Medical Genetics  2014;15:70.
Background
Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.
Methods
We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.
Results
Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.
Conclusions
We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis.
doi:10.1186/1471-2350-15-70
PMCID: PMC4083361  PMID: 24956927
Familial hypercholesterolaemia; Total cholesterol; LDLR; Molecular diagnostic testing; Next-generation sequencing; Primary care; Generation Scotland
19.  Molecular genetic contributions to socioeconomic status and intelligence 
Intelligence  2014;44(100):26-32.
Education, socioeconomic status, and intelligence are commonly used as predictors of health outcomes, social environment, and mortality. Education and socioeconomic status are typically viewed as environmental variables although both correlate with intelligence, which has a substantial genetic basis. Using data from 6815 unrelated subjects from the Generation Scotland study, we examined the genetic contributions to these variables and their genetic correlations. Subjects underwent genome-wide testing for common single nucleotide polymorphisms (SNPs). DNA-derived heritability estimates and genetic correlations were calculated using the ‘Genome-wide Complex Trait Analyses’ (GCTA) procedures. 21% of the variation in education, 18% of the variation in socioeconomic status, and 29% of the variation in general cognitive ability was explained by variation in common SNPs (SEs ~ 5%). The SNP-based genetic correlations of education and socioeconomic status with general intelligence were 0.95 (SE 0.13) and 0.26 (0.16), respectively. There are genetic contributions to intelligence and education with near-complete overlap between common additive SNP effects on these traits (genetic correlation ~ 1). Genetic influences on socioeconomic status are also associated with the genetic foundations of intelligence. The results are also compatible with substantial environmental contributions to socioeconomic status.
Highlights
•Generation Scotland is a large family-based cohort of ~ 24,000 people.•We investigate the genetic influences on education, SES, and intelligence.•Both DNA-based (subset of ~ 6500) and pedigree-based analyses are used.•Genetic effects on SES and education are linked to the genetic basis of intelligence.•There are also substantial environmental effects on all three traits.
doi:10.1016/j.intell.2014.02.006
PMCID: PMC4051988  PMID: 24944428
Generation Scotland; Intelligence; Education; Socioeconomic status; Genetics
20.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the rheumatic diseases  2012;72(3):427-436.
Objectives
Chronic widespread pain (CWP) is a common disorder affecting ~10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1,308 female CWP cases and 5,791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1,480 CWP cases and 7,989 controls (P<1×10−5). Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of CCT5 and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (MAF=43%; OR=1.30, 95%CI=1.19-1.42, P=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95%CI=1.10-1.24, P=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95%CI=1.14-1.32, P=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (P>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgia/Pain Syndromes; Epidemiology
21.  Substance misuse of gabapentin 
doi:10.3399/bjgp12X653516
PMCID: PMC3404313  PMID: 22867659
22.  Neuropathic pain in the community: More under-treated than refractory? 
Pain  2013;154(5):690-699.
Summary
There is a significant proportion of chronic pain that is persistent and neuropathic, appears undertreated or untreated, and is associated with poor health and quality of life.
Best current estimates of neuropathic pain prevalence come from studies using screening tools detecting pain with probable neuropathic features; the proportion experiencing significant, long-term neuropathic pain, and the proportion not responding to standard treatment are unknown. These “refractory” cases are the most clinically important to detect, being the most severe, requiring specialist treatment. The aim of this study was to estimate the proportion of neuropathic pain in the population that is “refractory,” and to quantify associated clinical and demographic features. We posted self-administered questionnaires to 10,000 adult patients randomly selected from 10 general practitioner practices in 5 UK locations. The questionnaire contained chronic pain identification and severity questions, cause of pain, SF-12, EQ-5D, S-LANSS (Self-administered Leeds Assessment of Neuropathic Signs and Symptoms), PSEQ (Pain Self-Efficacy Questionnaire), use of neuropathic pain medications, and health care utilisation. These data were combined to determine the presence and characteristics of “refractory” neuropathic pain according to the defining features identified by a Delphi survey of international experts. Graded categories of chronic pain with and without neuropathic characteristics were generated, incorporating the refractory criteria. Completed questionnaires were returned by 4451 individuals (response rate 47%); 399 had “chronic pain with neuropathic characteristics” (S-LANSS positive, 8.9% of the study sample); 215 (53.9%) also reported a positive relevant history (“Possible neuropathic pain”); and 98 (4.5% of all Chronic Pain) also reported an “adequate” trial of at least one neuropathic pain drug (“Treated possible neuropathic pain”). The most refractory cases were associated with dramatically poorer physical and mental health, lower pain self-efficacy, higher pain intensity and pain-related disability, and greater health care service use.
doi:10.1016/j.pain.2012.12.022
PMCID: PMC3630326  PMID: 23485369
Neuropathic pain; Chronic pain; Epidemiology; S-LANSS; Refractory
23.  Pedigree and genotyping quality analyses of over 10,000 DNA samples from the Generation Scotland: Scottish Family Health Study 
BMC Medical Genetics  2013;14:38.
