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1.  Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian’an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R.B.
Nature communications  2015;6:7756.
More than one hundred loci have been identified for age at menarche by genome-wide association studies (GWAS), but collectively these explain only ~3% of the trait variance. Here, we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08%-4.6%; effect sizes 0.08-1.25 years/allele; P<5×10−8). Additionally, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4×10−13) and FAAH2 (rs5914101, P=4.9×10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-years later menarche (P=2.8×10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively these novel variants explain ~0.5% variance, indicating these overlooked sources of variation do not substantially explain the ‘missing heritability’ of this complex trait.
doi:10.1038/ncomms8756
PMCID: PMC4538850  PMID: 26239645
2.  Corrigendum: Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E. | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian'an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R. B.
Nature Communications  2015;6:10257.
doi:10.1038/ncomms10257
PMCID: PMC4703878  PMID: 26674845
3.  Increasing the response rate of text messaging data collection: a delayed randomized controlled trial 
Objective To test the effectiveness of multiple interventions on increasing the response rate of text messaging for longitudinal data collection.
Methods Our cohort included 283 caregivers of children aged 6–12 months who were participating in an anemia program in rural China. Using text messages to collect data on anemia medication adherence, we conducted a delayed randomized controlled trial to test multiple interventions (an additional four reminders; a ¥5.0 (US$0.79) credit reward for replying; and a feedback text message). After a 6-week pilot study with week 7 as the baseline measurement, we randomly allocated all participants into two groups: group 1 (n = 142) and group 2 (n = 141). During weeks 8–11, we introduced the interventions to group 1, and in weeks 12–15 the intervention was introduced to both groups. We compared the response rates between groups and explored factors affecting the response rate.
Results During weeks 8–11, the response rates in group 1 increased and were significantly higher than in group 2 (p<0.05). During weeks 12–15, the response rate increased significantly in group 2 (p>0.05) and slightly decreased in group 1. Younger participants or participants who had children with lower hemoglobin concentration were more likely to reply (p = 0.02). Sending four reminders on the second day contributed to only 286 (11.7%) extra text messages.
Discussion Our study showed that multiple interventions were effective in increasing response rate of text messaging data collection in rural China.
Conclusions Larger multi-site studies are needed to find the most effective way of using these interventions to allow usage of text messaging data collection for health research.
doi:10.1136/amiajnl-2014-002845
PMCID: PMC4433373  PMID: 25332355
randomized controlled trial; program evaluation; nutrition surveys
4.  Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation 
Artigas, María Soler | Wain, Louise V. | Miller, Suzanne | Kheirallah, Abdul Kader | Huffman, Jennifer E. | Ntalla, Ioanna | Shrine, Nick | Obeidat, Ma'en | Trochet, Holly | McArdle, Wendy L. | Alves, Alexessander Couto | Hui, Jennie | Zhao, Jing Hua | Joshi, Peter K. | Teumer, Alexander | Albrecht, Eva | Imboden, Medea | Rawal, Rajesh | Lopez, Lorna M. | Marten, Jonathan | Enroth, Stefan | Surakka, Ida | Polasek, Ozren | Lyytikäinen, Leo-Pekka | Granell, Raquel | Hysi, Pirro G. | Flexeder, Claudia | Mahajan, Anubha | Beilby, John | Bossé, Yohan | Brandsma, Corry-Anke | Campbell, Harry | Gieger, Christian | Gläser, Sven | González, Juan R. | Grallert, Harald | Hammond, Chris J. | Harris, Sarah E. | Hartikainen, Anna-Liisa | Heliövaara, Markku | Henderson, John | Hocking, Lynne | Horikoshi, Momoko | Hutri-Kähönen, Nina | Ingelsson, Erik | Johansson, Åsa | Kemp, John P. | Kolcic, Ivana | Kumar, Ashish | Lind, Lars | Melén, Erik | Musk, Arthur W. | Navarro, Pau | Nickle, David C. | Padmanabhan, Sandosh | Raitakari, Olli T. | Ried, Janina S. | Ripatti, Samuli | Schulz, Holger | Scott, Robert A. | Sin, Don D. | Starr, John M. | Viñuela, Ana | Völzke, Henry | Wild, Sarah H. | Wright, Alan F. | Zemunik, Tatijana | Jarvis, Deborah L. | Spector, Tim D. | Evans, David M. | Lehtimäki, Terho | Vitart, Veronique | Kähönen, Mika | Gyllensten, Ulf | Rudan, Igor | Deary, Ian J. | Karrasch, Stefan | Probst-Hensch, Nicole M. | Heinrich, Joachim | Stubbe, Beate | Wilson, James F. | Wareham, Nicholas J. | James, Alan L. | Morris, Andrew P. | Jarvelin, Marjo-Riitta | Hayward, Caroline | Sayers, Ian | Strachan, David P. | Hall, Ian P. | Tobin, Martin D.
Nature Communications  2015;6:8658.
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.
doi:10.1038/ncomms9658
PMCID: PMC4686825  PMID: 26635082
5.  Global and regional estimates of COPD prevalence: Systematic review and meta–analysis 
Journal of Global Health  null;5(2):020415.
Background
The burden of chronic obstructive pulmonary disease (COPD) across many world regions is high. We aim to estimate COPD prevalence and number of disease cases for the years 1990 and 2010 across world regions based on the best available evidence in publicly accessible scientific databases.
Methods
We conducted a systematic search of Medline, EMBASE and Global Health for original, population–based studies providing spirometry–based prevalence rates of COPD across the world from January 1990 to December 2014. Random effects meta–analysis was conducted on extracted crude prevalence rates of COPD, with overall summaries of the meta–estimates (and confidence intervals) reported separately for World Health Organization (WHO) regions, the World Bank's income categories and settings (urban and rural). We developed a meta–regression epidemiological model that we used to estimate the prevalence of COPD in people aged 30 years or more.
Findings
Our search returned 37 472 publications. A total of 123 studies based on a spirometry–defined prevalence were retained for the review. From the meta–regression epidemiological model, we estimated about 227.3 million COPD cases in the year 1990 among people aged 30 years or more, corresponding to a global prevalence of 10.7% (95% confidence interval (CI) 7.3%–14.0%) in this age group. The number of COPD cases increased to 384 million in 2010, with a global prevalence of 11.7% (8.4%–15.0%). This increase of 68.9% was mainly driven by global demographic changes. Across WHO regions, the highest prevalence was estimated in the Americas (13.3% in 1990 and 15.2% in 2010), and the lowest in South East Asia (7.9% in 1990 and 9.7% in 2010). The percentage increase in COPD cases between 1990 and 2010 was the highest in the Eastern Mediterranean region (118.7%), followed by the African region (102.1%), while the European region recorded the lowest increase (22.5%). In 1990, we estimated about 120.9 million COPD cases among urban dwellers (prevalence of 13.2%) and 106.3 million cases among rural dwellers (prevalence of 8.8%). In 2010, there were more than 230 million COPD cases among urban dwellers (prevalence of 13.6%) and 153.7 million among rural dwellers (prevalence of 9.7%). The overall prevalence in men aged 30 years or more was 14.3% (95% CI 13.3%–15.3%) compared to 7.6% (95% CI 7.0%–8.2%) in women.
