Publications by authors named "Debbie A Lawlor"

590 Publications

Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study.

Thorax 2021 Jun 21. Epub 2021 Jun 21.

School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Adminstrative Region, China.

Introduction: Observational studies suggested lung function is inversely associated with cardiovascular disease (CVD) although these studies could be confounded. We conducted a two sample Mendelian randomisation study using summary statistics from genome-wide association studies (GWAS) to clarify the role of lung function in CVD and its risk factors, and conversely the role of CVD in lung function.

Methods: We obtained genetic instruments for forced expiratory volume in 1 s (FEV: 260) and forced vital capacity (FVC: 320) from publicly available UK Biobank summary statistics (n=421 986) and applied to GWAS summary statistics for coronary artery disease (CAD) (n=184 305), stroke (n=446 696), atrial fibrillation (n=1 030 836) and heart failure (n=977 320) and cardiovascular risk factors. Inverse variance weighting was used to assess the impact of lung function on these outcomes, with various sensitivity analyses. Bidirectional Mendelian randomisation was used to assess reverse causation.

Results: FEV and FVC were inversely associated with CAD (OR per SD increase, 0.72 (95% CI 0.63 to 0.82) and 0.70 (95%CI 0.62 to 0.78)), overall stroke (0.87 (95%CI 0.77 to 0.97), 0.90 (95% CI 0.82 to 1.00)) and some stroke subtypes. FEV and FVC were inversely associated with type 2 diabetes and systolic blood pressure. Sensitivity analyses produced similar findings although the association with CAD was attenuated after adjusting for height (eg, OR for 1SD FEV0.95 (0.75 to 1.19), but not for stroke or type 2 diabetes. There was no strong evidence for reverse causation.

Conclusion: Higher lung function likely protect against CAD and stroke.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215600DOI Listing
June 2021

Blood pressure variability and night-time dipping assessed by 24-hour ambulatory monitoring: Cross-sectional association with cardiac structure in adolescents.

PLoS One 2021 16;16(6):e0253196. Epub 2021 Jun 16.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Greater blood pressure (BP) is associated with greater left ventricular mass indexed to height2.7 (LVMi2.7) in adolescents. This study examined whether greater BP variability and reduced night-time dipping are associated with cardiac remodeling in a general population of adolescents. A cross-sectional analysis was undertaken in 587 UK adolescents (mean age 17.7 years; 43.1% male). BP was measured in a research clinic and using 24-hour ambulatory monitoring. We examined associations (for both systolic and diastolic BP) of: 1) clinic and 24-hour mean BP; 2) measures of 24-hour BP variability: standard deviation weighted for day/night (SDdn), variability independent of the mean (VIM) and average real variability (ARV); and 3) night-time dipping with cardiac structures. Cardiac structures were assessed by echocardiography: 1) LVMi2.7; 2) relative wall thickness (RWT); 3) left atrial diameter indexed to height (LADi) and 4) left ventricular internal diameter in diastole (LVIDD). Higher systolic BP was associated with greater LVMi2.7. Systolic and diastolic BP were associated with greater RWT. Associations were inconsistent for LADi and LVIDD. There was evidence for associations between both greater SDdn and ARV and higher RWT (per 1 SD higher diastolic ARV, mean difference in RWT was 0.13 SDs, 95% CI 0.045 to 0.21); these associations with RWT remained after adjustment for mean BP. There was no consistent evidence of associations between night-time dipping and cardiac structure. Measurement of BP variability, even in adolescents with blood pressure in the physiologic range, might benefit risk of cardiovascular remodeling assessment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208567PMC
June 2021

Associations of cord leptin and cord insulin with adiposity and blood pressure in White British and Pakistani children aged 4/5 years.

Wellcome Open Res 2019 15;4:157. Epub 2019 Oct 15.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.

