176 results found
Surendran P, Feofanova EV, Lahrouchi N, et al., 2021, Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals (vol 52, pg 1314, 2020), Nature Genetics, Pages: 1-2, ISSN: 1061-4036
Alkaf B, Blakemore A, Jarvelin M-R, et al., 2021, Secondary analyses of global datasets: do obesity and physical activity explain variation in diabetes risk across populations?, INTERNATIONAL JOURNAL OF OBESITY, Vol: 45, Pages: 944-956, ISSN: 0307-0565
Kenkre J, Ahmed A, Purkayastha S, et al., 2021, Who will benefit from bariatric surgery for diabetes? A protocol for an observational cohort study, BMJ Open, Vol: 11, ISSN: 2044-6055
Introduction Type 2 diabetes mellitus (T2DM) and obesity are pandemic diseases that lead to a great deal of morbidity and mortality. The most effective treatment for obesity and T2DM is bariatric or metabolic surgery; it can lead to long-term diabetes remission with 4 in 10 of those undergoing surgery having normal blood glucose on no medication 1 year postoperatively. However, surgery carries risks and, additionally, due to resource limitations, there is a restricted number of patients who can access this treatment. Moreover, not all those who undertake surgery respond equally well metabolically. The objective of the current research is to prospectively investigate predictors of T2DM response following metabolic surgery, including those directly involved in its aetiopathogenesis such as fat distribution and genetic variants. This will inform development of a clinically applicable model to help prioritise this therapy to those predicted to have remission.Methods and analysis A prospective multicentre observational cohort study of adult patients with T2DM and obesity undergoing Roux-en-Y gastric bypass surgery. Patients will be comprehensively assessed before surgery to determine their clinical, metabolic, psychological, genetic and fat distribution profiles. A multivariate logistic regression model will be used to assess the value of the factors derived from the preoperative assessment in terms of prediction of diabetes remission.Ethics and dissemination Formal ethics review was undertaken with a favourable opinion (UK HRA RES reference number 18/LO/0931). The dissemination plan is to present the results at conferences, in peer-reviewed journals as well as to lay media and to patient organisations.Trial registration details ClinicalTrials.gov, Identifier: NCT03842475.
Surendran P, Gao H, Zhang W, et al., 2020, Discovery of rare variants associated with blood pressure regulation trhough meta-analaysis of 1.3 million individuals, Nature Genetics, Vol: 52, Pages: 1314-1332, ISSN: 1061-4036
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (e.g.GATA5, PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
O'Kane M, Parretti HM, Pinkney J, et al., 2020, British Obesity and Metabolic Surgery Society Guidelines on perioperative and postoperative biochemical monitoring and micronutrient replacement for patients undergoing bariatric surgery-2020 update, OBESITY REVIEWS, Vol: 21, ISSN: 1467-7881
Pinola P, Polonen J, Ronkainen J, et al., 2020, Polycystic ovary syndrome and leukocyte telomere length: results of cross-sectional and longitudinal analyses in a birth cohort study, 36th Virtual Annual Meeting of the European-Society-of-Human-Reproduction-and-Embryology (ESHRE), Publisher: OXFORD UNIV PRESS, Pages: 85-85, ISSN: 0268-1161
Sato MS, Kyriakopoulos M, James A, et al., 2020, Hemizygous mutations in L1CAM in two unrelated male probands with childhood onset psychosis, PSYCHIATRIC GENETICS, Vol: 30, Pages: 73-82, ISSN: 0955-8829
Li C, Stoma S, Lotta LA, et al., 2020, Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length, American Journal of Human Genetics, Vol: 106, Pages: 389-404, ISSN: 0002-9297
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
Murphy J, Uttamlal T, Schmidtke KA, et al., 2020, Tracking physical activity using smart phone apps: assessing the ability of a current app and systematically collecting patient recommendations for future development, BMC Medical Informatics and Decision Making, Vol: 20, ISSN: 1472-6947
BACKGROUND: Within the United Kingdom's National Health System (NHS), patients suffering from obesity may be provided with bariatric surgery. After receiving surgery many of these patients require further support to continue to lose more weight or to maintain a healthy weight. Remotely monitoring such patients' physical activity and other health-related variables could provide healthworkers with a more 'ecologically valid' picture of these patients' behaviours to then provide more personalised support. The current study assesses the feasibility of two smartphone apps to do so. In addition, the study looks at the barriers and facilitators patients experience to using these apps effectively. METHODS: Participants with a BMI > 35 kg/m2 being considered for and who had previously undergone bariatric surgery were recruited. Participants were asked to install two mobile phone apps. The 'Moves' app automatically tracked participants' physical activity and the 'WLCompanion' app prompted participants to set goals and input other health-related information. Then, to learn about participants' facilitators and barriers to using the apps, some participants were asked to complete a survey informed by the Theoretical Domains Framework. The data were analysed using regressions and descriptive statistics. RESULTS: Of the 494 participants originally enrolled, 274 participants data were included in the analyses about their activity pre- and/or post-bariatric surgery (ages 18-65, M = 44.02, SD ± 11.29). Further analyses were performed on those 36 participants whose activity was tracked both pre- and post-surgery. Participants' activity levels pre- and post-surgery did not differ. In addition, 54 participants' survey responses suggested that the main facilitator to their continued use of the Moves app was its automatic nature, and the main barrier was its battery drain. CONCLUSIONS: The current study tracked physical activity in patien