Conclusions
Our findings suggest a high and growing prevalence of COPD, both globally and regionally. There is a paucity of studies in Africa, South East Asia and the Eastern Mediterranean region. There is a need for governments, policy makers and international organizations to consider strengthening collaborations to address COPD globally.
doi:10.7189/jogh.05-020415
PMCID: PMC4693508  PMID: 26755942
6.  Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder 
de Moor, Marleen H.M. | van den Berg, Stéphanie M. | Verweij, Karin J.H. | Krueger, Robert F. | Luciano, Michelle | Vasquez, Alejandro Arias | Matteson, Lindsay K. | Derringer, Jaime | Esko, Tõnu | Amin, Najaf | Gordon, Scott D. | Hansell, Narelle K. | Hart, Amy B. | Seppälä, Ilkka | Huffman, Jennifer E. | Konte, Bettina | Lahti, Jari | Lee, Minyoung | Miller, Mike | Nutile, Teresa | Tanaka, Toshiko | Teumer, Alexander | Viktorin, Alexander | Wedenoja, Juho | Abecasis, Goncalo R. | Adkins, Daniel E. | Agrawal, Arpana | Allik, Jüri | Appel, Katja | Bigdeli, Timothy B. | Busonero, Fabio | Campbell, Harry | Costa, Paul T. | Smith, George Davey | Davies, Gail | de Wit, Harriet | Ding, Jun | Engelhardt, Barbara E. | Eriksson, Johan G. | Fedko, Iryna O. | Ferrucci, Luigi | Franke, Barbara | Giegling, Ina | Grucza, Richard | Hartmann, Annette M. | Heath, Andrew C. | Heinonen, Kati | Henders, Anjali K. | Homuth, Georg | Hottenga, Jouke-Jan | Janzing, Joost | Jokela, Markus | Karlsson, Robert | Kemp, John P. | Kirkpatrick, Matthew G. | Latvala, Antti | Lehtimäki, Terho | Liewald, David C. | Madden, Pamela A.F. | Magri, Chiara | Magnusson, Patrik K.E. | Marten, Jonathan | Maschio, Andrea | Medland, Sarah E. | Mihailov, Evelin | Milaneschi, Yuri | Montgomery, Grant W. | Nauck, Matthias | Ouwens, Klaasjan G. | Palotie, Aarno | Pettersson, Erik | Polasek, Ozren | Qian, Yong | Pulkki-Råback, Laura | Raitakari, Olli T. | Realo, Anu | Rose, Richard J. | Ruggiero, Daniela | Schmidt, Carsten O. | Slutske, Wendy S. | Sorice, Rossella | Starr, John M. | Pourcain, Beate St | Sutin, Angelina R. | Timpson, Nicholas J. | Trochet, Holly | Vermeulen, Sita | Vuoksimaa, Eero | Widen, Elisabeth | Wouda, Jasper | Wright, Margaret J. | Zgaga, Lina | Scotland, Generation | Porteous, David | Minelli, Alessandra | Palmer, Abraham A. | Rujescu, Dan | Ciullo, Marina | Hayward, Caroline | Rudan, Igor | Metspalu, Andres | Kaprio, Jaakko | Deary, Ian J. | Räikkönen, Katri | Wilson, James F. | Keltikangas-Järvinen, Liisa | Bierut, Laura J. | Hettema, John M. | Grabe, Hans J. | van Duijn, Cornelia M. | Evans, David M. | Schlessinger, David | Pedersen, Nancy L. | Terracciano, Antonio | McGue, Matt | Penninx, Brenda W.J.H. | Martin, Nicholas G. | Boomsma, Dorret I.
JAMA psychiatry  2015;72(7):642-650.
Importance
Neuroticism is a personality trait that is briefly defined by emotional instability. It is a robust genetic risk factor for Major Depressive Disorder (MDD) and other psychiatric disorders. Hence, neuroticism is an important phenotype for psychiatric genetics. The Genetics of Personality Consortium (GPC) has created a resource for genome-wide association analyses of personality traits in over 63,000 participants (including MDD cases).
Objective
To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association (GWA) results based on 1000Genomes imputation, to evaluate if common genetic variants as assessed by Single Nucleotide Polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability, and to examine whether SNPs that predict neuroticism also predict MDD.
Setting
30 cohorts with genome-wide genotype, personality and MDD data from the GPC.
Participants
The study included 63,661 participants from 29 discovery cohorts and 9,786 participants from a replication cohort. Participants came from Europe, the United States or Australia.
Main outcome measure(s)
Neuroticism scores harmonized across all cohorts by Item Response Theory (IRT) analysis, and clinically assessed MDD case-control status.
Results
A genome-wide significant SNP was found in the MAGI1 gene (rs35855737; P=9.26 × 10−9 in the discovery meta-analysis, and P=2.38 × 10−8 in the meta-analysis of all 30 cohorts). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 of the discovery cohorts significantly predicted neuroticism in 2 independent cohorts. Importantly, polygenic scores also predicted MDD in these cohorts.
Conclusions and relevance
This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism, and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.
doi:10.1001/jamapsychiatry.2015.0554
PMCID: PMC4667957  PMID: 25993607
7.  Assessment of Malawi’s success in child mortality reduction through the lens of the Catalytic Initiative Integrated Health Systems Strengthening programme: Retrospective evaluation 
Journal of Global Health  null;5(2):020412.
Background
Malawi is estimated to have achieved its Millennium Development Goal (MDG) 4 target. This paper explores factors influencing progress in child survival in Malawi including coverage of interventions and the role of key national policies.
Methods
We performed a retrospective evaluation of the Catalytic Initiative (CI) programme of support (2007–2013). We developed estimates of child mortality using four population household surveys undertaken between 2000 and 2010. We recalculated coverage indicators for high impact child health interventions and documented child health programmes and policies. The Lives Saved Tool (LiST) was used to estimate child lives saved in 2013.
Results
The mortality rate in children under 5 years decreased rapidly in the 10 CI districts from 219 deaths per 1000 live births (95% confidence interval (CI) 189 to 249) in the period 1991–1995 to 119 deaths (95% CI 105 to 132) in the period 2006–2010. Coverage for all indicators except vitamin A supplementation increased in the 10 CI districts across the time period 2000 to 2013. The LiST analysis estimates that there were 10 800 child deaths averted in the 10 CI districts in 2013, primarily attributable to the introduction of the pneumococcal vaccine (24%) and increased household coverage of insecticide–treated bednets (19%). These improvements have taken place within a context of investment in child health policies and scale up of integrated community case management of childhood illnesses.
Conclusions
Malawi provides a strong example for countries in sub–Saharan Africa of how high impact child health interventions implemented within a decentralised health system with an established community–based delivery platform, can lead to significant reductions in child mortality.
doi:10.7189/jogh.05.020412
PMCID: PMC4652924  PMID: 26649176
8.  The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis 
Scientific Reports  2015;5:16119.