Cord leptin and cord insulin concentrations may be important biomarkers of child adiposity and cardiovascular health, especially in populations with an increased long-term risk of type 2 diabetes and cardiovascular diseases. We aimed to determine whether cord leptin and insulin are associated with adiposity and early cardiovascular health at age 4/5, and whether any associations differ between White British and Pakistani children. Using bi-ethnic cohort data from 6060 mother-offspring pairs (2717 (44.8%) White British, 3343 (55.2%) Pakistani), we examined associations of cord leptin and insulin with adiposity (BMI, skinfold thickness) and systolic and diastolic blood pressure at age 4/5. Cord leptin and insulin were higher in Pakistani compared to White British children (7.4 ng/ml versus 6.7 ng/ml and 4.1 mU/L versus 3.63 mU/L respectively). Associations with adiposity measurements were similar in both groups and close to the null value. For example, each 10 ng/ml higher cord leptin was associated with a difference in mean childhood BMI of 0.10 kg/m (95% CI 0.01, 0.19) in White British, 0.01 kg/m (95% CI -0.08, 0.10) in Pakistani and 0.04 kg/m (95% CI -0.02, 0.11) in both groups combined.  Associations with systolic and diastolic blood pressure were also close to the null and consistent in both groups. We found no evidence that cord leptin or insulin were likely to be valuable biomarkers for predicting later adiposity and blood pressure in White British or Pakistani children. For now, other factors such as family history and social-economic status may be more useful markers of risk.
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http://dx.doi.org/10.12688/wellcomeopenres.15433.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475957PMC
October 2019

Changes in parental smoking during pregnancy and risks of adverse birth outcomes and childhood overweight in Europe and North America: An individual participant data meta-analysis of 229,000 singleton births.

PLoS Med 2020 08 18;17(8):e1003182. Epub 2020 Aug 18.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom.

Background: Fetal smoke exposure is a common and key avoidable risk factor for birth complications and seems to influence later risk of overweight. It is unclear whether this increased risk is also present if mothers smoke during the first trimester only or reduce the number of cigarettes during pregnancy, or when only fathers smoke. We aimed to assess the associations of parental smoking during pregnancy, specifically of quitting or reducing smoking and maternal and paternal smoking combined, with preterm birth, small size for gestational age, and childhood overweight.

Methods And Findings: We performed an individual participant data meta-analysis among 229,158 families from 28 pregnancy/birth cohorts from Europe and North America. All 28 cohorts had information on maternal smoking, and 16 also had information on paternal smoking. In total, 22 cohorts were population-based, with birth years ranging from 1991 to 2015. The mothers' median age was 30.0 years, and most mothers were medium or highly educated. We used multilevel binary logistic regression models adjusted for maternal and paternal sociodemographic and lifestyle-related characteristics. Compared with nonsmoking mothers, maternal first trimester smoking only was not associated with adverse birth outcomes but was associated with a higher risk of childhood overweight (odds ratio [OR] 1.17 [95% CI 1.02-1.35], P value = 0.030). Children from mothers who continued smoking during pregnancy had higher risks of preterm birth (OR 1.08 [95% CI 1.02-1.15], P value = 0.012), small size for gestational age (OR 2.15 [95% CI 2.07-2.23], P value < 0.001), and childhood overweight (OR 1.42 [95% CI 1.35-1.48], P value < 0.001). Mothers who reduced the number of cigarettes between the first and third trimester, without quitting, still had a higher risk of small size for gestational age. However, the corresponding risk estimates were smaller than for women who continued the same amount of cigarettes throughout pregnancy (OR 1.89 [95% CI 1.52-2.34] instead of OR 2.20 [95% CI 2.02-2.42] when reducing from 5-9 to ≤4 cigarettes/day; OR 2.79 [95% CI 2.39-3.25] and OR 1.93 [95% CI 1.46-2.57] instead of OR 2.95 [95% CI 2.75-3.15] when reducing from ≥10 to 5-9 and ≤4 cigarettes/day, respectively [P values < 0.001]). Reducing the number of cigarettes during pregnancy did not affect the risks of preterm birth and childhood overweight. Among nonsmoking mothers, paternal smoking was associated with childhood overweight (OR 1.21 [95% CI 1.16-1.27], P value < 0.001) but not with adverse birth outcomes. Limitations of this study include the self-report of parental smoking information and the possibility of residual confounding. As this study only included participants from Europe and North America, results need to be carefully interpreted regarding other populations.

Conclusions: We observed that as compared to nonsmoking during pregnancy, quitting smoking in the first trimester is associated with the same risk of preterm birth and small size for gestational age, but with a higher risk of childhood overweight. Reducing the number of cigarettes, without quitting, has limited beneficial effects. Paternal smoking seems to be associated, independently of maternal smoking, with the risk of childhood overweight. Population strategies should focus on parental smoking prevention before or at the start, rather than during, pregnancy.
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http://dx.doi.org/10.1371/journal.pmed.1003182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433860PMC
August 2020

GLU: a software package for analysing continuously measured glucose levels in epidemiology.