Background
Generation Scotland: Scottish Family Health Study (GS:SFHS) is a family-based biobank of 24,000 participants with rich phenotype and DNA available for genetic research. This paper describes the laboratory results from genotyping 32 single nucleotide polymorphisms (SNPs) on DNA from over 10,000 participants who attended GS:SFHS research clinics. The analysis described here was undertaken to test the quality of genetic information available to researchers. The success rate of each marker genotyped (call rate), minor allele frequency and adherence to Mendelian inheritance are presented. The few deviations in marker transmission in the 925 parent-child trios analysed were assessed as to whether they were likely to be miscalled genotypes, data or sample handling errors, or pedigree inaccuracies including non-paternity.
Methods
The first 10,450 GS:SFHS clinic participants who had spirometry and smoking data available and DNA extracted were selected. 32 SNPs were assayed, chosen as part of a replication experiment from a Genome-Wide Association Study meta-analysis of lung function.
Results
In total 325,336 genotypes were returned. The overall project pass rate (32 SNPs on 10,450 samples) was 97.29%. A total of 925 parent-child trios were assessed for transmission of the SNP markers, with 16 trios indicating evidence of inconsistency in the recorded pedigrees.
Conclusions
The Generation Scotland: Scottish Family Health Study used well-validated study methods and can produce good quality genetic data, with a low error rate. The GS:SFHS DNA samples are of high quality and the family groups were recorded and processed with accuracy during collection of the cohort.
doi:10.1186/1471-2350-14-38
PMCID: PMC3614907  PMID: 23521772
Genetics; SNP Genotyping; Parent-child trios; Error rate; Non paternity; Generation Scotland; Biobank
24.  “I feel so stupid because I can’t give a proper answer…” How older adults describe chronic pain: a qualitative study 
BMC Geriatrics  2012;12:78.
Background
Over 50% of older adults experience chronic pain. Poorly managed pain threatens independent functioning, limits social activities and detrimentally affects emotional wellbeing. Yet, chronic pain is not fully understood from older adults’ perspectives; subsequently, pain management in later life is not necessarily based on their priorities or needs. This paper reports a qualitative exploration of older adults’ accounts of living with chronic pain, focusing on how they describe pain, with a view to informing approaches to its assessment.
Methods
Cognitively intact men and women aged over sixty-five who lived in the community opted into the study through responding to advertisements in the media and via contacts with groups and organisations in North-East Scotland. Interviews were transcribed and thematically analysed using a framework approach.
Results
Qualitative individual interviews and one group interview were undertaken with 23 older adults. Following analysis, the following main themes emerged: diversity in conceptualising pain using a simple numerical score; personalising the meaning of pain by way of stories, similes and metaphors; and, contextualising pain in relation to its impact on activities.
Conclusions
The importance of attending to individuals’ stories as a meaningful way of describing pain for older adults is highlighted, suggesting that a narrative approach, as recommended and researched in other areas of medicine, may usefully be applied in pain assessment for older adults. Along with the judicious use of numerical tools, this requires innovative methods to elicit verbal accounts, such as using similes and metaphors to help older adults describe and discuss their experience, and contextualising the effects of pain on activities that are important to them.
doi:10.1186/1471-2318-12-78
PMCID: PMC3544685  PMID: 23276327
Older adults; Ageing; Qualitative research; Stories; Metaphors; Chronic pain; Community
25.  Genetic variation in Hyperpolarization-activated cyclic nucleotide-gated channels and its relationship with neuroticism, cognition and risk of depression 
Frontiers in Genetics  2012;3:116.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1–4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1–4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.
doi:10.3389/fgene.2012.00116
PMCID: PMC3387669  PMID: 22783272
stress; depression; HCN channel; genetics; association; cognition; neuroticism

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