Host genetic factors have frequently been implicated in respiratory infectious diseases, often with inconsistent results in replication studies. We identified 386 studies from the total of 24,823 studies identified in a systematic search of four bibliographic databases. We performed meta-analyses of studies on tuberculosis, influenza, respiratory syncytial virus, SARS-Coronavirus and pneumonia. One single-nucleotide polymorphism from IL4 gene was significant for pooled respiratory infections (rs2070874; 1.66 [1.29–2.14]). We also detected an association of TLR2 gene with tuberculosis (rs5743708; 3.19 [2.03–5.02]). Subset analyses identified CCL2 as an additional risk factor for tuberculosis (rs1024611; OR = 0.79 [0.72–0.88]). The IL4-TLR2-CCL2 axis could be a highly interesting target for translation towards clinical use. However, this conclusion is based on low credibility of evidence - almost 95% of all identified studies had strong risk of bias or confounding. Future studies must build upon larger-scale collaborations, but also strictly adhere to the highest evidence-based principles in study design, in order to reduce research waste and provide clinically translatable evidence.
doi:10.1038/srep16119
PMCID: PMC4630784  PMID: 26524966
9.  Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study 
Vimaleswaran, Karani S | Cavadino, Alana | Berry, Diane J | Jorde, Rolf | Dieffenbach, Aida Karina | Lu, Chen | Alves, Alexessander Couto | Heerspink, Hiddo J Lambers | Tikkanen, Emmi | Eriksson, Joel | Wong, Andrew | Mangino, Massimo | Jablonski, Kathleen A | Nolte, Ilja M | Houston, Denise K | Ahluwalia, Tarunveer Singh | van der Most, Peter J | Pasko, Dorota | Zgaga, Lina | Thiering, Elisabeth | Vitart, Veronique | Fraser, Ross M | Huffman, Jennifer E | de Boer, Rudolf A | Schöttker, Ben | Saum, Kai-Uwe | McCarthy, Mark I | Dupuis, Josée | Herzig, Karl-Heinz | Sebert, Sylvain | Pouta, Anneli | Laitinen, Jaana | Kleber, Marcus E | Navis, Gerjan | Lorentzon, Mattias | Jameson, Karen | Arden, Nigel | Cooper, Jackie A | Acharya, Jayshree | Hardy, Rebecca | Raitakari, Olli | Ripatti, Samuli | Billings, Liana K | Lahti, Jari | Osmond, Clive | Penninx, Brenda W | Rejnmark, Lars | Lohman, Kurt K | Paternoster, Lavinia | Stolk, Ronald P | Hernandez, Dena G | Byberg, Liisa | Hagström, Emil | Melhus, Håkan | Ingelsson, Erik | Mellström, Dan | Ljunggren, Östen | Tzoulaki, Ioanna | McLachlan, Stela | Theodoratou, Evropi | Tiesler, Carla M T | Jula, Antti | Navarro, Pau | Wright, Alan F | Polasek, Ozren | Hayward, Caroline | Wilson, James F | Rudan, Igor | Salomaa, Veikko | Heinrich, Joachim | Campbell, Harry | Price, Jacqueline F | Karlsson, Magnus | Lind, Lars | Michaëlsson, Karl | Bandinelli, Stefania | Frayling, Timothy M | Hartman, Catharina A | Sørensen, Thorkild I A | Kritchevsky, Stephen B | Langdahl, Bente Lomholt | Eriksson, Johan G | Florez, Jose C | Spector, Tim D | Lehtimäki, Terho | Kuh, Diana | Humphries, Steve E | Cooper, Cyrus | Ohlsson, Claes | März, Winfried | de Borst, Martin H | Kumari, Meena | Kivimaki, Mika | Wang, Thomas J | Power, Chris | Brenner, Hermann | Grimnes, Guri | van der Harst, Pim | Snieder, Harold | Hingorani, Aroon D | Pilz, Stefan | Whittaker, John C | Järvelin, Marjo-Riitta | Hyppönen, Elina
Summary
Background
Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk.
Methods
In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium.
Findings
In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97−0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96−0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002).
Interpretation
Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
doi:10.1016/S2213-8587(14)70113-5
PMCID: PMC4582411  PMID: 24974252
10.  Rare coding variants and X-linked loci associated with age at menarche 
Lunetta, Kathryn L. | Day, Felix R. | Sulem, Patrick | Ruth, Katherine S. | Tung, Joyce Y. | Hinds, David A. | Esko, Tõnu | Elks, Cathy E. | Altmaier, Elisabeth | He, Chunyan | Huffman, Jennifer E. | Mihailov, Evelin | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Stolk, Lisette | Teumer, Alexander | Thompson, Deborah J. | Traglia, Michela | Wang, Carol A. | Yerges-Armstrong, Laura M. | Antoniou, Antonis C. | Barbieri, Caterina | Coviello, Andrea D. | Cucca, Francesco | Demerath, Ellen W. | Dunning, Alison M. | Gandin, Ilaria | Grove, Megan L. | Gudbjartsson, Daniel F. | Hocking, Lynne J. | Hofman, Albert | Huang, Jinyan | Jackson, Rebecca D. | Karasik, David | Kriebel, Jennifer | Lange, Ethan M. | Lange, Leslie A. | Langenberg, Claudia | Li, Xin | Luan, Jian'an | Mägi, Reedik | Morrison, Alanna C. | Padmanabhan, Sandosh | Pirie, Ailith | Polasek, Ozren | Porteous, David | Reiner, Alex P. | Rivadeneira, Fernando | Rudan, Igor | Sala, Cinzia F. | Schlessinger, David | Scott, Robert A. | Stöckl, Doris | Visser, Jenny A. | Völker, Uwe | Vozzi, Diego | Wilson, James G. | Zygmunt, Marek | Boerwinkle, Eric | Buring, Julie E. | Crisponi, Laura | Easton, Douglas F. | Hayward, Caroline | Hu, Frank B. | Liu, Simin | Metspalu, Andres | Pennell, Craig E. | Ridker, Paul M. | Strauch, Konstantin | Streeten, Elizabeth A. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Wellons, Melissa | Franceschini, Nora | Chasman, Daniel I. | Thorsteinsdottir, Unnur | Murray, Anna | Stefansson, Kari | Murabito, Joanne M. | Ong, Ken K. | Perry, John R. B.
Nature Communications  2015;6:7756.
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08–4.6%; effect sizes 0.08–1.25 years per allele; P<5 × 10−8). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10−13) and FAAH2 (rs5914101, P=4.9 × 10−10). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10−11), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the ‘missing heritability' of this complex trait.
Previous studies have linked over 100 genomic loci to age-at-menarche but that work was restricted to common autosomal variation. Here, Lunetta et al. identify associations with rare protein-coding and X-linked variants, implicating new mechanisms that regulate puberty timing.
doi:10.1038/ncomms8756
PMCID: PMC4538850  PMID: 26239645
11.  Improving health aid for a better planet: The planning, monitoring and evaluation tool (PLANET) 
Journal of Global Health  null;5(2):020404.