Wilson MSJ, Knight S, Vaughan-Shaw P, et al., 2019, A modified AUGIS Delphi process to establish research priorities in bariatric and metabolic surgery, CLINICAL OBESITY, Vol: 10, ISSN: 1758-8103
Cooiman MI, Kleinendorst L, Aarts EO, et al., 2019, Genetic Obesity and Bariatric Surgery Outcome in 1014 Patients with Morbid Obesity, OBESITY SURGERY, Vol: 30, Pages: 470-477, ISSN: 0960-8923
Yiorkas AM, Leinhard O, Blakemore AI, 2019, Population-based assessment of the phenotypic profile of Melanocortin-4 Receptor mutation carriers, 52nd Conference of the European-Society-of-Human-Genetics (ESHG), Publisher: NATURE PUBLISHING GROUP, Pages: 1763-1764, ISSN: 1018-4813
Almansoori S, Alsters SI, Chahal HS, et al., 2019, Analysis of genes associated with obesity phenotypes in mouse models, reveals new potentially causative mutations for monogenic obesity in humans, 52nd Conference of the European-Society-of-Human-Genetics (ESHG), Publisher: NATURE PUBLISHING GROUP, Pages: 1838-1838, ISSN: 1018-4813
Alves AC, De Silva NMG, Karhunen V, et al., 2019, GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI, Science Advances, Vol: 5, ISSN: 2375-2548
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here we combine genome-wide association studies with modelling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score and co-localization analyses to determine how developmental timings, molecular pathways and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult BMI, with variants associated with adult BMI acting as early as 4-6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
Evangelou E, Gao H, Blakeley P, et al., 2019, New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders, Nature Human Behaviour, Vol: 3, Pages: 950-961, ISSN: 2397-3374
Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d−1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.
Fairbrother U, Kidd E, Buxton J, et al., 2019, Blood glucose, BMI and telomere length in a cohort of Colombian schoolchildren, 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Publisher: NATURE PUBLISHING GROUP, Pages: 1038-1039, ISSN: 1018-4813
Kidd ED, Walley A, Buxton J, et al., 2019, Impact of diet, household income and stress on telomere length in a cohort of Colombian schoolchildren, 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Publisher: NATURE PUBLISHING GROUP, Pages: 1022-1023, ISSN: 1018-4813
Szepietowski O, Alsters S, Mahir G, et al., 2019, Recent-Onset Type 2 Diabetes Is Defined As < 10 Years Duration, 10th Annual Scientific Meeting of the British-Obesity-and-Metabolic-Surgery-Society (BOMSS), Publisher: SPRINGER, Pages: S11-S11, ISSN: 0960-8923
Ji Y, Yiorkas AM, Frau F, et al., 2019, Genome-wide and abdominal MRI data provide evidence that a genetically determined favorable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease, and hypertension, Diabetes, Vol: 68, Pages: 207-219, ISSN: 0012-1797
Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.
De Silva M, Sebert S, Alves AC, et al., 2018, Genetic architecture of early growth phenotypes gives insights into their link with later obesity, Publisher: NATURE PUBLISHING GROUP
Macare C, Ducci F, Zhang Y, et al., 2018, A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response, European Neuropsychopharmacology, Vol: 28, Pages: 1103-1114, ISSN: 0924-977X
The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10−4) and higher plasma cotinine levels (p = 7.0 × 10−5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.
Ramzi NH, Yiorkas AM, Sebert S, et al., 2018, Relationship between BMI and emotion-handling capacity in an adult Finnish population: the Northern Finland Birth Cohort 1966, PLoS ONE, Vol: 13, ISSN: 1932-6203
BackgroundAlexithymia, a difficulty in identifying and expressing emotions, has been associated with obesity and eating disorders in small-scale cross-sectional studies. Here, we assess the relationship between body mass index (BMI) and alexithymia in a large cohort of free-living Finnish adults over a 15-year period.MethodsParticipants were drawn from the Northern Finnish Birth Cohort 1966 (NFBC1966). The 20-Item Toronto Alexithymia Scale (TAS-20) was used as a measure of alexithymia and was completed at the age of 31 years (31y: n = 4841), and 46 years (46y: n = 5404). BMI was recorded at both time points. Where data at both time points were available (n = 3274), the relationship between changes in BMI and TAS-20 over this time period was also investigated.ResultsBMI was significantly and positively associated with TAS-20 score (p<0.0001, both at 31 years and at 46 years of ages). The association remained statistically significant after adjustment for potential confounders (sex, marital status and several socio-economic indicators). In individuals who experienced the greatest change in BMI (in either direction) over the 15-year period, there was a modest mean increase in TAS-20 score.ConclusionsOur data revealed that TAS-20 score was correlated with and co-varied with body mass status. We suggest that future clinical research should consider the role of alexithymia in obesity. Further investigation of this relationship is warranted to ensure that the needs of obese subjects with undiagnosed alexithymia are considered in the design of weight management programmes.
