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1.  Across-cohort QC analyses of GWAS summary statistics from complex traits 
Genome-wide association studies (GWASs) have been successful in discovering SNP trait associations for many quantitative traits and common diseases. Typically, the effect sizes of SNP alleles are very small and this requires large genome-wide association meta-analyses (GWAMAs) to maximize statistical power. A trend towards ever-larger GWAMA is likely to continue, yet dealing with summary statistics from hundreds of cohorts increases logistical and quality control problems, including unknown sample overlap, and these can lead to both false positive and false negative findings. In this study, we propose four metrics and visualization tools for GWAMA, using summary statistics from cohort-level GWASs. We propose methods to examine the concordance between demographic information, and summary statistics and methods to investigate sample overlap. (I) We use the population genetics Fst statistic to verify the genetic origin of each cohort and their geographic location, and demonstrate using GWAMA data from the GIANT Consortium that geographic locations of cohorts can be recovered and outlier cohorts can be detected. (II) We conduct principal component analysis based on reported allele frequencies, and are able to recover the ancestral information for each cohort. (III) We propose a new statistic that uses the reported allelic effect sizes and their standard errors to identify significant sample overlap or heterogeneity between pairs of cohorts. (IV) To quantify unknown sample overlap across all pairs of cohorts, we propose a method that uses randomly generated genetic predictors that does not require the sharing of individual-level genotype data and does not breach individual privacy.
doi:10.1038/ejhg.2016.106
PMCID: PMC5159754  PMID: 27552965
2.  Population genetic differentiation of height and body mass index across Europe 
Nature genetics  2015;47(11):1357-1362.
Across-nation differences in the mean of complex traits such as obesity and stature are common1–8, but the reasons for these differences are not known. Here, we find evidence that many independent loci of small effect combine to create population genetic differences in height and body mass index (BMI) in a sample of 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased estimates of effect sizes from 17,500 sib pairs, we estimate that 24% (95% CI: 9%, 41%) and 8% (95% CI: 4%, 16%) of the captured additive genetic variance for height and BMI across Europe are attributed to among-population genetic differences. Population genetic divergence differed significantly from that expected under a null model (P <3.94e−08 for height and P<5.95e−04 for BMI), and we find an among-population genetic correlation for tall and slender nations (r = −0.80 (95% CI: −0.95, −0.60), contrasting no genetic correlation between height and BMI within populations (r = −0.016, 95% CI: −0.041, 0.001), consistent with selection on height genes that also act to reduce BMI. Observations of mean height across nations correlated with the predicted genetic means for height (r = 0.51, P<0.001), so that a proportion of observed differences in height within Europe reflect genetic factors. In contrast, observed mean BMI did not correlate with the genetic estimates (P<0.58), implying that genetic differentiation in BMI is masked by environmental differences across Europe.
doi:10.1038/ng.3401
PMCID: PMC4984852  PMID: 26366552
3.  Omics-squared: human genomic, transcriptomic and phenotypic data for genetic analysis workshop 19 
BMC Proceedings  2016;10(Suppl 7):71-77.
Background
The Genetic Analysis Workshops (GAW) are a forum for development, testing, and comparison of statistical genetic methods and software. Each contribution to the workshop includes an application to a specified data set. Here we describe the data distributed for GAW19, which focused on analysis of human genomic and transcriptomic data.
Methods
GAW19 data were donated by the T2D-GENES Consortium and the San Antonio Family Heart Study and included whole genome and exome sequences for odd-numbered autosomes, measures of gene expression, systolic and diastolic blood pressures, and related covariates in two Mexican American samples. These two samples were a collection of 20 large families with whole genome sequence and transcriptomic data and a set of 1943 unrelated individuals with exome sequence. For each sample, simulated phenotypes were constructed based on the real sequence data. ‘Functional’ genes and variants for the simulations were chosen based on observed correlations between gene expression and blood pressure. The simulations focused primarily on additive genetic models but also included a genotype-by-medication interaction. A total of 245 genes were designated as ‘functional’ in the simulations with a few genes of large effect and most genes explaining < 1 % of the trait variation. An additional phenotype, Q1, was simulated to be correlated among related individuals, based on theoretical or empirical kinship matrices, but was not associated with any sequence variants. Two hundred replicates of the phenotypes were simulated. The GAW19 data are an expansion of the data used at GAW18, which included the family-based whole genome sequence, blood pressure, and simulated phenotypes, but not the gene expression data or the set of 1943 unrelated individuals with exome sequence.
doi:10.1186/s12919-016-0008-y
PMCID: PMC5133484  PMID: 27980614
4.  Independent test assessment using the extreme value distribution theory 
BMC Proceedings  2016;10(Suppl 7):245-249.
The new generation of whole genome sequencing platforms offers great possibilities and challenges for dissecting the genetic basis of complex traits. With a very high number of sequence variants, a naïve multiple hypothesis threshold correction hinders the identification of reliable associations by the overreduction of statistical power. In this report, we examine 2 alternative approaches to improve the statistical power of a whole genome association study to detect reliable genetic associations. The approaches were tested using the Genetic Analysis Workshop 19 (GAW19) whole genome sequencing data. The first tested method estimates the real number of effective independent tests actually being performed in whole genome association project by the use of an extreme value distribution and a set of phenotype simulations. Given the familiar nature of the GAW19 data and the finite number of pedigree founders in the sample, the number of correlations between genotypes is greater than in a set of unrelated samples. Using our procedure, we estimate that the effective number represents only 15 % of the total number of independent tests performed. However, even using this corrected significance threshold, no genome-wide significant association could be detected for systolic and diastolic blood pressure traits.
