Publications by authors named "David P Strachan"

211 Publications

The rising tide of dementia deaths: triangulation of data from three routine data sources using the Clinical Practice Research Datalink.

BMC Geriatr 2021 06 21;21(1):375. Epub 2021 Jun 21.

Population Health Research Institute, St George's University of London, Cranmer Terrace, SW17 0RE, London, United Kingdom.

Background: Dementia is currently the leading certified underlying cause of death in England. We assess how dementia recording on Office for National Statistics death certificates (ONS) corresponded to recording in general practice records (GP) and Hospital Episode Statistics (HES).

Methods: Retrospective study of deaths (2001-15) in 153 English General Practices contributing to the Clinical Practice Research Datalink, with linked ONS and HES records.

Results: Of 207,068 total deaths from any cause, 19,627 mentioned dementia on the death certificate with 10,253 as underlying cause; steady increases occurred from 2001 to 2015 (any mention 5.3 to 15.4 %, underlying cause 2.7 to 10 %). Including all data sources, recording of any dementia increased from 13.2 to 28.6 %. In 2015, only 53.8 % of people dying with dementia had dementia recorded on their death certificates. Among deaths mentioning dementia on the death certificate, the recording of a prior diagnosis of dementia in GP and HES rose markedly over the same period. In 2001, only 76.3 % had a prior diagnosis in GP and/or HES records; by 2015 this had risen to 95.7 %. However, over the same period the percentage of all deaths with dementia recorded in GP or HES but not mentioned on the death certificate rose from 7.9 to 13.3 %.

Conclusions: Dementia recording in all data sources increased between 2001 and 2015. By 2015 the vast majority of deaths mentioning dementia had supporting evidence in primary and/or secondary care. However, death certificates were still providing an inadequate picture of the number of people dying with dementia.
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http://dx.doi.org/10.1186/s12877-021-02306-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218386PMC
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

Impact of early life geohelminths on wheeze, asthma and atopy in Ecuadorian children at 8 years.

Allergy 2021 Mar 20. Epub 2021 Mar 20.

Population Health Research Institute, St George's University of London, London, UK.

Background: Early-life exposures to geohelminths may protect against development of wheeze/asthma and atopy.

Objective: To study the effect of maternal geohelminths and infections in children during the first 5 years on atopy, wheeze/asthma and airways reactivity/inflammation at 8 years.

Methods: Birth cohort of 2404 neonates followed to 8 years in rural Ecuador. Data on wheeze/asthma were collected by questionnaire and atopy by skin prick test (SPT) reactivity to 9 allergens. We measured airways reactivity to bronchodilator, fractional exhaled nitric oxide (FeNO) and nasal eosinophilia. Stool samples were examined for geohelminths by microscopy.

Results: 1933 (80.4%) children were evaluated at 8 years. Geohelminths were detected in 45.8% of mothers and 45.5% of children to 5 years. Frequencies of outcomes at 8 years were as follows: wheeze (6.6%), asthma between 5 and 8 years (7.9%), SPT (14.7%), airways reactivity (10%) and elevated FeNO (10.3%) and nasal eosinophilia (9.2%). Any maternal geohelminth was associated with reduced SPT prevalence (OR 0.72). Childhood Trichuris trichiura infections during the first 5 years were associated with reduced wheeze (OR 0.57) but greater parasite burdens with Ascaris lumbricoides at 5 years were associated with increased wheeze (OR 2.83) and asthma (OR 2.60). Associations between maternal geohelminths and wheeze/asthma were modified by atopy. Parasite-specific effects on wheeze/asthma and airways reactivity and inflammation were observed in non-atopic children.

Conclusions: Our data provide novel evidence for persistent effects of in utero geohelminth exposures on childhood atopy but highlight the complex nature of the relationship between geohelminths and the airways. Registered as an observational study (ISRCTN41239086).
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http://dx.doi.org/10.1111/all.14821DOI Listing
March 2021

Gut microbiota development during infancy: Impact of introducing allergenic foods.

J Allergy Clin Immunol 2021 Feb;147(2):613-621.e9

Unit for Population-Based Dermatology Research, St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, United Kingdom. Electronic address:

Background: The gut microbiota potentially plays an important role in the immunologic education of the host during early infancy.