Int J Epidemiol 2020 06;49(3):744-757

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Continuous glucose monitors (CGM) record interstitial glucose levels 'continuously', producing a sequence of measurements for each participant (e.g. the average glucose level every 5 min over several days, both day and night). To analyse these data, researchers tend to derive summary variables such as the area under the curve (AUC), to then use in subsequent analyses. To date, a lack of consistency and transparency of precise definitions used for these summary variables has hindered interpretation, replication and comparison of results across studies. We present GLU, an open-source software package for deriving a consistent set of summary variables from CGM data. GLU performs quality control of each CGM sample (e.g. addressing missing data), derives a diverse set of summary variables (e.g. AUC and proportion of time spent in hypo-, normo- and hyper- glycaemic levels) covering six broad domains, and outputs these (with quality control information) to the user. GLU is implemented in R and is available on GitHub at https://github.com/MRCIEU/GLU. Git tag v0.2 corresponds to the version presented here.
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http://dx.doi.org/10.1093/ije/dyaa004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394960PMC
June 2020

Common variation at 16p11.2 is associated with glycosuria in pregnancy: findings from a genome-wide association study in European women.

Hum Mol Genet 2020 07;29(12):2098-2106

Medical Research Council Integrative Epidemiology Unit, Avon Longitudinal Study of Parents and Children, Population Health Science, Bristol Medical School, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.

Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10-13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.
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http://dx.doi.org/10.1093/hmg/ddaa054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390941PMC
July 2020

Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study.

BMC Med 2020 03 23;18(1):71. Epub 2020 Mar 23.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Background: Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner.

Methods: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations.

Results: Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null.

Conclusions: The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.
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http://dx.doi.org/10.1186/s12916-020-01515-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087394PMC
March 2020

A maternal serum metabolite ratio predicts fetal growth restriction at term.

Nat Med 2020 03 11;26(3):348-353. Epub 2020 Mar 11.

Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, UK.

Fetal growth restriction (FGR) is the major single cause of stillbirth and is also associated with neonatal morbidity and mortality, impaired health and educational achievement in childhood and with a range of diseases in later life. Effective screening and intervention for FGR is an unmet clinical need. Here, we performed ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) metabolomics on maternal serum at 12, 20 and 28 weeks of gestational age (wkGA) using 175 cases of term FGR and 299 controls from the Pregnancy Outcome Prediction (POP) study, conducted in Cambridge, UK, to identify predictive metabolites. Internal validation using 36 wkGA samples demonstrated that a ratio of the products of the relative concentrations of two positively associated metabolites (1-(1-enyl-stearoyl)-2-oleoyl-GPC (P-18:0/18:1) and 1,5-anhydroglucitol) to the product of the relative concentrations of two negatively associated metabolites (5α-androstan-3α,17α-diol disulfate and N1,N12-diacetylspermine) predicted FGR at term. The ratio had approximately double the discrimination as compared to a previously developed angiogenic biomarker, the soluble fms-like tyrosine kinase 1:placental growth factor (sFLT1:PlGF) ratio (AUC 0.78 versus 0.64, P = 0.0001). We validated the predictive performance of the metabolite ratio in two sub-samples of a demographically dissimilar cohort, Born in Bradford (BiB), conducted in Bradford, UK (P = 0.0002). Screening and intervention using this metabolite ratio in conjunction with ultrasonic imaging at around 36 wkGA could plausibly prevent adverse events through enhanced fetal monitoring and targeted induction of labor.
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http://dx.doi.org/10.1038/s41591-020-0804-9DOI Listing
March 2020

Publisher Correction: Population reference and healthy standard blood pressure range charts in pregnancy: findings from the Born in Bradford cohort study.

Sci Rep 2020 Mar 11;10(1):4849. Epub 2020 Mar 11.

Bradford Institute for Health Research, Temple Bank House, Bradford Royal Infirmary, Duckworth Lane, Bradford, BD9 6RJ, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-61787-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064565PMC
March 2020

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.