The second approach implements a biological relevance-driven hypothesis tested by exploiting prior computational predictions on the effect of nonsynonymous genetic variants detected in a whole genome sequencing association study. This guided testing approach was able to identify 2 promising single-nucleotide polymorphisms (SNPs), 1 for each trait, targeting biologically relevant genes that could help shed light on the genesis of the human hypertension. The first gene, PFH14, associated with systolic blood pressure, interacts directly with genes involved in calcium-channel formation and the second gene, MAP4, encodes a microtubule-associated protein and had already been detected by previous genome-wide association study experiments conducted in an Asian population. Our results highlight the necessity of the development of alternative approached to improve the efficiency on the detection of reasonable candidate associations in whole genome sequencing studies.
doi:10.1186/s12919-016-0038-5
PMCID: PMC5133519  PMID: 27980644
5.  Lessons and Perspectives from a 25-Year Bioelectromagnetics Research Program 
The question of whether electromagnetic fields from electric power or telecommunications systems can be linked unequivocally to health detriments has occupied scientific research endeavors for nearly half a century. For 25 years, the bioelectromagnetic research group at Swinburne University in Melbourne, Australia, has pursued a series of investigations with relevant endpoints, such as neurophysiological and neuropsychological effects, cell calcium level changes, proliferation, and genotoxic effects. Most have shown no significant changes due to fields, however, in some pilot studies significant changes were revealed, but in most cases these were not replicated in follow-up studies. This highlights a feature of this research area, generally; the unambiguous identification of small changes in noisy data where the understanding of possible interaction mechanisms is lacking. On the other hand, mathematical modelling studies, particularly with respect to fields near metallic implants, in workers exposed to fields in harsh environmental conditions and at very high frequencies (THz), continue to add to the expanding knowledge database on the characteristics of the complex electromagnetic environment we live in today.
doi:10.3390/ijerph13100950
PMCID: PMC5086689  PMID: 27669282
electromagnetic fields; radiofrequency fields; magnetic fields; tissue electric properties
6.  Bioelectromagnetics Research within an Australian Context: The Australian Centre for Electromagnetic Bioeffects Research (ACEBR) 
Mobile phone subscriptions continue to increase across the world, with the electromagnetic fields (EMF) emitted by these devices, as well as by related technologies such as Wi-Fi and smart meters, now ubiquitous. This increase in use and consequent exposure to mobile communication (MC)-related EMF has led to concern about possible health effects that could arise from this exposure. Although much research has been conducted since the introduction of these technologies, uncertainty about the impact on health remains. The Australian Centre for Electromagnetic Bioeffects Research (ACEBR) is a National Health and Medical Research Council Centre of Research Excellence that is undertaking research addressing the most important aspects of the MC-EMF health debate, with a strong focus on mechanisms, neurodegenerative diseases, cancer, and exposure dosimetry. This research takes as its starting point the current scientific status quo, but also addresses the adequacy of the evidence for the status quo. Risk communication research complements the above, and aims to ensure that whatever is found, it is communicated effectively and appropriately. This paper provides a summary of this ACEBR research (both completed and ongoing), and discusses the rationale for conducting it in light of the prevailing science.
doi:10.3390/ijerph13100967
PMCID: PMC5086706  PMID: 27690076
bioelectromagnetics; EMF; RF bioeffects; research
7.  The Role of E-Cadherin in Maintaining the Barrier Function of Corneal Epithelium after Treatment with Cultured Autologous Oral Mucosa Epithelial Cell Sheet Grafts for Limbal Stem Deficiency 
Journal of Ophthalmology  2016;2016:4805986.
The role of E-cadherin in epithelial barrier function of cultured autologous oral mucosa epithelial cell sheet (CAOMECS) grafts was examined. CAOMECS were cultured on a temperature-responsive surface and grafted onto rabbit corneas with Limbal Stem Cell Deficiency (LSCD). E-cadherin levels were significantly higher in CAOMECS compared to normal and LSCD epithelium. Beta-catenin colocalized with E-cadherin in CAOMECS cell membranes while phosphorylated beta-catenin was significantly increased. ZO-1, occludin, and Cnx43 were also strongly expressed in CAOMECS. E-cadherin and beta-catenin localization at the cell membrane was reduced in LSCD corneas, while CAOMECS-grafted corneas showed a restoration of E-cadherin and beta-catenin expression. LSCD corneas did not show continuous staining for ZO-1 or for Cnx43, while CAOMECS-grafted corneas showed a positive expression of ZO-1 and Cnx43. Cascade Blue® hydrazide did not pass through CAOMECS. Because E-cadherin interactions are calcium-dependent, EGTA was used to chelate calcium and disrupt cell adhesion. EGTA-treated CAOMECS completely detached from cell culture surface, and E-cadherin levels were significantly decreased. In conclusion, E cadherin high expression contributed to CAOMECS tight and gap junction protein recruitment at the cell membrane, thus promoting cellular adhesion and a functional barrier to protect the ocular surface.
doi:10.1155/2016/4805986
PMCID: PMC5061954  PMID: 27777792
8.  Genetic evidence for causal relationships between maternal obesity-related traits and birth weight 
JAMA  2016;315(11):1129-1140.
Structured abstract
Importance
Neonates born to overweight/obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.
Objective
To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.
Design, Setting and Participants
We used Mendelian randomization to test whether maternal BMI and obesity-related traits are causally related to offspring birth weight. Mendelian randomization makes use of the fact that genotypes are randomly determined at conception and are thus not confounded by non-genetic factors. Data were analysed on 30,487 women from 18 studies. Participants were of European ancestry from population- or community-based studies located in Europe, North America or Australia and participating in the Early Growth Genetics (EGG) Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. We tested associations between a genetic score of 30 BMI-associated single nucleotide polymorphisms (SNPs) and (i) maternal BMI and (ii) birth weight, to estimate the causal relationship between BMI and birth weight. Analyses were repeated for other obesity-related traits.