Objective: We sought to determine how the infant gut microbiota evolve during infancy, particularly in relation to hygiene-related environmental factors, atopic disorders, and a randomized introduction of allergenic solids.

Methods: A total of 1303 exclusively breast-fed infants were enrolled in a dietary randomized controlled trial (Enquiring About Tolerance study) from 3 months of age. In this nested longitudinal study, fecal samples were collected at baseline, with additional sampling of selected cases and controls at 6 and 12 months to study the evolution of their gut microbiota, using 16S ribosomal RNA gene-targeted amplicon sequencing.

Results: In the 288 baseline samples from exclusively breast-fed infant at 3 months, the gut microbiota was highly heterogeneous, forming 3 distinct clusters: Bifidobacterium-rich, Bacteroides-rich, and Escherichia/Shigella-rich. Mode of delivery was the major discriminating factor. Increased Clostridium sensu stricto relative abundance at 3 months was associated with presence of atopic dermatitis on examination at age 3 and 12 months. From the selected cases and controls with longitudinal samples (n = 70), transition to Bacteroides-rich communities and influx of adult-specific microbes were observed during the first year of life. The introduction of allergenic solids promoted a significant increase in Shannon diversity and representation of specific microbes, such as genera belonging to Prevotellaceae and Proteobacteria (eg, Escherichia/Shigella), as compared with infants recommended to exclusively breast-feed.

Conclusions: Specific gut microbiota characteristics of samples from 3-month-old breast-fed infants were associated with cesarean birth, and greater Clostridium sensu stricto abundance was associated with atopic dermatitis. The randomized introduction of allergenic solids from age 3 months alongside breast-feeding was associated with differential dynamics of maturation of the gut microbial communities.
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http://dx.doi.org/10.1016/j.jaci.2020.09.042DOI Listing
February 2021

Trends in worldwide asthma prevalence.

Eur Respir J 2020 12 24;56(6). Epub 2020 Dec 24.

Population Health Research Institute, St George's University of London, London, UK.

This review of trends in worldwide asthma prevalence starts with defining how asthma prevalence is measured in populations and how it is analysed. Four population studies of asthma across at least two regions are described: European Community Respiratory Health Survey (ECRHS), the International Study of Wheezing in Infants (EISL), the International Study of Asthma and Allergies in Childhood (ISAAC) and the World Health Survey (WHS). Two of these (ISAAC and WHS) covered all the regions of the world; each using its own standardised questionnaire-based methodology with cross-sectional study design, suitable for large populations. EISL (2005 and 2012) and ISAAC (1996-1997 and 2002-2003) have undertaken a second cross-sectional population survey from which trends are available: EISL in three centres in two countries; ISAAC 106 centres in 56 countries (13-14 year olds) and 66 centres in 37 countries (6-7 year olds). Key results from these studies are presented. Unfortunately, there is no new worldwide data outside of EISL since 2003. Global Burden of Disease estimates of asthma prevalence have varied greatly. Recent reliable worldwide data on asthma prevalence and trends is needed; the Global Asthma Network Phase I will provide this in 2021.
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http://dx.doi.org/10.1183/13993003.02094-2020DOI Listing
December 2020

Retinal Vascular Tortuosity and Diameter Associations with Adiposity and Components of Body Composition.

Obesity (Silver Spring) 2020 09 29;28(9):1750-1760. Epub 2020 Jul 29.

Population Health Research Institute, St George's, University of London, London, UK.

Objective: The aim of this study was to assess whether adiposity or body composition relates to microvascular characteristics of the retina, indicative of cardiometabolic function.

Methods: A fully automated QUARTZ software processed retinal images from 68,550 UK Biobank participants (aged 40-69 years). Differences in retinal vessel diameter and tortuosity with body composition measures from the Tanita analyzer were obtained by using multilevel regression analyses adjusted for age, sex, ethnicity, clinic, smoking, and Townsend deprivation index.

Results: Venular tortuosity and diameter increased by approximately 2% (P < 10 ) and 0.6 μm (P < 10 ), respectively, per SD increase in BMI, waist circumference index, waist-hip ratio, total body fat mass index, and fat-free mass index (FFMI). Venular associations with adiposity persisted after adjustment for FFMI, whereas associations with FFMI were weakened by FMI adjustment. Arteriolar diameter (not tortuosity) narrowing with FFMI was independent of adiposity (-0.6 μm; -0.7 to -0.4 μm per SD increment of FFMI), while adiposity associations with arteriolar diameter were largely nonsignificant after adjustment for FFMI.