Genome Med 2020 03 2;12(1):25. Epub 2020 Mar 2.

Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada.

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.

Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung.

Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels.

Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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http://dx.doi.org/10.1186/s13073-020-0716-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050134PMC
March 2020

Circulating Fatty Acids and Risk of Coronary Heart Disease and Stroke: Individual Participant Data Meta-Analysis in Up to 16 126 Participants.

J Am Heart Assoc 2020 03 2;9(5):e013131. Epub 2020 Mar 2.

Institute of Cardiovascular Science University College London London United Kingdom.

Background We aimed at investigating the association of circulating fatty acids with coronary heart disease (CHD) and stroke risk. Methods and Results We conducted an individual-participant data meta-analysis of 5 UK-based cohorts and 1 matched case-control study. Fatty acids (ie, omega-3 docosahexaenoic acid, omega-6 linoleic acid, monounsaturated and saturated fatty acids) were measured at baseline using an automated high-throughput serum nuclear magnetic resonance metabolomics platform. Data from 3022 incident CHD cases (13 104 controls) and 1606 incident stroke cases (13 369 controls) were included. Logistic regression was used to model the relation between fatty acids and odds of CHD and stroke, adjusting for demographic and lifestyle variables only (ie, minimally adjusted model) or with further adjustment for other fatty acids (ie, fully adjusted model). Although circulating docosahexaenoic acid, but not linoleic acid, was related to lower CHD risk in the fully adjusted model (odds ratio, 0.85; 95% CI, 0.76-0.95 per standard unit of docosahexaenoic acid), there was evidence of high between-study heterogeneity and effect modification by study design. Stroke risk was consistently lower with increasing circulating linoleic acid (odds ratio for fully adjusted model, 0.82; 95% CI, 0.75-0.90). Circulating monounsaturated fatty acids were associated with higher CHD risk across all models and with stroke risk in the fully adjusted model (odds ratio, 1.22; 95% CI, 1.03-1.44). Saturated fatty acids were not related to increased CHD risk in the fully adjusted model (odds ratio, 0.94; 95% CI, 0.82-1.09), or stroke risk. Conclusions We found consistent evidence that linoleic acid was associated with decreased risk of stroke and that monounsaturated fatty acids were associated with increased risk of CHD. The different pattern between CHD and stroke in terms of fatty acids risk profile suggests future studies should be cautious about using composite events. Different study designs are needed to assess which, if any, of the associations observed is causal.
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http://dx.doi.org/10.1161/JAHA.119.013131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335585PMC
March 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

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 modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization 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 body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the 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.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Population reference and healthy standard blood pressure range charts in pregnancy: findings from the Born in Bradford cohort study.

Sci Rep 2019 12 11;9(1):18847. Epub 2019 Dec 11.

Bradford Institute for Health Research, Temple Bank House, Bradford Royal Infirmary, Duckworth Lane, Bradford, BD9 6RJ, UK.

Women who develop gestational hypertension are at increased risk of adverse perinatal and longer-term outcomes. Reference charts may aid early detection of raised blood pressure (BP) and in doing so reduce adverse outcome risk. We used repeated BP measurements to produce 'reference' (whole population) and 'standard' (healthy pregnancies only) gestational-age-specific BP charts for all pregnant women (irrespective of ethnicity) and for White British (WB) and Pakistani (P) women. We included 9218 women recruited to the Born in Bradford study with 74,770 BPs. 19% of the whole population, 11% and 25% of WB and P women respectively were defined as healthy pregnancies. For reference and standard charts, for all women and each ethnic group, SBP/DBP at 12 and 20 weeks gestation was similar before rising at 37 weeks. DBP/SBP of reference charts for all women and for each ethnic group were higher than those of the corresponding standard charts. Compared to WB, P women had lower SBP/DBP at 12, 20 and 37 weeks gestation. To conclude; maternal population BP reference charts are higher compared to standard charts (healthy pregnancies) and are influenced by ethnicity.
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http://dx.doi.org/10.1038/s41598-019-55324-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906473PMC
December 2019

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population.

Clin Endocrinol (Oxf) 2020 01 20;92(1):29-37. Epub 2019 Nov 20.