Background
International development assistance for health (DAH) quadrupled between 1990 and 2012, from US$ 5.6 billion to US$ 28.1 billion. This generates an increasing need for transparent and replicable tools that could be used to set investment priorities, monitor the distribution of funding in real time, and evaluate the impact of those investments.
Methods
In this paper we present a methodology that addresses these three challenges. We call this approach PLANET, which stands for planning, monitoring and evaluation tool. Fundamentally, PLANET is based on crowdsourcing approach to obtaining information relevant to deployment of large–scale programs. Information is contributed in real time by a diverse group of participants involved in the program delivery.
Findings
PLANET relies on real–time information from three levels of participants in large–scale programs: funders, managers and recipients. At each level, information is solicited to assess five key risks that are most relevant to each level of operations. The risks at the level of funders involve systematic neglect of certain areas, focus on donor’s interests over that of program recipients, ineffective co–ordination between donors, questionable mechanisms of delivery and excessive loss of funding to “middle men”. At the level of managers, the risks are corruption, lack of capacity and/or competence, lack of information and /or communication, undue avoidance of governmental structures / preference to non–governmental organizations and exclusion of local expertise. At the level of primary recipients, the risks are corruption, parallel operations / “verticalization”, misalignment with local priorities and lack of community involvement, issues with ethics, equity and/or acceptability, and low likelihood of sustainability beyond the end of the program’s implementation.
Interpretation
PLANET is intended as an additional tool available to policy–makers to prioritize, monitor and evaluate large–scale development programs. In this, it should complement tools such as LiST (for health care/interventions), EQUIST (for health care/interventions) and CHNRI (for health research), which also rely on information from local experts and on local context to set priorities in a transparent, user–friendly, replicable, quantifiable and specific, algorithmic–like manner.
doi:10.7189/jogh.05.020404
PMCID: PMC4544236  PMID: 26322228
12.  New genetic loci link adipose and insulin biology to body fat distribution 
Shungin, Dmitry | Winkler, Thomas W | Croteau-Chonka, Damien C | Ferreira, Teresa | Locke, Adam E | Mägi, Reedik | Strawbridge, Rona J | Pers, Tune H | Fischer, Krista | Justice, Anne E | Workalemahu, Tsegaselassie | Wu, Joseph M.W. | Buchkovich, Martin L | Heard-Costa, Nancy L | Roman, Tamara S | Drong, Alexander W | Song, Ci | Gustafsson, Stefan | Day, Felix R | Esko, Tonu | Fall, Tove | Kutalik, Zoltán | Luan, Jian’an | Randall, Joshua C | Scherag, André | Vedantam, Sailaja | Wood, Andrew R | Chen, Jin | Fehrmann, Rudolf | Karjalainen, Juha | Kahali, Bratati | Liu, Ching-Ti | Schmidt, Ellen M | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bragg-Gresham, Jennifer L | Buyske, Steven | Demirkan, Ayse | Ehret, Georg B | Feitosa, Mary F | Goel, Anuj | Jackson, Anne U | Johnson, Toby | Kleber, Marcus E | Kristiansson, Kati | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J | Prokopenko, Inga | Stančáková, Alena | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Van Vliet-Ostaptchouk, Jana V | Yengo, Loïc | Zhang, Weihua | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Böhringer, Stefan | Bonnet, Fabrice | Böttcher, Yvonne | Bruinenberg, Marcel | Carba, Delia B | Caspersen, Ida H | Clarke, Robert | Daw, E Warwick | Deelen, Joris | Deelman, Ewa | Delgado, Graciela | Doney, Alex SF | Eklund, Niina | Erdos, Michael R | Estrada, Karol | Eury, Elodie | Friedrich, Nele | Garcia, Melissa E | Giedraitis, Vilmantas | Gigante, Bruna | Go, Alan S | Golay, Alain | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grewal, Jagvir | Groves, Christopher J | Haller, Toomas | Hallmans, Goran | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heikkilä, Kauko | Herzig, Karl-Heinz | Helmer, Quinta | Hillege, Hans L | Holmen, Oddgeir | Hunt, Steven C | Isaacs, Aaron | Ittermann, Till | James, Alan L | Johansson, Ingegerd | Juliusdottir, Thorhildur | Kalafati, Ioanna-Panagiota | Kinnunen, Leena | Koenig, Wolfgang | Kooner, Ishminder K | Kratzer, Wolfgang | Lamina, Claudia | Leander, Karin | Lee, Nanette R | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Mach, François | Magnusson, Patrik KE | Mahajan, Anubha | McArdle, Wendy L | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Mills, Rebecca | Moayyeri, Alireza | Monda, Keri L | Mooijaart, Simon P | Mühleisen, Thomas W | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Nagaraja, Ramaiah | Nalls, Michael A | Narisu, Narisu | Glorioso, Nicola | Nolte, Ilja M | Olden, Matthias | Rayner, Nigel W | Renstrom, Frida | Ried, Janina S | Robertson, Neil R | Rose, Lynda M | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Sennblad, Bengt | Seufferlein, Thomas | Sitlani, Colleen M | Smith, Albert Vernon | Stirrups, Kathleen | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Swift, Amy J | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorand, Barbara | Thorleifsson, Gudmar | Tomaschitz, Andreas | Troffa, Chiara | van Oort, Floor VA | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Wennauer, Roman | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Zhang, Qunyuan | Zhao, Jing Hua | Brennan, Eoin P. | Choi, Murim | Eriksson, Per | Folkersen, Lasse | Franco-Cereceda, Anders | Gharavi, Ali G | Hedman, Åsa K | Hivert, Marie-France | Huang, Jinyan | Kanoni, Stavroula | Karpe, Fredrik | Keildson, Sarah | Kiryluk, Krzysztof | Liang, Liming | Lifton, Richard P | Ma, Baoshan | McKnight, Amy J | McPherson, Ruth | Metspalu, Andres | Min, Josine L | Moffatt, Miriam F | Montgomery, Grant W | Murabito, Joanne M | Nicholson, George | Nyholt, Dale R | Olsson, Christian | Perry, John RB | Reinmaa, Eva | Salem, Rany M | Sandholm, Niina | Schadt, Eric E | Scott, Robert A | Stolk, Lisette | Vallejo, Edgar E. | Westra, Harm-Jan | Zondervan, Krina T | Amouyel, Philippe | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Blangero, John | Brown, Morris J | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chines, Peter S | Claudi-Boehm, Simone | Collins, Francis S | Crawford, Dana C | Danesh, John | de Faire, Ulf | de Geus, Eco JC | Dörr, Marcus | Erbel, Raimund | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Forouhi, Nita G | Forrester, Terrence | Franco, Oscar H | Gansevoort, Ron T | Gieger, Christian | Gudnason, Vilmundur | Haiman, Christopher A | Harris, Tamara B | Hattersley, Andrew T | Heliövaara, Markku | Hicks, Andrew A | Hingorani, Aroon D | Hoffmann, Wolfgang | Hofman, Albert | Homuth, Georg | Humphries, Steve E | Hyppönen, Elina | Illig, Thomas | Jarvelin, Marjo-Riitta | Johansen, Berit | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kooner, Jaspal S | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C | McKenzie, Colin A | McKnight, Barbara | Musk, Arthur W | Möhlenkamp, Stefan | Morris, Andrew D | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Palmer, Lyle J | Penninx, Brenda W | Peters, Annette | Pramstaller, Peter P | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ridker, Paul M | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Shuldiner, Alan R | Staessen, Jan A | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Strauch, Konstantin | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Vohl, Marie-Claude | Völker, Uwe | Vollenweider, Peter | Wilson, James F | Witteman, Jacqueline C | Adair, Linda S | Bochud, Murielle | Boehm, Bernhard O | Bornstein, Stefan R | Bouchard, Claude | Cauchi, Stéphane | Caulfield, Mark J | Chambers, John C | Chasman, Daniel I | Cooper, Richard S | Dedoussis, George | Ferrucci, Luigi | Froguel, Philippe | Grabe, Hans-Jörgen | Hamsten, Anders | Hui, Jennie | Hveem, Kristian | Jöckel, Karl-Heinz | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | März, Winfried | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E | Saleheen, Danish | Sinisalo, Juha | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Stefansson, Kari | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G | Uusitupa, Matti | van der Harst, Pim | Veronesi, Giovanni | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Abecasis, Goncalo R | Assimes, Themistocles L | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | Deloukas, Panos | Franke, Lude | Frayling, Timothy M | Groop, Leif C | Hunter, David J. | Kaplan, Robert C | O’Connell, Jeffrey R | Qi, Lu | Schlessinger, David | Strachan, David P | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Willer, Cristen J | Visscher, Peter M | Yang, Jian | Hirschhorn, Joel N | Zillikens, M Carola | McCarthy, Mark I | Speliotes, Elizabeth K | North, Kari E | Fox, Caroline S | Barroso, Inês | Franks, Paul W | Ingelsson, Erik | Heid, Iris M | Loos, Ruth JF | Cupples, L Adrienne | Morris, Andrew P | Lindgren, Cecilia M | Mohlke, Karen L
Nature  2015;518(7538):187-196.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
doi:10.1038/nature14132
PMCID: PMC4338562  PMID: 25673412
13.  Assembling GHERG: Could “academic crowd–sourcing” address gaps in global health estimates? 
Journal of Global Health  null;5(1):010101.
In recent months, the World Health Organization (WHO), independent academic researchers, the Lancet and PLoS Medicine journals worked together to improve reporting of population health estimates. The new guidelines for accurate and transparent health estimates reporting (likely to be named GATHER), which are eagerly awaited, represent a helpful move that should benefit the field of global health metrics. Building on this progress and drawing from a tradition of Child Health Epidemiology Reference Group (CHERG)’s successful work model, we would like to propose a new initiative – “Global Health Epidemiology Reference Group” (GHERG). We see GHERG as an informal and entirely voluntary international collaboration of academic groups who are willing to contribute to improving disease burden estimates and respect the principles of the new guidelines – a form of “academic crowd–sourcing”. The main focus of GHERG will be to identify the “gap areas” where not much information is available and/or where there is a lot of uncertainty present about the accuracy of the existing estimates. This approach should serve to complement the existing WHO and IHME estimates and to represent added value to both efforts.
doi:10.7189/jogh.05.010101
PMCID: PMC4593291  PMID: 26445671
14.  Prevalence of schizophrenia in China between 1990 and 2010 
Journal of Global Health  null;5(1):010410.
Background
Dramatic development and changes in lifestyle in many low and middle–income countries (LMIC) over the past three decades may have affected mental health of their populations. Being the largest country and having the most striking record of development, industrialization and urbanization, China provides an important opportunity for studying the nature and magnitude of possible effects.
Methods
We reviewed CNKI, WanFang and PubMed databases for epidemiological studies of schizophrenia in mainland China published between 1990 and 2010. We identified 42 studies that reported schizophrenia prevalence using internationally recognized diagnostic criteria, with breakdown by rural and urban residency. The analysis involved a total of 2 284 957 persons, with 10 506 diagnosed with schizophrenia. Bayesian methods were used to estimate the probability of case of schizophrenia (“prevalence”) by type of residency in different years.
Findings
In urban China, lifetime prevalence was 0.39% (0.37–0.41%) in 1990, 0.57% (0.55–0.59%) in 2000 and 0.83% (0.75–0.91%) in 2010. In rural areas, the corresponding rates were 0.37% (0.34–0.40%), 0.43% (0.42–0.44%) and 0.50% (0.47–0.53%). In 1990 there were 3.09 (2.87–3.32) million people in China affected with schizophrenia during their lifetime. The number of cases rose to 7.16 (6.57–7.75) million in 2010, a 132% increase, while the total population increased by 18%. The contribution of cases from urban areas to the overall burden increased from 27% in 1990 to 62% in 2010.
Conclusions
The prevalence of schizophrenia in China has more than doubled between 1990 and 2010, with rates being particularly high in the most developed areas of modern China. This has broad implications, as the ongoing development in LMIC countries may be increasing the global prevalence of schizophrenia.
doi:10.7189/jogh.05.010410
PMCID: PMC4663755  PMID: 26649171
15.  Genome-Wide Association Study for Circulating Tissue Plasminogen Activator (tPA) Levels and Functional Follow-up Implicates Endothelial STXBP5 and STX2 
Huang, Jie | Huffman, Jennifer E. | Yamkauchi, Munekazu | Trompet, Stella | Asselbergs, Folkert W. | Sabater-Lleal, Maria | Trégouët, David-Alexandre | Chen, Wei-Min | Smith, Nicholas L. | Kleber, Marcus E. | Shin, So-Youn | Becker, Diane M. | Tang, Weihong | Dehghan, Abbas | Johnson, Andrew D. | Truong, Vinh | Folkersen, Lasse | Yang, Qiong | Oudot-Mellakh, Tiphaine | Buckley, Brendan M. | Moore, Jason H. | Williams, Frances M.K. | Campbell, Harry | Silbernagel, Günther | Vitart, Veronique | Rudan, Igor | Tofler, Geoffrey H. | Navis, Gerjan J. | DeStefano, Anita | Wright, Alan F. | Chen, Ming-Huei | de Craen, Anton J.M. | Worrall, Bradford B. | Rudnicka, Alicja R. | Rumley, Ann | Bookman, Ebony B. | Psaty, Bruce M. | Chen, Fang | Keene, Keith L. | Franco, Oscar H. | Böhm, Bernhard O. | Uitterlinden, Andre G. | Carter, Angela M. | Jukema, J. Wouter | Sattar, Naveed | Bis, Joshua C. | Ikram, Mohammad A. | Sale, Michèle M. | McKnight, Barbara | Fornage, Myriam | Ford, Ian | Taylor, Kent | Slagboom, P. Eline | McArdle, Wendy L. | Hsu, Fang-Chi | Franco-Cereceda, Anders | Goodall, Alison H. | Yanek, Lisa R. | Furie, Karen L. | Cushman, Mary | Hofman, Albert | Witteman, Jacqueline CM. | Folsom, Aaron R. | Basu, Saonli | Matijevic, Nena | van Gilst, Wiek H. | Wilson, James F. | Westendorp, Rudi G.J. | Kathiresan, Sekar | Reilly, Muredach P. | Tracy, Russell P. | Polasek, Ozren | Winkelmann, Bernhard R. | Grant, Peter J. | Hillege, Hans L. | Cambien, Francois | Stott, David J. | Lowe, Gordon D. | Spector, Timothy D. | Meigs, James B. | Marz, Winfried | Eriksson, Per | Becker, Lewis C. | Morange, Pierre-Emmanuel | Soranzo, Nicole | Williams, Scott M. | Hayward, Caroline | van der Harst, Pim | Hamsten, Anders | Lowenstein, Charles J. | Strachan, David P. | O'Donnell, Christopher J.