Exposures
Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, HDL-cholesterol level, vitamin D status and adiponectin level.
Main Outcome(s) and Measure(s)
Offspring birth weight measured by trained study personnel (n=2 studies), from medical records (n= 10 studies) or from maternal report (n=6 studies).
Results
Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The genetic score for BMI was associated with a 2g (95%CI: 0, 3g) higher offspring birth weight per maternal BMI-raising allele (P=0.008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8g (95%CI: 6, 10g) per glucose-raising allele (P=7×10−14) and −4g (95%CI: −6, −2g) per SBP-raising allele (P=1×10−5), respectively. A 1 standard deviation (1 SD ≈ 4kg/m2) genetically higher maternal BMI was associated with a 55g (95% CI: 17, 93g) higher birth weight. A 1-SD genetically higher maternal fasting glucose (≈ 0.4mmol/L) or SBP (10mmHg) were associated with a 114g (95%CI: 80, 147g) higher or −208g (95% CI: −394, −21g) lower birth weight, respectively. For BMI and fasting glucose these genetic associations were consistent with the observational associations, but for SBP, the genetic and observational associations were in opposite directions.
Conclusions and Relevance
In this Mendelian randomization study of more than 30,000 women with singleton offspring from 18 studies, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal systolic blood pressure was shown to be potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
doi:10.1001/jama.2016.1975
PMCID: PMC4811305  PMID: 26978208
9.  Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci 
PLoS Genetics  2016;12(8):e1006125.
Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans.
Author Summary
Numerous studies have identified links between too little or too much sleep and circadian misalignment with metabolic disorders such as obesity and type 2 diabetes. However, cause-and-effect is not easily determined, because of multiple confounding factors affecting both sleep patterns and disease risk. Using the first release of the UK Biobank study, which combines detailed measurements and questionnaire data with genetic data, we investigate the genetics of two self-report sleep measures, chronotype and average sleep duration, in 128,266 white British individuals. We replicate previous genetic associations and identify seven and two novel genetic variants influencing chronotype and sleep duration, respectively. Associated variants are located near genes implicated in circadian rhythm regulation (RGS16, PER2), near a serotonin receptor gene (HTR6) and another gene (INADL) encoding a protein thought to be important in photosensitive retinal cells, cells known to communicate with the brain’s primary circadian pacemaker. Using the genetic risk factors, we estimate the unconfounded causal associations of BMI and type 2 diabetes on sleep patterns (and vice versa) through Mendelian Randomisation. However, we find no evidence for causal associations in either direction. The full UK Biobank release of 500,000 individuals will boost our power to detect causal associations.
doi:10.1371/journal.pgen.1006125
PMCID: PMC4975467  PMID: 27494321
10.  Prosaposin is a regulator of progranulin levels and oligomerization 
Nature Communications  2016;7:11992.
Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels. Here we show that both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels. Intriguingly, PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers, partly through a protein–protein interaction. PSAP-induced changes in PGRN levels and oligomerization replicate in human-derived fibroblasts obtained from a GRN mutation carrier, further supporting PSAP as a potential PGRN-related therapeutic target. Future studies should focus on addressing the relevance and cellular mechanism by which PGRN oligomeric species provide neuroprotection.
Increasing progranulin (PGRN) levels is a promising approach for treating frontotemporal dementia and other neurodegenerative diseases. Here Nicholson et al. show that the prosaposin (PSAP) locus is associated with plasma PGRN levels and demonstrate that PSAP can alter PGRN levels and its oligomerization.
doi:10.1038/ncomms11992
PMCID: PMC4931318  PMID: 27356620
11.  Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance 
The Journal of Experimental Medicine  2015;212(13):2223-2234.
Vukovic et al. report that Hif-1α and Hif-2α are not required for leukemia stem cell maintenance and AML propagation, but they act synergistically to suppress leukemia development in mice. Furthermore, knockout of HIF-2α or pharmacological inhibition of the HIF pathway in human AML cells has no impact on their survival and proliferation under hypoxic conditions.
Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance.
doi:10.1084/jem.20150452
PMCID: PMC4689165  PMID: 26642852
12.  EP3/FP dual receptor agonist ONO-9054 administered morning or evening to patients with open-angle glaucoma or ocular hypertension: results of a randomised crossover study 
Background/aims
The novel prostaglandin E (EP) 3 and prostaglandin F (FP) receptor agonist ONO-9054 is effective in lowering intraocular pressure (IOP) in patients with ocular hypertension and open-angle glaucoma when administered once daily. This study compares the effects of morning (AM) versus evening (PM) dosing of ONO-9054 on tolerability and IOP lowering.
Methods
This was a single-centre, randomised, double-masked, two-sequence, placebo-controlled crossover study in 12 subjects with bilateral primary open-angle glaucoma or ocular hypertension. Two 14-day crossover regimens were separated by a 2-week washout: ONO-9054 (1 drop to each eye) in the morning (07:00) and vehicle in the evening (19:00) and vice versa. IOP was measured multiple times during select days. Ocular examinations also evaluated safety and tolerability.