Musculoskeletal Research Unit, Translation Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Objective: Bone turnover, which regulates bone mass, may exert metabolic consequences, particularly on markers of glucose metabolism and adiposity. To better understand these relationships, we examined cross-sectional associations between bone turnover markers (BTMs) and metabolic traits in a population with high bone mass (HBM, BMD Z-score ≥+3.2).

Design: β-C-terminal telopeptide of type-I collagen (β-CTX), procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin were assessed by electrochemiluminescence immunoassays. Metabolic traits, including lipids and glycolysis-related metabolites, were measured using nuclear magnetic resonance spectroscopy. Associations of BTMs with metabolic traits were assessed using generalized estimating equation linear regression, accounting for within-family correlation, adjusting for potential confounders (age, sex, height, weight, menopause, bisphosphonate and oral glucocorticoid use).

Results: A total of 198 adults with HBM had complete data, mean [SD] age 61.6 [13.7] years; 77% were female. Of 23 summary metabolic traits, citrate was positively related to all BTMs: adjusted β  = 0.050 (95% CI 0.024, 0.076), P = 1.71 × 10 , β  = 6.54 × 10 (1.87 × 10 , 0.001), P = .006 and β  = 2.40 × 10 (6.49 × 10 , 4.14 × 10 ), P = .007 (β = increase in citrate (mmol/L) per 1 µg/L BTM increase). Inverse relationships of β-CTX (β = -0.276 [-0.434, -0.118], P = 6.03 × 10 ) and osteocalcin (-0.004 [-0.007, -0.001], P = .020) with triglycerides were also identified. We explored the generalizability of these associations in 3664 perimenopausal women (age 47.9 [4.4] years) from a UK family cohort. We confirmed a positive, albeit lower magnitude, association between β-CTX and citrate (adjusted β  = 0.020 [0.013, 0.026], P = 1.95 × 10 ) and an inverse association of similar magnitude between β-CTX and triglycerides (β = -0.354 [-0.471, -0.237], P = 3.03 × 10 ).

Conclusions: Bone resorption is positively related to circulating citrate and inversely related to triglycerides. Further studies are justified to determine whether plasma citrate or triglyceride concentrations are altered by factors known to modulate bone resorption, such as bisphosphonates.
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http://dx.doi.org/10.1111/cen.14119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017780PMC
January 2020

The Parkinson's Disease Mendelian Randomization Research Portal.

Mov Disord 2019 12 28;34(12):1864-1872. Epub 2019 Oct 28.

Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

Background: Mendelian randomization is a method for exploring observational associations to find evidence of causality.

Objective: To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research.

Methods: We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest.

Results: We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol.

Conclusions: We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973052PMC
December 2019

Determinants of Intima-Media Thickness in the Young: The ALSPAC Study.

JACC Cardiovasc Imaging 2021 02 11;14(2):468-478. Epub 2019 Oct 11.

Vascular Physiology Unit, UCL Institute of Cardiovascular Science, London, United Kingdom. Electronic address:

Objectives: This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years.

Background: Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood.

Methods: Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences.

Results: Fat-free mass (FFM) and systolic blood pressure were the only modifiable risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% confidence interval [CI]: 0.004 to 0.010; p < 0.001), whereas fat mass was negatively associated with cIMT (difference: -0.0032; 95% CI: 0.004 to -0.001; p = 0.001). Similar results were obtained when investigating cumulative exposure to these factors throughout adolescence. An increase in cIMT maintained circumferential wall stress in the face of increased mean arterial pressure when increases in body mass were attributable to increased FFM, but not fat mass. Risk factor-associated differences in the radial artery occurred in the media alone, and there was little evidence of a relationship between intimal thickness and any risk factor.

Conclusions: Subtle changes in cIMT in the young may predominantly involve the media and represent physiological adaptations as opposed to subclinical atherosclerosis. Other vascular measures may be more appropriate for the identification of arterial disease before adulthood.
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http://dx.doi.org/10.1016/j.jcmg.2019.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851110PMC
February 2021

Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium.

Diabetes Care 2020 01 10;43(1):98-105. Epub 2019 Oct 10.

Population Health Science, Bristol Medical School, University of Bristol, Bristol, U.K.

Objective: Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium.

Research Design And Methods: Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate.

Results: Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the promoter, and the other (chr 10: 135341870-135342620) was located in the gene body of . Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted value threshold of 0.05.