Szepietowski O, Alsters SI, Mahir G, et al., 2018, PREDICTING REMISSION OF NON-INSULIN TREATED TYPE 2 DIABETES AFTER RYGB, 23rd World Congress of the International-Federation-for-the-Surgery-of-Obesity-and-Metabolic-Disorders (IFSO), Publisher: SPRINGER, Pages: 191-191, ISSN: 0960-8923
Yaghootkar H, Ji Y, Yiorkas AM, et al., 2018, Carrying more 'favourable adiposity' genetic factors is associated with higher adiposity but lower ectopic fat and lower risk of Type 2 diabetes, Publisher: WILEY, Pages: 27-27, ISSN: 0742-3071
Kraja AT, Evangelou E, Tzoulaki I, et al., 2017, New blood pressure associated loci identified in meta-analyses of 475,000 individuals, Circulation: Cardiovascular Genetics, Vol: 10, ISSN: 1942-325X
Background—Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Methods and Results—Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10−8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.Conclusions—We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
Schierding W, Antony J, Karhunen V, et al., 2017, GWAS on prolonged gestation (post-term birth): analysis of successive Finnish birth cohorts., Journal of Medical Genetics, Vol: 55, Pages: 55-63, ISSN: 1468-6244
Background Gestation is a crucial timepoint in human development. Deviation from a term gestational age correlates with both acute and long-term adverse health effects for the child. Both being born preterm and post-term, that is, having short and long gestational ages, are heritable and influenced by the prenatal and perinatal environment. Despite the obvious heritable component, specific genetic influences underlying differences in gestational age are poorly understood.Methods We investigated the genetic architecture of gestational age in 9141 individuals, including 1167 born post-term, across two Northern Finland cohorts born in 1966 or 1986.Results Here we identify one globally significant intronic genetic variant within the ADAMTS13 gene that is associated with prolonged gestation (p=4.85×10−8). Additional variants that reached suggestive levels of significance were identified within introns at the ARGHAP42 and TKT genes, and in the upstream (5’) intergenic regions of the B3GALT5 and SSBP2 genes. The variants near the ADAMTS13, B3GALT5, SSBP2 and TKT loci are linked to alterations in gene expression levels (cis-eQTLs). Luciferase assays confirmed the allele specific enhancer activity for the BGALT5 and TKT loci.Conclusions Our findings provide the first evidence of a specific genetic influence associated with prolonged gestation. This study forms a foundation for a better understanding of the genetic and long-term health risks faced by induced and post-term individuals. The long-term risks for induced individuals who have a previously overlooked post-term potential may be a major issue for current health providers.
Fiamoncini J, Yiorkas AM, Gedrich K, et al., 2017, Determinants of postprandial plasma bile acid kinetics in human volunteers, AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, Vol: 313, Pages: G300-G312, ISSN: 0193-1857
Williams DM, Buxton JL, Kantomaa MT, et al., 2017, Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults, AMERICAN JOURNAL OF EPIDEMIOLOGY, Vol: 185, Pages: 529-537, ISSN: 0002-9262
Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952–5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations.
Surendran P, Drenos F, Young R, et al., 2016, Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension, Nature Genetics, Vol: 48, Pages: 1151-1161, ISSN: 1546-1718
High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.
Tharakan G, Scott R, Szepietowski O, et al., 2016, Limitations of the DiaRem Score in Predicting Remission of Diabetes Following Roux-En-Y Gastric Bypass (RYGB) in an ethnically Diverse Population from a Single Institution in the UK, Obesity Surgery, Vol: 27, Pages: 782-786, ISSN: 1708-0428
PurposeThis study aimed to determine the predictive power of the DiaRem score following Roux-en-Y gastric bypass to identify patients who would have diabetes remission at 1 year in an ethnically diverse population.MethodsWe performed a retrospective review of 262 patients with type 2 diabetes mellitus who underwent RYGB at the Imperial Weight Centre, UK, from 2007 to 2014. Data was collected on the parameters required to calculate the DiaRem score as well as pre- and post-surgical weight and the ethnicity of the subjects.ResultsThe studied cohort was ethnically diverse (61.3 % Caucasian, 10.3 % Asian, 5.3 % black, 2.6 % mixed and 20.6 % other). At 1-year post-surgery, there were significant reductions in mean weight (133.4 to 94.3 kg) and BMI (46.7 to 33.3 kg/m2). The mean HbA1c decreased from 8.2 to 6.1 %, and 32.5 % of the cohort underwent either partial or complete remission. 67.8 % of the patients that were classified in group 1 of the DiaRem score (most likely to have remission) had complete remission. However, 22.9 % of the patients predicted to have the least chance of remission had either partial or complete remission.ConclusionsIn this ethnically diverse cohort, the DiaRem score remains a useful tool to predict diabetes remission in those that have a low DiaRem score (high chance for remission) but was more limited in its predictive power in those with a high DiaRem score (least likely to have remission). Caution must be used in the application of this model in populations other than the US white Caucasian population used to derive the score.
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