Results
Mild ocular hyperaemia, reported by six subjects with PM dosing, was the most frequent adverse event. Mild to moderate dryness was also slightly more frequent after PM dosing. Maximum IOP reduction from baseline occurred on day 2 with decreases from baseline of −7.4 mm Hg (−30.8%) for AM dosing and −9.1 mm Hg, (−38.0%) for PM dosing; after 14 days, mean reduction in IOP was −6.8 mm Hg (−28.6%) for AM dosing and −7.5 mm Hg (−31.0%) for PM dosing.
Conclusions
PM dosing of ONO-0954 was associated with a slightly increased frequency of mild hyperaemia and mild to moderate dryness. Both dosing schedules provided sustained reduction in IOP.
Trial registration number
NCT01670266.
doi:10.1136/bjophthalmol-2015-307000
PMCID: PMC4893083  PMID: 26453641
Glaucoma; Intraocular pressure; Pharmacology
13.  Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination 
Cell Reports  2016;15(11):2475-2487.
Summary
Variable (V), diversity (D), and joining (J) (V(D)J) recombination is the first determinant of antigen receptor diversity. Understanding how recombination is regulated requires a comprehensive, unbiased readout of V gene usage. We have developed VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products. We reveal a 200-fold range of recombination efficiency among recombining V genes in the primary mouse Igh repertoire. We used machine learning to integrate these data with local chromatin profiles to identify combinatorial patterns of epigenetic features that associate with active VH gene recombination. These features localize downstream of VH genes and are excised by recombination, revealing a class of cis-regulatory element that governs recombination, distinct from expression. We detect two mutually exclusive chromatin signatures at these elements, characterized by CTCF/RAD21 and PAX5/IRF4, which segregate with the evolutionary history of associated VH genes. Thus, local chromatin signatures downstream of VH genes provide an essential layer of regulation that determines recombination efficiency.
Graphical Abstract
Highlights
•VDJ-seq enables precise quantification of antibody V(D)J recombination products•Two distinct cis-regulatory designs characterize actively recombining V genes•Putative recombination regulatory elements map downstream of mouse Igh V genes•Recombination regulatory architecture reflects the V genes’ evolutionary history
Bolland et al. develop a technique to quantitatively profile antigen receptor diversity. Using VDJ-seq in the mouse Igh locus, they uncover the regulatory logic underlying the highly varying recombination rates of V gene segments, with implications for immune disorders and aberrant recombination in cancer.
doi:10.1016/j.celrep.2016.05.020
PMCID: PMC4914699  PMID: 27264181
14.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Mӓnnistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurđsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövӓlti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
15.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Männistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurðsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövälti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
16.  Mendelian randomization study of height and risk of colorectal cancer 
Background: For men and women, taller height is associated with increased risk of all cancers combined. For colorectal cancer (CRC), it is unclear whether the differential association of height by sex is real or is due to confounding or bias inherent in observational studies. We performed a Mendelian randomization study to examine the association between height and CRC risk.
Methods: To minimize confounding and bias, we derived a weighted genetic risk score predicting height (using 696 genetic variants associated with height) in 10 226 CRC cases and 10 286 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height, genetically predicted height and CRC.
Results: Using conventional methods, increased height (per 10-cm increment) was associated with increased CRC risk (OR = 1.08, 95% CI = 1.02–1.15). In sex-specific analyses, height was associated with CRC risk for women (OR = 1.15, 95% CI = 1.05–1.26), but not men (OR = 0.98, 95% CI = 0.92–1.05). Consistent with these results, carrying greater numbers of (weighted) height-increasing alleles (per 1-unit increase) was associated with higher CRC risk for women and men combined (OR = 1.07, 95% CI = 1.01–1.14) and for women (OR = 1.09, 95% CI = 1.01–1.19). There was weaker evidence of an association for men (OR = 1.05, 95% CI = 0.96–1.15).
Conclusion: We provide evidence for a causal association between height and CRC for women. The CRC-height association for men remains unclear and warrants further investigation in other large studies.
doi:10.1093/ije/dyv082
PMCID: PMC4481609  PMID: 25997436
Body height; colorectal cancer; epidemiology
17.  A REVIEW OF LOW-INTENSITY ULTRASOUND FOR CANCER THERAPY 
Ultrasound in medicine & biology  2015;41(4):905-928.
The literature describing the use of low-intensity ultrasound in four major areas of cancer therapy was reviewed - sonodynamic therapy, ultrasound mediated chemotherapy, ultrasound mediated gene delivery and antivascular ultrasound therapy. Each technique consistently resulted in the death of cancer cells and the bioeffects of ultrasound were primarily attributed to thermal actions and inertial cavitation. In each therapeutic modality, theranostic contrast agents composed of microbubbles played a role in both therapy and vascular imaging. The development of these agents is important as it establishes a therapeutic-diagnostic platform which can monitor the success of anti-cancer therapy. Little attention, however, has been given to either the direct assessment of the underlying mechanisms of the observed bioeffects or to the viability of these therapies in naturally occurring cancers in larger mammals; if such investigations provided encouraging data there could be a prompt application of a therapy technique in treating cancer patients.
doi:10.1016/j.ultrasmedbio.2014.11.019
PMCID: PMC4362523  PMID: 25728459
Low-intensity ultrasound; Cancer therapy; Sonodynamic therapy; Ultrasound mediated chemotherapy; Antivascular ultrasound; Ultrasound bioeffects; Microbubble contrast agent
18.  Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively 
Diabetologia  2016;59:1214-1221.
Aims/hypothesis
Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases.
Methods
We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity.
Results
Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (pDOMDEV = 3 × 10−5) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m2, 27.54 (95% CI 27.50, 27.58) kg/m2 and 28.07 (95% CI 28.00, 28.14) kg/m2, respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (pDOMDEV = 0.003; meta-analysis pDOMDEV = 1 × 10−7). For type 2 diabetes, we detected a recessive effect (pDOMDEV = 5 × 10−4) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance.