Conclusions: This demonstrates, on an unprecedented scale, that venular tortuosity and diameter are more strongly associated with adiposity, whereas arteriolar diameter relates more strongly to fat-free mass. Different attributes of the retinal microvasculature may reflect distinct roles of body composition and fatness on the cardiometabolic system.
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http://dx.doi.org/10.1002/oby.22885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116641PMC
September 2020

Retinal Vasculometry Associations With Glaucoma: Findings From the European Prospective Investigation of Cancer-Norfolk Eye Study.

Am J Ophthalmol 2020 12 25;220:140-151. Epub 2020 Jul 25.

NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, United Kingdom; Integrative Epidemiology Research Group, UCL Institute of Ophthalmology, London, United Kingdom.

Purpose: To examine retinal vasculometry associations with different glaucomas in older British people.

Design: Cross-sectional study.

Methods: A total of 8,623 European Prospective Investigation into Cancer-Norfolk Eye study participants were examined, who underwent retinal imaging, ocular biometry assessment, and clinical ascertainment of ocular hypertensive or glaucoma status (including glaucoma suspect [GS], high-tension open-angle glaucoma [HTG], and normal-tension glaucoma [NTG]). Automated measures of arteriolar and venular tortuosity, area, and width from retinal images were obtained. MainOutcomeMeasures: Associations between glaucoma and retinal vasculometry outcomes were analyzed using multilevel linear regression, adjusted for age, sex, height, axial length, intraocular and systemic blood pressure, and within-person clustering, to provide absolute differences in width and area, and percentage differences in vessel tortuosity. Presence or absence of within-person-between-eye differences in retinal vasculometry by diagnoses were examined.

Results: A total of 565,593 vessel segments from 5,947 participants (mean age 67.6 years, SD 7.6 years, 57% women) were included; numbers with HTG, NTG, and GS in at least 1 eye were 87, 82, and 439, respectively. Thinner arterioles (-3.2 μm; 95% confidence interval [CI] -4.4 μm, -1.9 μm) and venules (-2.7 μm; 95% CI -4.9 μm, -0.5 μm) were associated with HTG. Reduced venular area was associated with HTG (-0.2 mm; 95% CI -0.3 mm, -0.1 mm) and NTG (-0.2 mm; 95% CI -0.3 mm, -0.0 mm). Less tortuous retinal arterioles and venules were associated with all glaucomas, but only significantly for GS (-3.9%; 95% CI -7.7%, -0.1% and -4.8%; 95% CI -7.4%, -2.1%, respectively). There was no evidence of within-person-between-eye differences in retinal vasculometry associations by diagnoses.

Conclusions: Retinal vessel width associations with glaucoma and novel associations with vessel area and tortuosity, together with no evidence of within-person-between-eye differences in retinal vasculometry, suggest a vascular cause of glaucoma.
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http://dx.doi.org/10.1016/j.ajo.2020.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706353PMC
December 2020

Comparison of individual-level and population-level risk factors for rhinoconjunctivitis, asthma, and eczema in the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three.

World Allergy Organ J 2020 Jun 2;13(6):100123. Epub 2020 Jul 2.

Population Health Research Institute, St George's University of London, London, United Kingdom.

Background: Symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema in children cluster at both the individual and population levels.

Objectives: To assess individual-level and school-level risk factors for symptoms of rhinoconjunctivitis and compare them to corresponding associations with symptoms of asthma and eczema in Phase Three of the International Study of Asthma and Allergies in Childhood.

Methods: We studied 116,863 children aged 6-7 years from 2163 schools in 59 centres and 22 countries and 224,436 adolescents aged 13-14 years from 2037 schools in 97 centres in 41 countries. Multilevel logistic regression models were fitted with random intercepts for school, centre, and country, adjusting for sex and maternal education at the child level. Associations between symptoms and a range of lifestyle and environmental risk factors were assessed for both the child's exposure and mean exposure at the school. Models were fitted for rhinoconjunctivitis, asthma, and eczema singly (unimorbidity) and for combinations of these conditions (multimorbidity).