Objective
Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases (CVD). We conducted a meta-analysis of genome-wide association studies (GWAS) to identify novel correlates of circulating levels of tPA.
Approach and Results
Fourteen cohort studies with tPA measures (N=26,929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P <5.0×10−8). The first locus is on 6q24.3, with the lead SNP (rs9399599, P=2.9×10−14) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739, P=1.3×10−9) is intronic to POLB and less than 200kb away from the tPA encoding gene PLAT. We identified a non-synonymous SNP (rs2020921) in modest LD with rs3136739 (r2 = 0.50) within exon 5 of PLAT (P=2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826, P=1.0×10−9) within intron 7 of STX2. We further found evidence for association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased release of tPA from vascular endothelial cells, while silencing of STX2 increased tPA release. Through an in-silico lookup, we found no associations of the three lead SNPs with coronary artery disease or stroke.
Conclusions
We identified three loci associated with circulating tPA levels, the PLAT region, STXBP5 and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.
doi:10.1161/ATVBAHA.113.302088
PMCID: PMC4009733  PMID: 24578379
tissue plasminogen activator; genome-wide association study; meta-analysis; cardiovascular disease risk; fibrinolysis; hemostasis
16.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
17.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita 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B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, 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I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
18.  Genomic prediction of complex human traits: relatedness, trait architecture and predictive meta-models 
Human Molecular Genetics  2015;24(14):4167-4182.
We explore the prediction of individuals' phenotypes for complex traits using genomic data. We compare several widely used prediction models, including Ridge Regression, LASSO and Elastic Nets estimated from cohort data, and polygenic risk scores constructed using published summary statistics from genome-wide association meta-analyses (GWAMA). We evaluate the interplay between relatedness, trait architecture and optimal marker density, by predicting height, body mass index (BMI) and high-density lipoprotein level (HDL) in two data cohorts, originating from Croatia and Scotland. We empirically demonstrate that dense models are better when all genetic effects are small (height and BMI) and target individuals are related to the training samples, while sparse models predict better in unrelated individuals and when some effects have moderate size (HDL). For HDL sparse models achieved good across-cohort prediction, performing similarly to the GWAMA risk score and to models trained within the same cohort, which indicates that, for predicting traits with moderately sized effects, large sample sizes and familial structure become less important, though still potentially useful. Finally, we propose a novel ensemble of whole-genome predictors with GWAMA risk scores and demonstrate that the resulting meta-model achieves higher prediction accuracy than either model on its own. We conclude that although current genomic predictors are not accurate enough for diagnostic purposes, performance can be improved without requiring access to large-scale individual-level data. Our methodologically simple meta-model is a means of performing predictive meta-analysis for optimizing genomic predictions and can be easily extended to incorporate multiple population-level summary statistics or other domain knowledge.
doi:10.1093/hmg/ddv145
PMCID: PMC4476450  PMID: 25918167
19.  Prevalence of rheumatoid arthritis in low– and middle–income countries: A systematic review and analysis 
Journal of Global Health  null;5(1):010409.
Background
Rheumatoid arthritis (RA) is an autoimmune disorder that affects the small joints of the body. It is one of the leading causes of chronic morbidity in high–income countries, but little is known about the burden of this disease in low– and middle–income countries (LMIC).
Methods
The aim of this study was to estimate the prevalence of RA in six of the World Health Organization's (WHO) regions that harbour LMIC by identifying all relevant studies in those regions. To accomplish this aim various bibliographic databases were searched: PubMed, EMBASE, Global Health, LILACS and the Chinese databases CNKI and WanFang. Studies were selected based on pre–defined inclusion criteria, including a definition of RA based on the 1987 revision of the American College of Rheumatology (ACR) definition.
Results
Meta–estimates of regional RA prevalence rates for countries of low or middle income were 0.40% (95% CI: 0.23–0.57%) for Southeast Asian, 0.37% (95% CI: 0.23–0.51%) for Eastern Mediterranean, 0.62% (95% CI: 0.47–0.77%) for European, 1.25% (95% CI: 0.64–1.86%) for American and 0.42% (95% CI: 0.30–0.53%) for Western Pacific regions. A formal meta–analysis could not be performed for the sub–Saharan African region due to limited data. Male prevalence of RA in LMIC was 0.16% (95% CI: 0.11–0.20%) while the prevalence in women reached 0.75% (95% CI: 0.60–0.90%). This difference between males and females was statistically significant (P < 0.0001). The prevalence of RA did not differ significantly between urban and rural settings (P = 0.353). These prevalence estimates represent 2.60 (95% CI: 1.85–3.34%) million male sufferers and 12.21 (95% CI: 9.78–14.67%) million female sufferers in LMIC in the year 2000, and 3.16 (95% CI: 2.25–4.05%) million affected males and 14.87 (95% CI: 11.91–17.86%) million affected females in LMIC in the year 2010.
Conclusion
Given that majority of the world’s population resides in LMIC, the number of affected people is substantial, with a projection to increase in the coming years. Therefore, policy makers and health–care providers need to plan to address a significant disease burden both socially and economically.