Conclusions: Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of , a gene associated with autism spectrum disorder, and the gene body of , which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.
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http://dx.doi.org/10.2337/dc19-0524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925578PMC
January 2020

Metabolic profiling of adolescent non-alcoholic fatty liver disease.

Wellcome Open Res 2018 19;3:166. Epub 2019 Sep 19.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.

Adolescent non-alcoholic fatty liver disease (NAFLD) is associated with cardiometabolic risk factors. The association between adolescent NAFLD and a wide range of metabolic biomarkers is unclear. We have attempted to determine the differences in metabolic profile of adolescents with and without markers of NAFLD. We performed cross-sectional analyses in a sample of 3,048 participants from the Avon Longitudinal Study of Parents and Children at age 17. We used three indicators of NAFLD: ALT >40 U/l; AST >40 U/l and ultrasound scan-assessed steatosis. Associations between each measure of NAFLD and 154 metabolic traits, assessed by Nuclear Magnetic Resonance, were analyzed by multivariable linear regression, adjusting for age, sex and BMI. All three indicators of NAFLD were associated with ~0.5 standard deviation (SD) greater concentrations of all extremely large to small very low-density lipoproteins (VLDL) measures. ALT >40U/l was associated with ~0.5SD greater concentrations of very small VLDLs, intermediate-density lipoproteins and low-density lipoproteins. Concentrations of most cholesterols, including remnant cholesterol, all triglycerides and monounsaturated fatty acids, in addition to glycoprotein acetyls (inflammatory marker), were also higher in participants with NAFLD. We have identified differing metabolic profiles between adolescents with and without indicators of NAFLD. These results provide the foundations for future research to determine whether these differences persist and result in adverse future cardiometabolic health.
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http://dx.doi.org/10.12688/wellcomeopenres.14974.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338132PMC
September 2019

Sex and area differences in the association between adiposity and lipid profile in Malawi.

BMJ Glob Health 2019 11;4(5):e001542. Epub 2019 Sep 11.

Malawi Epidemiology and Intervention Research Unit (MEIRU), Lilongwe and Karonga, Malawi.

Background: Evidence from high-income countries shows that higher adiposity results in an adverse lipid profile, but it is unclear whether this association is similar in Sub-Saharan African (SSA) populations. This study aimed to assess the association between total and central adiposity measures and lipid profile in Malawi, exploring differences by sex and area of residence (rural/urban).

Methods: In this cross-sectional study, data from 12 096 rural and 12 847 urban Malawian residents were used. The associations of body mass index (BMI) and waist to hip ratio (WHR) with fasting lipids (total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG)) were assessed by area and sex.

Results: After adjusting for potential confounders, higher BMI and WHR were linearly associated with increased TC, LDL-C and TG and reduced HDL-C. BMI was more strongly related to fasting lipids than was WHR. The associations of adiposity with adverse lipid profile were stronger in rural compared with urban residents. For instance, one SD increase in BMI was associated with 0.23 mmol/L (95% CI 0.19 to 0.26) increase in TC in rural women and 0.13 mmol/L (95% CI 0.11 to 0.15) in urban women. Sex differences in the associations between adiposity and lipids were less evident.

Conclusions: The consistent associations observed of higher adiposity with adverse lipid profiles in men and women living in rural and urban areas of Malawi highlight the emerging adverse cardio-metabolic epidemic in this poor population. Our findings underline the potential utility of BMI in estimating cardiovascular risk and highlight the need for greater investment to understand the long-term health outcomes of obesity and adverse lipid profiles and the extent to which lifestyle changes and treatments effectively prevent and modify adverse cardio-metabolic outcomes.
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http://dx.doi.org/10.1136/bmjgh-2019-001542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747887PMC
September 2019

Blood pressure change across pregnancy in white British and Pakistani women: analysis of data from the Born in Bradford cohort.

Sci Rep 2019 09 13;9(1):13199. Epub 2019 Sep 13.

Centre for Exercise, Nutrition and Health Sciences, University of Bristol, Bristol, UK.