Results: Generally, associations between symptoms and exposures at the school level were similar in direction and magnitude to those at the child level. Associations with multimorbidity were stronger than for unimorbidity, particularly in individuals with symptoms of all three diseases, but risk factor associations found in conventional single disease analyses persisted among children with only one condition, after excluding multimorbid groups.Comparisons of individuals with only one disease showed that many risk factor associations were consistent across the three conditions. More strongly associated with asthma were low birthweight, cat exposure in infancy, and current maternal smoking. Current paracetamol use was more strongly associated with asthma and rhinoconjunctivitis than eczema. Breastfeeding was more strongly associated with eczema than asthma or rhinoconjunctivitis.The direction and magnitude of most risk factor associations were similar in affluent and non-affluent countries, although notable exceptions include farm animal contact in infancy and larger sibships, which were associated with increased risk of rhinoconjunctivitis in non-affluent countries but reduced risk in affluent countries. In both age groups, current paracetamol use increased risk of each disease to a greater extent in affluent countries than in non-affluent countries. Effects of paracetamol and antibiotics in infancy were more consistent between richer and poorer settings.

Conclusions: Most of the environmental and lifestyle correlates of rhinoconjunctivitis, asthma and eczema in childhood display similarity across the three conditions, even in less affluent settings where allergic sensitisation is less likely to explain the concordant epidemiological patterns.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1016/j.waojou.2020.100123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334817PMC
June 2020

Associations of Retinal Microvascular Diameters and Tortuosity With Blood Pressure and Arterial Stiffness: United Kingdom Biobank.

Hypertension 2019 12 30;74(6):1383-1390. Epub 2019 Oct 30.

From the Population Health Research Institute, St George's University of London, United Kingdom (R.J.T., C.G.O., P.H.W., D.P.S., A.R.R.).

To examine the baseline associations of retinal vessel morphometry with blood pressure (BP) and arterial stiffness in United Kingdom Biobank. The United Kingdom Biobank included 68 550 participants aged 40 to 69 years who underwent nonmydriatic retinal imaging, BP, and arterial stiffness index assessment. A fully automated image analysis program (QUARTZ [Quantitative Analysis of Retinal Vessel Topology and Size]) provided measures of retinal vessel diameter and tortuosity. The associations between retinal vessel morphology and cardiovascular disease risk factors/outcomes were examined using multilevel linear regression to provide absolute differences in vessel diameter and percentage differences in tortuosity (allowing within person clustering), adjusted for age, sex, ethnicity, clinic, body mass index, smoking, and deprivation index. Greater arteriolar tortuosity was associated with higher systolic BP (relative increase, 1.2%; 95% CI, 0.9; 1.4% per 10 mmHg), higher mean arterial pressure, 1.3%; 0.9, 1.7% per 10 mmHg, and higher pulse pressure (PP, 1.8%; 1.4; 2.2% per 10 mmHg). Narrower arterioles were associated with higher systolic BP (-0.9 µm; -0.94, -0.87 µm per 10 mmHg), mean arterial pressure (-1.5 µm; -1.5, -1.5 µm per 10 mmHg), PP (-0.7 µm; -0.8, -0.7 µm per 10 mmHg), and arterial stiffness index (-0.12 µm; -0.14, -0.09 µm per ms/m). Associations were in the same direction but marginally weaker for venular tortuosity and diameter. This study assessing the retinal microvasculature at scale has shown clear associations between retinal vessel morphometry, BP, and arterial stiffness index. These observations further our understanding of the preclinical disease processes and interplay between microvascular and macrovascular disease.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069386PMC
December 2019

Clinical onset of atopic eczema: Results from 2 nationally representative British birth cohorts followed through midlife.

J Allergy Clin Immunol 2019 09 28;144(3):710-719. Epub 2019 Jun 28.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Background: Atopic eczema onset is described primarily in early childhood, and the frequency and characteristics of adult-onset disease remain controversial.

Objective: We sought to determine the proportion of subjects who report atopic eczema symptoms between birth and midadulthood and to examine demographic, immunologic, and genetic factors associated with period of symptom onset.

Methods: We conducted a longitudinal study using data from 2 nationally representative community-based birth cohorts from the United Kingdom: the British Cohort Studies 1958 and 1970. Subjects were followed from birth through age 42 to 50 years. The primary outcome was the age period of self-reported atopic eczema symptom onset based on repeated measures of self-reported atopic eczema at each survey wave.