doi:10.7189/jogh.05.010409
PMCID: PMC4416333  PMID: 25969732
20.  Genetic studies of body mass index yield new insights for obesity biology 
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Adrienne | Cusi, Daniele | Danesh, John | de Faire, Ulf | den Ruijter, Hester M. | Dominiczak, Anna F. | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G. | Farrall, Martin | Felix, Stephan B. | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G. | Forrester, Terrence | Franco, Oscar H. | Gansevoort, Ron T. | Gejman, Pablo V. | Gieger, Christian | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Alistair S. | Harris, Tamara B. | Hattersley, Andrew T. | Hicks, Andrew A. | Hindorff, Lucia A. | Hingorani, Aroon D. | Hofman, Albert | Homuth, Georg | Hovingh, G. Kees | Humphries, Steve E. | Hunt, Steven C. | Hyppönen, Elina | Illig, Thomas | Jacobs, Kevin B. | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Johansen, Berit | Jousilahti, Pekka | Jukema, J. Wouter | Jula, Antti M. | Kaprio, Jaakko | Kastelein, John J. P. | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Knekt, Paul | Kooner, Jaspal S. | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T. | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A. | Langenberg, Claudia | Marchand, Loic Le | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C. | McKenzie, Colin A. | McKnight, Barbara | Moll, Frans L. | Morris, Andrew D. | Morris, Andrew P. | Murray, Jeffrey C. | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J. | Ong, Ken K. | Madden, Pamela A. F. | Pasterkamp, Gerard | Peden, John F. | Peters, Annette | Postma, Dirkje S. | Pramstaller, Peter P. | Price, Jackie F. | Qi, Lu | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Ridker, Paul M. | Rioux, John D. | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J. | Saramies, Jouko | Sarzynski, Mark A. | Schunkert, Heribert | Schwarz, Peter E. H. | Sever, Peter | Shuldiner, Alan R. | Sinisalo, Juha | Stolk, Ronald P. | Strauch, Konstantin | Tönjes, Anke | Trégouët, David-Alexandre | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Völker, Uwe | Waeber, Gérard | Willemsen, Gonneke | Witteman, Jacqueline C. | Zillikens, M. Carola | Adair, Linda S. | Amouyel, Philippe | Asselbergs, Folkert W. | Assimes, Themistocles L. | Bochud, Murielle | Boehm, Bernhard O. | Boerwinkle, Eric | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C. | Chanock, Stephen J. | Cooper, Richard S. | de Bakker, Paul I. W. | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W. | Froguel, Philippe | Groop, Leif C. | Haiman, Christopher A. | Hamsten, Anders | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Kaplan, Robert C. | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G. | März, Winfried | Melbye, Mads | Metspalu, Andres | Moebus, Susanne | Munroe, Patricia B. | Njølstad, Inger | Oostra, Ben A. | Palmer, Colin N. A. | Pedersen, Nancy L. | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E. | Saleheen, Danish | Sattar, Naveed | Schadt, Eric E. | Schlessinger, David | Slagboom, P. Eline | Snieder, Harold | Spector, Tim D. | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Weir, David R. | Wichmann, H-Erich | Wilson, James F. | Zanen, Pieter | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Heid, Iris M. | O’Connell, Jeffrey R. | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | Franke, Lude | Frayling, Timothy M. | McCarthy, Mark I. | Visscher, Peter M. | Scherag, André | Willer, Cristen J. | Boehnke, Michael | Mohlke, Karen L. | Lindgren, Cecilia M. | Beckmann, Jacques S. | Barroso, Inês | North, Kari E. | Ingelsson, Erik | Hirschhorn, Joel N. | Loos, Ruth J. F. | Speliotes, Elizabeth K.
Nature  2015;518(7538):197-206.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
doi:10.1038/nature14177
PMCID: PMC4382211  PMID: 25673413
21.  Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans 
Huffman, Jennifer E. | Albrecht, Eva | Teumer, Alexander | Mangino, Massimo | Kapur, Karen | Johnson, Toby | Kutalik, Zoltán | Pirastu, Nicola | Pistis, Giorgio | Lopez, Lorna M. | Haller, Toomas | Salo, Perttu | Goel, Anuj | Li, Man | Tanaka, Toshiko | Dehghan, Abbas | Ruggiero, Daniela | Malerba, Giovanni | Smith, Albert V. | Nolte, Ilja M. | Portas, Laura | Phipps-Green, Amanda | Boteva, Lora | Navarro, Pau | Johansson, Asa | Hicks, Andrew A. | Polasek, Ozren | Esko, Tõnu | Peden, John F. | Harris, Sarah E. | Murgia, Federico | Wild, Sarah H. | Tenesa, Albert | Tin, Adrienne | Mihailov, Evelin | Grotevendt, Anne | Gislason, Gauti K. | Coresh, Josef | D'Adamo, Pio | Ulivi, Sheila | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Kolcic, Ivana | Fisher, Krista | Viigimaa, Margus | Metter, Jeffrey E. | Masciullo, Corrado | Trabetti, Elisabetta | Bombieri, Cristina | Sorice, Rossella | Döring, Angela | Reischl, Eva | Strauch, Konstantin | Hofman, Albert | Uitterlinden, Andre G. | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J. | Dalbeth, Nicola | Stamp, Lisa | Smit, Johannes H. | Kirin, Mirna | Nagaraja, Ramaiah | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Farrington, Susan M. | Theodoratou, Evropi | Jula, Antti | Salomaa, Veikko | Sala, Cinzia | Hengstenberg, Christian | Burnier, Michel | Mägi, Reedik | Klopp, Norman | Kloiber, Stefan | Schipf, Sabine | Ripatti, Samuli | Cabras, Stefano | Soranzo, Nicole | Homuth, Georg | Nutile, Teresa | Munroe, Patricia B. | Hastie, Nicholas | Campbell, Harry | Rudan, Igor | Cabrera, Claudia | Haley, Chris | Franco, Oscar H. | Merriman, Tony R. | Gudnason, Vilmundur | Pirastu, Mario | Penninx, Brenda W. | Snieder, Harold | Metspalu, Andres | Ciullo, Marina | Pramstaller, Peter P. | van Duijn, Cornelia M. | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J. | Dunlop, Malcolm G. | Wilson, James F. | Gasparini, Paolo | Gyllensten, Ulf | Spector, Tim D. | Wright, Alan F. | Hayward, Caroline | Watkins, Hugh | Perola, Markus | Bochud, Murielle | Kao, W. H. Linda | Caulfield, Mark | Toniolo, Daniela | Völzke, Henry | Gieger, Christian | Köttgen, Anna | Vitart, Veronique
PLoS ONE  2015;10(3):e0119752.
We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
doi:10.1371/journal.pone.0119752
PMCID: PMC4374966  PMID: 25811787
22.  Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels 
van Leeuwen, Elisabeth M. | Karssen, Lennart C. | Deelen, Joris | Isaacs, Aaron | Medina-Gomez, Carolina | Mbarek, Hamdi | Kanterakis, Alexandros | Trompet, Stella | Postmus, Iris | Verweij, Niek | van Enckevort, David J. | Huffman, Jennifer E. | White, Charles C. | Feitosa, Mary F. | Bartz, Traci M. | Manichaikul, Ani | Joshi, Peter K. | Peloso, Gina M. | Deelen, Patrick | van Dijk, Freerk | Willemsen, Gonneke | de Geus, Eco J. | Milaneschi, Yuri | Penninx, Brenda W.J.H. | Francioli, Laurent C. | Menelaou, Androniki | Pulit, Sara L. | Rivadeneira, Fernando | Hofman, Albert | Oostra, Ben A. | Franco, Oscar H. | Leach, Irene Mateo | Beekman, Marian | de Craen, Anton J.M. | Uh, Hae-Won | Trochet, Holly | Hocking, Lynne J. | Porteous, David J. | Sattar, Naveed | Packard, Chris J. | Buckley, Brendan M. | Brody, Jennifer A. | Bis, Joshua C. | Rotter, Jerome I. | Mychaleckyj, Josyf C. | Campbell, Harry | Duan, Qing | Lange, Leslie A. | Wilson, James F. | Hayward, Caroline | Polasek, Ozren | Vitart, Veronique | Rudan, Igor | Wright, Alan F. | Rich, Stephen S. | Psaty, Bruce M. | Borecki, Ingrid B. | Kearney, Patricia M. | Stott, David J. | Adrienne Cupples, L. | Jukema, J. Wouter | van der Harst, Pim | Sijbrands, Eric J. | Hottenga, Jouke-Jan | Uitterlinden, Andre G. | Swertz, Morris A. | van Ommen, Gert-Jan B. | de Bakker, Paul I.W. | Eline Slagboom, P. | Boomsma, Dorret I. | Wijmenga, Cisca | van Duijn, Cornelia M.