The incidence of gestational hypertension (GH) and pre-eclampsia (PE) is increasing. Use of blood pressure (BP) change patterns may improve early detection of BP abnormalities. We used Linear spline random-effects models to estimate BP patterns across pregnancy for white British and Pakistani women. Pakistani women compared to white British women had lower BP during the first two trimesters of pregnancy, irrespective of the development of GH or PE or presence of a risk factor. Pakistani compared to white British women with GH and PE showed steeper BP increases towards the end of pregnancy. Pakistani women were half as likely to develop GH, but as likely to develop PE than white British women. To conclude; BP trajectories differ by ethnicity. Because GH developed evenly from 20 weeks gestation, and PE occurred more commonly after 36 weeks in both ethnic groups, the lower BP up to the third trimester in Pakistani women resulted in a lower GH rate, whereas PE rates, influenced by the steep third trimester BP increase were similar. Criteria for diagnosing GH and PE may benefit from considering ethnic differences in BP change across pregnancy.
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http://dx.doi.org/10.1038/s41598-019-49722-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744423PMC
September 2019

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.

Nat Commun 2019 09 2;10(1):3927. Epub 2019 Sep 2.

Center for Craniofacial and Dental Genetics, Department of Oral Biology School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
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http://dx.doi.org/10.1038/s41467-019-11881-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718389PMC
September 2019

Paternal impact on the life course development of obesity and type 2 diabetes in the offspring.

Diabetologia 2019 10 27;62(10):1802-1810. Epub 2019 Aug 27.

MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.

The aetiologies of obesity and type 2 diabetes are incredibly complex, but the potential role of paternal influences remains relatively understudied. A better understanding of paternal influences on offspring risk of obesity and type 2 diabetes could have profound implications for public health, clinical practice and society. In this review, we outline potential biological and social mechanisms through which fathers might exert an impact on the health of their offspring. We also present a systematically compiled overview of the current evidence linking paternal factors to offspring development of obesity and type 2 diabetes throughout the life course. Although evidence is accumulating to support paternal associations with offspring outcomes, more high-quality research is needed to overcome specific methodological challenges and provide stronger causal evidence.
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http://dx.doi.org/10.1007/s00125-019-4919-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731203PMC
October 2019

Direct and BMI-mediated effect of birthweight on childhood cardio-metabolic health-a birth cohort study.

Int J Obes (Lond) 2019 10 22;43(10):1923-1931. Epub 2019 Jul 22.

EPIUnit - Instituto de Saúde Pública, Universidade do Porto, Porto, Portugal.

Background: Different directions of the association of birthweight with cardio-metabolic health have been found, especially in children, which may be explained by the mediating effect of attained adiposity. We aimed to untangle direct and BMI-mediated associations of birthweight with childhood cardio-metabolic indicators.

Methods: Children from Generation XXI birth cohort were included (n = 4881). Birthweight was abstracted from clinical files. At age 4 and 7, children were re-evaluated. Glucose, triglycerides, LDL-cholesterol, systolic (SBP) and diastolic blood pressure (DBP) z-scores were the cardio-metabolic traits analyzed. Regression coefficients and respective 95% confidence intervals [β (95%CI)] were computed using path analysis.

Results: Birthweight had inverse total effect on SBP at age 4 [-0.005 (-0.010; -0.001)] and 7 [-0.011 (-0.017; -0.006)] and DBP at 7 [-0.008 (-0.012; -0.004)]. Direct effects were found for SBP at 4 [-0.013 (-0.018; -0.009)] and 7 [-0.014 (-0.019; -0.009)], and DBP at 7 [-0.010 (-0.015; -0.006)], explaining the inverse total effects. Positive BMI-mediated indirect effects were found for all cardio-metabolic traits: higher birthweight was associated with higher childhood BMI, which in turn was associated with higher levels of cardio-metabolic traits.

Conclusions: Positive BMI-mediated effect of birthweight on all cardio-metabolic traits was found. However, direct effects were in the opposite direction, significant for blood pressure, which may explain the diversity of results observed in the literature. Combining the direct and BMI-mediated effects, higher birthweight was associated with lower blood pressure at age 7 and have no effect on other cardio-metabolic traits.
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http://dx.doi.org/10.1038/s41366-019-0413-1DOI Listing
October 2019

Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization studies.

Eur J Endocrinol 2019 Oct;181(4):429-438

BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Objective: The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD).

Design And Methods: Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses).

Results: In the two prospective nested case-control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06-1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98-1.15.