Conclusions/interpretation
Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci.
Access to research materials
Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-016-3908-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-016-3908-5
PMCID: PMC4869698  PMID: 26961502
Association analysis; BMI; CDKAL1; FTO; Genetics; Non-additive effects; Type 2 diabetes; UK Biobank
19.  Height, body mass index, and socioeconomic status: mendelian randomisation study in UK Biobank 
Objective To determine whether height and body mass index (BMI) have a causal role in five measures of socioeconomic status.
Design Mendelian randomisation study to test for causal effects of differences in stature and BMI on five measures of socioeconomic status. Mendelian randomisation exploits the fact that genotypes are randomly assigned at conception and thus not confounded by non-genetic factors.
Setting UK Biobank.
Participants 119 669 men and women of British ancestry, aged between 37 and 73 years.
Main outcome measures Age completed full time education, degree level education, job class, annual household income, and Townsend deprivation index.
Results In the UK Biobank study, shorter stature and higher BMI were observationally associated with several measures of lower socioeconomic status. The associations between shorter stature and lower socioeconomic status tended to be stronger in men, and the associations between higher BMI and lower socioeconomic status tended to be stronger in women. For example, a 1 standard deviation (SD) higher BMI was associated with a £210 (€276; $300; 95% confidence interval £84 to £420; P=6×10−3) lower annual household income in men and a £1890 (£1680 to £2100; P=6×10−15) lower annual household income in women. Genetic analysis provided evidence that these associations were partly causal. A genetically determined 1 SD (6.3 cm) taller stature caused a 0.06 (0.02 to 0.09) year older age of completing full time education (P=0.01), a 1.12 (1.07 to 1.18) times higher odds of working in a skilled profession (P=6×10−7), and a £1130 (£680 to £1580) higher annual household income (P=4×10−8). Associations were stronger in men. A genetically determined 1 SD higher BMI (4.6 kg/m2) caused a £2940 (£1680 to £4200; P=1×10−5) lower annual household income and a 0.10 (0.04 to 0.16) SD (P=0.001) higher level of deprivation in women only.
Conclusions These data support evidence that height and BMI play an important partial role in determining several aspects of a person’s socioeconomic status, especially women’s BMI for income and deprivation and men’s height for education, income, and job class. These findings have important social and health implications, supporting evidence that overweight people, especially women, are at a disadvantage and that taller people, especially men, are at an advantage.
doi:10.1136/bmj.i582
PMCID: PMC4783516  PMID: 26956984
20.  Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism 
Nature  2015;528(7582):418-421.
Summary
Neuroblastoma is a pediatric malignancy that typically arises in early childhood and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumors with excellent outcomes to widely metastatic disease where long-term survival is approximately 40% despite intensive therapy1. A previous genome-wide association study (GWAS) identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumor cells2. Here we sought to discover the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding sites. SNP rs2168101 G>T was the most highly associated variant (combined P=7.47×10-29, Odds Ratio 0.65, 95% CI: 0.60-0.70) and resided in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G-allele that is associated with tumor formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P=0.028) in neuroblastoma primary tumors and ablates GATA3 binding (P<0.0001). We demonstrate allelic imbalance favoring the G-containing strand in tumors heterozygous for this SNP as demonstrated both by RNA sequencing (P<0.0001) and reporter assays (P=0.002). These findings show that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumor cells.
doi:10.1038/nature15540
PMCID: PMC4775078  PMID: 26560027
21.  Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants 
Aging (Albany NY)  2016;8(3):547-560.
Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus (CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7×10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.
doi:10.18632/aging.100930
PMCID: PMC4833145  PMID: 27015805
aging; longevity; GWAS; genetic; human
22.  Mucin-Inspired Thermoresponsive Synthetic Hydrogels Induce Stasis in Human Pluripotent Stem Cells and Human Embryos 
ACS Central Science  2016;2(2):65-74.
Human pluripotent stem cells (hPSCs; both embryonic and induced pluripotent) rapidly proliferate in adherent culture to maintain their undifferentiated state. However, for mammals exhibiting delayed gestation (diapause), mucin-coated embryos can remain dormant for days or months in utero, with their constituent PSCs remaining pluripotent under these conditions. Here we report cellular stasis for both hPSC colonies and preimplantation embryos immersed in a wholly synthetic thermoresponsive gel comprising poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) [PGMA55-PHPMA135] diblock copolymer worms. This hydroxyl-rich mucin-mimicking nonadherent 3D gel maintained PSC viability and pluripotency in the quiescent G0 state without passaging for at least 14 days. Similarly, gel-coated human embryos remain in a state of suspended animation (diapause) for up to 8 days. The discovery of a cryptic cell arrest mechanism for both hPSCs and embryos suggests an important connection between the cellular mechanisms that evoke embryonic diapause and pluripotency. Moreover, such synthetic worm gels offer considerable utility for the short-term (weeks) storage of either pluripotent stem cells or human embryos without cryopreservation.