Nature Communications  2015;6:6065.
Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10−4), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
Frequencies of rare variants fluctuate over populations, hampering gene discovery. Here the authors use a population-specific reference panel, the Genome of the Netherlands, to discover four novel loci involved in lipid metabolism, including an exonic variant in ABCA6.
doi:10.1038/ncomms7065
PMCID: PMC4366498  PMID: 25751400
23.  Prevalence of Mobile Phones and Factors Influencing Usage by Caregivers of Young Children in Daily Life and for Health Care in Rural China: A Mixed Methods Study 
PLoS ONE  2015;10(3):e0116216.
Introduction
To capitalise on mHealth, we need to understand the use of mobile phones both in daily life and for health care.
Objective
To assess the prevalence and factors that influence usage of mobile phones by caregivers of young children.
Materials and Methods
A mixed methods approach was used, whereby a survey (N=1854) and semi-structured interviews (N=17) were conducted concurrently. The quantitative and qualitative data obtained were compared and integrated. Participants were caregivers of young children in Zhao County, Hebei Province, China.
Results
Four main themes were found: (i) trends in mobile phone ownership; (ii) usage of mobile phone functions; (iii) factors influencing replying to text messages; and (iv) uses of mobile phones for health care. The majority of 1,854 survey participants (1,620; 87.4%) used mobile phones, but usage was much higher among mothers (1,433; 92.6%) and fathers (41; 100.0%) compared to grandparents (142; 54.6%). Parents were able to send text messages, grandparents often not. Factors influencing the decision to reply to text messages in daily life were checking the mobile phone, trusting the sender, emotion or feeling when receiving a text message, the importance of replying and ease of use of text messages. Of 1,620 survey participants who used a mobile phone, about one in four (432; 26.7%) had used it for health care in the past three months and most (1,110; 93.5%) of 1,187 who had not wished to use their phone to receive health information.
Conclusion
We found that usage of mobile phones is high, several factors influencing usage and an interest of caregivers to use phones for health care in Zhao County, rural China, which can be used to inform studies in settings with similar characteristics. Future work needs to assess factors influencing mobile phone usage in-depth to optimize experiences of users for specific mHealth-based interventions.
doi:10.1371/journal.pone.0116216
PMCID: PMC4366174  PMID: 25789477
24.  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
25.  Ancient human genomes suggest three ancestral populations for present-day Europeans 
Lazaridis, Iosif | Patterson, Nick | Mittnik, Alissa | Renaud, Gabriel | Mallick, Swapan | Kirsanow, Karola | Sudmant, Peter H. | Schraiber, Joshua G. | Castellano, Sergi | Lipson, Mark | Berger, Bonnie | Economou, Christos | Bollongino, Ruth | Fu, Qiaomei | Bos, Kirsten I. | Nordenfelt, Susanne | Li, Heng | de Filippo, Cesare | Prüfer, Kay | Sawyer, Susanna | Posth, Cosimo | Haak, Wolfgang | Hallgren, Fredrik | Fornander, Elin | Rohland, Nadin | Delsate, Dominique | Francken, Michael | Guinet, Jean-Michel | Wahl, Joachim | Ayodo, George | Babiker, Hamza A. | Bailliet, Graciela | Balanovska, Elena | Balanovsky, Oleg | Barrantes, Ramiro | Bedoya, Gabriel | Ben-Ami, Haim | Bene, Judit | Berrada, Fouad | Bravi, Claudio M. | Brisighelli, Francesca | Busby, George B. J. | Cali, Francesco | Churnosov, Mikhail | Cole, David E. C. | Corach, Daniel | Damba, Larissa | van Driem, George | Dryomov, Stanislav | Dugoujon, Jean-Michel | Fedorova, Sardana A. | Romero, Irene Gallego | Gubina, Marina | Hammer, Michael | Henn, Brenna M. | Hervig, Tor | Hodoglugil, Ugur | Jha, Aashish R. | Karachanak-Yankova, Sena | Khusainova, Rita | Khusnutdinova, Elza | Kittles, Rick | Kivisild, Toomas | Klitz, William | Kučinskas, Vaidutis | Kushniarevich, Alena | Laredj, Leila | Litvinov, Sergey | Loukidis, Theologos | Mahley, Robert W. | Melegh, Béla | Metspalu, Ene | Molina, Julio | Mountain, Joanna | Näkkäläjärvi, Klemetti | Nesheva, Desislava | Nyambo, Thomas | Osipova, Ludmila | Parik, Jüri | Platonov, Fedor | Posukh, Olga | Romano, Valentino | Rothhammer, Francisco | Rudan, Igor | Ruizbakiev, Ruslan | Sahakyan, Hovhannes | Sajantila, Antti | Salas, Antonio | Starikovskaya, Elena B. | Tarekegn, Ayele | Toncheva, Draga | Turdikulova, Shahlo | Uktveryte, Ingrida | Utevska, Olga | Vasquez, René | Villena, Mercedes | Voevoda, Mikhail | Winkler, Cheryl | Yepiskoposyan, Levon | Zalloua, Pierre | Zemunik, Tatijana | Cooper, Alan | Capelli, Cristian | Thomas, Mark G. | Ruiz-Linares, Andres | Tishkoff, Sarah A. | Singh, Lalji | Thangaraj, Kumarasamy | Villems, Richard | Comas, David | Sukernik, Rem | Metspalu, Mait | Meyer, Matthias | Eichler, Evan E. | Burger, Joachim | Slatkin, Montgomery | Pääbo, Svante | Kelso, Janet | Reich, David | Krause, Johannes
Nature  2014;513(7518):409-413.
We sequenced the genomes of a ~7,000 year old farmer from Germany and eight ~8,000 year old hunter-gatherers from Luxembourg and Sweden. We analyzed these and other ancient genomes1–4 with 2,345 contemporary humans to show that most present Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE) related to Upper Paleolithic Siberians3, who contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations’ deep relationships and show that EEF had ~44% ancestry from a “Basal Eurasian” population that split prior to the diversification of other non-African lineages.
doi:10.1038/nature13673
PMCID: PMC4170574  PMID: 25230663

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