Conclusions: All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.
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http://dx.doi.org/10.1530/EJE-19-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733337PMC
October 2019

A Cross-Cohort Study Examining the Associations of Metabolomic Profile and Subclinical Atherosclerosis in Children and Their Parents: The Child Health CheckPoint Study and Avon Longitudinal Study of Parents and Children.

J Am Heart Assoc 2019 07 9;8(14):e011852. Epub 2019 Jul 9.

3 Murdoch Children's Research Institute Parkville Victoria Australia.

Background High-throughput nuclear magnetic resonance profiling of circulating metabolites is suggested as an adjunct for cardiovascular risk evaluation. The relationship between metabolites and subclinical atherosclerosis remains unclear, particularly among children. Therefore, we examined the associations of metabolites with carotid intima-media thickness ( cIMT ) and arterial pulse wave velocity ( PWV ). Methods and Results Data from two independent population-based studies was examined; (1) cross-sectional associations with cIMT and PWV in 1178 children (age 11-12 years, 51% female) and 1316 parents (mean age 45 years, 87% female) from the CheckPoint study (Australia); and (2) longitudinal associations in 4249 children (metabolites at 7-8 years, PWV at 10-11 years, 52% female), and cross-sectional associations in 4171 of their mothers (mean age 48 years, cIMT data) from ALSPAC (The Avon Longitudinal Study of Parents and Children; UK ). Metabolites were measured by the same nuclear magnetic resonance platform in both studies, comprising of 69 biomarkers. Biophysical assessments included body mass index, blood pressure, cIMT and PWV . In linear regression analyses adjusted for age, sex, body mass index, and blood pressure, there was no evidence of metabolite associations in either children or adults for cIMT at a 10% false discovery threshold. In CheckPoint adults, glucose was positively, and some high-density lipoprotein-cholesterol derived measures and amino acids (glutamine, histidine, tyrosine) inversely associated with PWV. Conclusions These data suggest that in children circulating metabolites have no consistent association with cIMT and PWV once adjusted for body mass index and blood pressure. In their middle-aged parents, some evidence of metabolite associations with PWV were identified that warrant further investigation.
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http://dx.doi.org/10.1161/JAHA.118.011852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662147PMC
July 2019

Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.

BMJ 2019 Jun 26;365:l2327. Epub 2019 Jun 26.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Objective: To examine whether sleep traits have a causal effect on risk of breast cancer.

Design: Mendelian randomisation study.

Setting: UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study.

Participants: 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis.

Exposures: Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.

Main Outcome Measure: Breast cancer diagnosis.

Results: In multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy.

Conclusions: Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.
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http://dx.doi.org/10.1136/bmj.l2327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592406PMC
June 2019

Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns.

Hypertension 2019 08 24;74(2):375-383. Epub 2019 Jun 24.

Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA (S.L.R.-S., E.O., M.-F.H.).

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635125PMC
August 2019

Associations of mortality with own blood pressure using son's blood pressure as an instrumental variable.

Sci Rep 2019 06 20;9(1):8986. Epub 2019 Jun 20.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

High systolic blood pressure (SBP) causes cardiovascular disease (CVD) and is associated with mortality from other causes, but conventional multivariably-adjusted results may be confounded. Here we used a son's SBP (>1 million Swedish men) as an instrumental variable for parental SBP and examined associations with parents' cause-specific mortality, avoiding reverse causation. The hazard ratio for CVD mortality per SD (10.80 mmHg) of SBP was 1.49 (95% CI: 1.43, 1.56); SBP was positively associated with coronary heart disease and stroke. SBP was also associated positively with all-cause, diabetes and kidney cancer mortality, and negatively with external causes. Negative associations with respiratory-related mortality were probably confounded by smoking. Hazard ratios for other causes were imprecise or null. Diastolic blood pressure gave similar results to SBP. CVD hazard ratios were intermediate between those from conventional multivariable studies and Mendelian randomization and stronger than those from clinical trials, approximately consistent with an effect of exposure duration on effect sizes. Plots of parental mortality against offspring SBP were approximately linear, supporting calls for lower SBP targets. Results suggest that conventional multivariable analyses of mortality and SBP are not substantially confounded by reverse causation and confirm positive effects of SBP on all-cause, CVD and diabetes mortality.
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http://dx.doi.org/10.1038/s41598-019-45391-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586810PMC
June 2019
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