Wholly synthetic mucin-mimicking hydroxyl-functional diblock copolymers self-assemble to form thermoresponsive aqueous hydrogels that induce stasis in human pluripotent stem cells and human embryos.
doi:10.1021/acscentsci.5b00370
PMCID: PMC4827554  PMID: 27163030
23.  Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 
Kilpeläinen, Tuomas O. | Carli, Jayne F. Martin | Skowronski, Alicja A. | Sun, Qi | Kriebel, Jennifer | Feitosa, Mary F | Hedman, Åsa K. | Drong, Alexander W. | Hayes, James E. | Zhao, Jinghua | Pers, Tune H. | Schick, Ursula | Grarup, Niels | Kutalik, Zoltán | Trompet, Stella | Mangino, Massimo | Kristiansson, Kati | Beekman, Marian | Lyytikäinen, Leo-Pekka | Eriksson, Joel | Henneman, Peter | Lahti, Jari | Tanaka, Toshiko | Luan, Jian'an | Greco M, Fabiola Del | Pasko, Dorota | Renström, Frida | Willems, Sara M. | Mahajan, Anubha | Rose, Lynda M. | Guo, Xiuqing | Liu, Yongmei | Kleber, Marcus E. | Pérusse, Louis | Gaunt, Tom | Ahluwalia, Tarunveer S. | Ju Sung, Yun | Ramos, Yolande F. | Amin, Najaf | Amuzu, Antoinette | Barroso, Inês | Bellis, Claire | Blangero, John | Buckley, Brendan M. | Böhringer, Stefan | I Chen, Yii-Der | de Craen, Anton J. N. | Crosslin, David R. | Dale, Caroline E. | Dastani, Zari | Day, Felix R. | Deelen, Joris | Delgado, Graciela E. | Demirkan, Ayse | Finucane, Francis M. | Ford, Ian | Garcia, Melissa E. | Gieger, Christian | Gustafsson, Stefan | Hallmans, Göran | Hankinson, Susan E. | Havulinna, Aki S | Herder, Christian | Hernandez, Dena | Hicks, Andrew A. | Hunter, David J. | Illig, Thomas | Ingelsson, Erik | Ioan-Facsinay, Andreea | Jansson, John-Olov | Jenny, Nancy S. | Jørgensen, Marit E. | Jørgensen, Torben | Karlsson, Magnus | Koenig, Wolfgang | Kraft, Peter | Kwekkeboom, Joanneke | Laatikainen, Tiina | Ladwig, Karl-Heinz | LeDuc, Charles A. | Lowe, Gordon | Lu, Yingchang | Marques-Vidal, Pedro | Meisinger, Christa | Menni, Cristina | Morris, Andrew P. | Myers, Richard H. | Männistö, Satu | Nalls, Mike A. | Paternoster, Lavinia | Peters, Annette | Pradhan, Aruna D. | Rankinen, Tuomo | Rasmussen-Torvik, Laura J. | Rathmann, Wolfgang | Rice, Treva K. | Brent Richards, J | Ridker, Paul M. | Sattar, Naveed | Savage, David B. | Söderberg, Stefan | Timpson, Nicholas J. | Vandenput, Liesbeth | van Heemst, Diana | Uh, Hae-Won | Vohl, Marie-Claude | Walker, Mark | Wichmann, Heinz-Erich | Widén, Elisabeth | Wood, Andrew R. | Yao, Jie | Zeller, Tanja | Zhang, Yiying | Meulenbelt, Ingrid | Kloppenburg, Margreet | Astrup, Arne | Sørensen, Thorkild I. A. | Sarzynski, Mark A. | Rao, D. C. | Jousilahti, Pekka | Vartiainen, Erkki | Hofman, Albert | Rivadeneira, Fernando | Uitterlinden, André G. | Kajantie, Eero | Osmond, Clive | Palotie, Aarno | Eriksson, Johan G. | Heliövaara, Markku | Knekt, Paul B. | Koskinen, Seppo | Jula, Antti | Perola, Markus | Huupponen, Risto K. | Viikari, Jorma S. | Kähönen, Mika | Lehtimäki, Terho | Raitakari, Olli T. | Mellström, Dan | Lorentzon, Mattias | Casas, Juan P. | Bandinelli, Stefanie | März, Winfried | Isaacs, Aaron | van Dijk, Ko W. | van Duijn, Cornelia M. | Harris, Tamara B. | Bouchard, Claude | Allison, Matthew A. | Chasman, Daniel I. | Ohlsson, Claes | Lind, Lars | Scott, Robert A. | Langenberg, Claudia | Wareham, Nicholas J. | Ferrucci, Luigi | Frayling, Timothy M. | Pramstaller, Peter P. | Borecki, Ingrid B. | Waterworth, Dawn M. | Bergmann, Sven | Waeber, Gérard | Vollenweider, Peter | Vestergaard, Henrik | Hansen, Torben | Pedersen, Oluf | Hu, Frank B. | Eline Slagboom, P | Grallert, Harald | Spector, Tim D. | Jukema, J.W. | Klein, Robert J. | Schadt, Erik E | Franks, Paul W. | Lindgren, Cecilia M. | Leibel, Rudolph L. | Loos, Ruth J. F.
Nature Communications  2016;7:10494.
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
doi:10.1038/ncomms10494
PMCID: PMC4740377  PMID: 26833098
24.  Directional dominance on stature and cognition in diverse human populations 
Joshi, Peter K. | Esko, Tonu | Mattsson, Hannele | Eklund, Niina | Gandin, Ilaria | Nutile, Teresa | Jackson, Anne U. | Schurmann, Claudia | Smith, Albert V. | Zhang, Weihua | Okada, Yukinori | Stančáková, Alena | Faul, Jessica D. | Zhao, Wei | Bartz, Traci M. | Concas, Maria Pina | Franceschini, Nora | Enroth, Stefan | Vitart, Veronique | Trompet, Stella | Guo, Xiuqing | Chasman, Daniel I. | O’Connel, Jeffery R. | Corre, Tanguy | Nongmaithem, Suraj S. | Chen, Yuning | Mangino, Massimo | Ruggiero, Daniela | Traglia, Michela | Farmaki, Aliki-Eleni | Kacprowski, Tim | Bjonnes, Andrew | van der Spek, Ashley | Wu, Ying | Giri, Anil K. | Yanek, Lisa R. | Wang, Lihua | Hofer, Edith | Rietveld, Cornelius A. | McLeod, Olga | Cornelis, Marilyn C. | Pattaro, Cristian | Verweij, Niek | Baumbach, Clemens | Abdellaoui, Abdel | Warren, Helen R. | Vuckovic, Dragana | Mei, Hao | Bouchard, Claude | Perry, John R.B. | Cappellani, Stefania | Mirza, Saira S. | Benton, Miles C. | Broeckel, Ulrich | Medland, Sarah E. | Lind, Penelope A. | Malerba, Giovanni | Drong, Alexander | Yengo, Loic | Bielak, Lawrence F. | Zhi, Degui | van der Most, Peter J. | Shriner, Daniel | Mägi, Reedik | Hemani, Gibran | Karaderi, Tugce | Wang, Zhaoming | Liu, Tian | Demuth, Ilja | Zhao, Jing Hua | Meng, Weihua | Lataniotis, Lazaros | van der Laan, Sander W. | Bradfield, Jonathan P. | Wood, Andrew R. | Bonnefond, Amelie | Ahluwalia, Tarunveer S. | Hall, Leanne M. | Salvi, Erika | Yazar, Seyhan | Carstensen, Lisbeth | de Haan, Hugoline G. | Abney, Mark | Afzal, Uzma | Allison, Matthew A. | Amin, Najaf | Asselbergs, Folkert W. | Bakker, Stephan J.L. | Barr, R. Graham | Baumeister, Sebastian E. | Benjamin, Daniel J. | Bergmann, Sven | Boerwinkle, Eric | Bottinger, Erwin P. | Campbell, Archie | Chakravarti, Aravinda | Chan, Yingleong | Chanock, Stephen J. | Chen, Constance | Chen, Y.-D. Ida | Collins, Francis S. | Connell, John | Correa, Adolfo | Cupples, L. Adrienne | Smith, George Davey | Davies, Gail | Dörr, Marcus | Ehret, Georg | Ellis, Stephen B. | Feenstra, Bjarke | Feitosa, Mary F. | Ford, Ian | Fox, Caroline S. | Frayling, Timothy M. | Friedrich, Nele | Geller, Frank | Scotland, Generation | Gillham-Nasenya, Irina | Gottesman, Omri | Graff, Misa | Grodstein, Francine | Gu, Charles | Haley, Chris | Hammond, Christopher J. | Harris, Sarah E. | Harris, Tamara B. | Hastie, Nicholas D. | Heard-Costa, Nancy L. | Heikkilä, Kauko | Hocking, Lynne J. | Homuth, Georg | Hottenga, Jouke-Jan | Huang, Jinyan | Huffman, Jennifer E. | Hysi, Pirro G. | Ikram, M. Arfan | Ingelsson, Erik | Joensuu, Anni | Johansson, Åsa | Jousilahti, Pekka | Jukema, J. Wouter | Kähönen, Mika | Kamatani, Yoichiro | Kanoni, Stavroula | Kerr, Shona M. | Khan, Nazir M. | Koellinger, Philipp | Koistinen, Heikki A. | Kooner, Manraj K. | Kubo, Michiaki | Kuusisto, Johanna | Lahti, Jari | Launer, Lenore J. | Lea, Rodney A. | Lehne, Benjamin | Lehtimäki, Terho | Liewald, David C.M. | Lind, Lars | Loh, Marie | Lokki, Marja-Liisa | London, Stephanie J. | Loomis, Stephanie J. | Loukola, Anu | Lu, Yingchang | Lumley, Thomas | Lundqvist, Annamari | Männistö, Satu | Marques-Vidal, Pedro | Masciullo, Corrado | Matchan, Angela | Mathias, Rasika A. | Matsuda, Koichi | Meigs, James B. | Meisinger, Christa | Meitinger, Thomas | Menni, Cristina | Mentch, Frank D. | Mihailov, Evelin | Milani, Lili | Montasser, May E. | Montgomery, Grant W. | Morrison, Alanna | Myers, Richard H. | Nadukuru, Rajiv | Navarro, Pau | Nelis, Mari | Nieminen, Markku S. | Nolte, Ilja M. | O’Connor, George T. | Ogunniyi, Adesola | Padmanabhan, Sandosh | Palmas, Walter R. | Pankow, James S. | Patarcic, Inga | Pavani, Francesca | Peyser, Patricia A. | Pietilainen, Kirsi | Poulter, Neil | Prokopenko, Inga | Ralhan, Sarju | Redmond, Paul | Rich, Stephen S. | Rissanen, Harri | Robino, Antonietta | Rose, Lynda M. | Rose, Richard | Sala, Cinzia | Salako, Babatunde | Salomaa, Veikko | Sarin, Antti-Pekka | Saxena, Richa | Schmidt, Helena | Scott, Laura J. | Scott, William R. | Sennblad, Bengt | Seshadri, Sudha | Sever, Peter | Shrestha, Smeeta | Smith, Blair H. | Smith, Jennifer A. | Soranzo, Nicole | Sotoodehnia, Nona | Southam, Lorraine | Stanton, Alice V. | Stathopoulou, Maria G. | Strauch, Konstantin | Strawbridge, Rona J. | Suderman, Matthew J. | Tandon, Nikhil | Tang, Sian-Tsun | Taylor, Kent D. | Tayo, Bamidele O. | Töglhofer, Anna Maria | Tomaszewski, Maciej | Tšernikova, Natalia | Tuomilehto, Jaakko | Uitterlinden, Andre G. | Vaidya, Dhananjay | van Hylckama Vlieg, Astrid | van Setten, Jessica | Vasankari, Tuula | Vedantam, Sailaja | Vlachopoulou, Efthymia | Vozzi, Diego | Vuoksimaa, Eero | Waldenberger, Melanie | Ware, Erin B. | Wentworth-Shields, William | Whitfield, John B. | Wild, Sarah | Willemsen, Gonneke | Yajnik, Chittaranjan S. | Yao, Jie | Zaza, Gianluigi | Zhu, Xiaofeng | Project, The BioBank Japan | Salem, Rany M. | Melbye, Mads | Bisgaard, Hans | Samani, Nilesh J. | Cusi, Daniele | Mackey, David A. | Cooper, Richard S. | Froguel, Philippe | Pasterkamp, Gerard | Grant, Struan F.A. | Hakonarson, Hakon | Ferrucci, Luigi | Scott, Robert A. | Morris, Andrew D. | Palmer, Colin N.A. | Dedoussis, George | Deloukas, Panos | Bertram, Lars | Lindenberger, Ulman | Berndt, Sonja I. | Lindgren, Cecilia M. | Timpson, Nicholas J. | Tönjes, Anke | Munroe, Patricia B. | Sørensen, Thorkild I.A. | Rotimi, Charles N. | Arnett, Donna K. | Oldehinkel, Albertine J. | Kardia, Sharon L.R. | Balkau, Beverley | Gambaro, Giovanni | Morris, Andrew P. | Eriksson, Johan G. | Wright, Margie J. | Martin, Nicholas G. | Hunt, Steven C. | Starr, John M. | Deary, Ian J. | Griffiths, Lyn R. | Tiemeier, Henning | Pirastu, Nicola | Kaprio, Jaakko | Wareham, Nicholas J. | Pérusse, Louis | Wilson, James G. | Girotto, Giorgia | Caulfield, Mark J. | Raitakari, Olli | Boomsma, Dorret I. | Gieger, Christian | van der Harst, Pim | Hicks, Andrew A. | Kraft, Peter | Sinisalo, Juha | Knekt, Paul | Johannesson, Magnus | Magnusson, Patrik K.E. | Hamsten, Anders | Schmidt, Reinhold | Borecki, Ingrid B. | Vartiainen, Erkki | Becker, Diane M. | Bharadwaj, Dwaipayan | Mohlke, Karen L. | Boehnke, Michael | van Duijn, Cornelia M. | Sanghera, Dharambir K. | Teumer, Alexander | Zeggini, Eleftheria | Metspalu, Andres | Gasparini, Paolo | Ulivi, Sheila | Ober, Carole | Toniolo, Daniela | Rudan, Igor | Porteous, David J. | Ciullo, Marina | Spector, Tim D. | Hayward, Caroline | Dupuis, Josée | Loos, Ruth J.F. | Wright, Alan F. | Chandak, Giriraj R. | Vollenweider, Peter | Shuldiner, Alan | Ridker, Paul M. | Rotter, Jerome I. | Sattar, Naveed | Gyllensten, Ulf | North, Kari E. | Pirastu, Mario | Psaty, Bruce M. | Weir, David R. | Laakso, Markku | Gudnason, Vilmundur | Takahashi, Atsushi | Chambers, John C. | Kooner, Jaspal S. | Strachan, David P. | Campbell, Harry | Hirschhorn, Joel N. | Perola, Markus | Polašek, Ozren | Wilson, James F.
Nature  2015;523(7561):459-462.
Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
doi:10.1038/nature14618
PMCID: PMC4516141  PMID: 26131930
25.  Mitogen-activated protein kinase (MEK/ERK) inhibition sensitizes cancer cells to centromere-associated protein E inhibition 
Inhibition of centromere-associated protein-E (CENP-E) has demonstrated preclinical anti-tumor activity in a number of tumor types including neuroblastoma. A potent small molecule inhibitor of the kinesin motor activity of CENP-E has recently been developed (GSK923295). To identify an effective drug combination strategy for GSK923295 in neuroblastoma, we performed a screen of siRNAs targeting a prioritized set of genes that function in therapeutically tractable signaling pathways. We found that siRNAs targeted to extracellular signal-related kinase 1 (ERK1) significantly sensitized neuroblastoma cells to GSK923295-induced growth inhibition (p = 0.01). Inhibition of ERK1 activity using pharmacologic inhibitors of mitogen-activated ERK kinase (MEK1/2) showed significant synergistic growth inhibitory activity when combined with GSK923295 in neuroblastoma, lung, pancreatic and colon carcinoma cell lines. Synergistic growth inhibitory activity of combined MEK/ERK and CENP-E inhibition was a result of increased mitotic arrest and apoptosis. There was a significant correlation between ERK1/2 phosphorylation status in neuroblastoma cell lines and GSK923295 growth inhibitory activity (r = 0.823, p = 0.0006). Consistent with this result we found that lung cancer cell lines harboring RAS mutations, which leads to oncogenic activation of MEK/ERK signaling, were significantly more resistant than cell lines with wild-type RAS to GSK923295-induced growth inhibition (p = 0.047). Here we have identified (MEK/ERK) activity as a potential biomarker of relative GSK923295 sensitivity and have shown the synergistic effect of combinatorial MEK/ERK pathway and CENP-E inhibition across different cancer cell types including neuroblastoma.
doi:10.1002/ijc.27781
PMCID: PMC4706358  PMID: 22948716
CENP-E; GSK923295; ERK; MEK; neuroblastoma; Ras

Results 1-25 (109)