Results: The annual period prevalence of atopic eczema ranged from 5% to 15% in 2 cohorts of more than 17,000 participants each followed from birth through middle age. There was no clear trend in prevalence by age, and among adults reporting active atopic eczema during a given year, only 38% had symptom onset reported in childhood. When compared with subjects whose eczema started in childhood, those with adult-onset disease were more likely to be women, from Scotland or Northern England, of lower childhood socioeconomic group, smokers in adulthood, and less likely to have a history of asthma. In a subanalysis using data from the 1958 cohort only, genetic mutations previously associated with atopic eczema, including filaggrin-null mutations, and allergen-specific IgE were more common among those with childhood-onset disease.

Conclusion: Rates of self-reported atopic eczema remain high after childhood, and adult-onset atopic eczema has different risk factor associations than childhood-onset eczema.
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http://dx.doi.org/10.1016/j.jaci.2019.05.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721832PMC
September 2019

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

Nat Genet 2019 03 25;51(3):494-505. Epub 2019 Feb 25.

Department of Internal Medicine and Environmental Health Center, School of Medicine, Kangwon National University, Chuncheon, South Korea.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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http://dx.doi.org/10.1038/s41588-018-0342-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546635PMC
March 2019

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Nat Genet 2019 03 25;51(3):481-493. Epub 2019 Feb 25.

Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
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http://dx.doi.org/10.1038/s41588-018-0321-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397078PMC
March 2019

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

Circulation 2019 01;139(5):620-635

Institute of Cardiovascular and Medical Sciences (P.W.), University of Glasgow, UK.

Background: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

Methods: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

Results: We identified 13 novel genome-wide significant ( P≤2.5×10) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

Conclusions: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438386PMC
January 2019

Are Environmental Factors for Atopic Eczema in ISAAC Phase Three due to Reverse Causation?

J Invest Dermatol 2019 05 4;139(5):1023-1036. Epub 2018 Dec 4.

Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6-7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37-1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10-2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34-1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21-1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00-1.82 and OR = 0.94, 95% CI = 0.69-1.28, respectively). At ages 13-14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51-1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33-1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84-3.59 and OR = 2.38, 95% CI = 1.52-3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27-1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07-1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.
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http://dx.doi.org/10.1016/j.jid.2018.08.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478380PMC
May 2019

Are environmental risk factors for current wheeze in the International Study of Asthma and Allergies in Childhood (ISAAC) phase three due to reverse causation?

Clin Exp Allergy 2019 04 23;49(4):430-441. Epub 2019 Jan 23.

Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.

Background: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global prevalence of symptoms of asthma in children. We undertook comprehensive analyses addressing risk factors for asthma symptoms in combination, at both the individual and the school level, to explore the potential role of reverse causation due to selective avoidance or confounding by indication.

Objective: To explore the role of reverse causation in risk factors of asthma symptoms.

Methods: We compared two sets of multilevel logistic regression analyses, using (a) individual level exposure data and (b) school level average exposure (ie prevalence), in two different age groups. In individual level analyses, reverse causation is a possible concern if individual level exposure statuses were changed as a result of asthma symptoms or diagnosis. School level analyses may suffer from ecologic confounding, but reverse causation is less of a concern because individual changes in exposure status as a result of asthma symptoms would only have a small effect on overall school exposure levels.

Results: There were 131 924 children aged 6-7 years (2428 schools, 25 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (odds ratio = 2.06; 95% confidence interval 1.97-2.16), early life antibiotic use (1.65; 1.58-1.73) and open fire cooking (1.44; 1.26-1.65). In school level analyses, these risk factors again showed increased risks. There were 238 586 adolescents aged 13-14 years (2072 schools, 42 countries) with complete exposure, outcome and confounder data. The strongest associations in individual level analyses (fully adjusted) were for current paracetamol use (1.80; 1.75-1.86), cooking on an open fire (1.32; 1.22-1.43) and maternal tobacco use (1.23; 1.18-1.27). In school level analyses, these risk factors again showed increased risks.

Conclusions & Clinical Relevance: These analyses strengthen the potentially causal interpretation of previously reported individual level findings, by providing evidence against reverse causation.
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http://dx.doi.org/10.1111/cea.13325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487816PMC
April 2019

Can environment or allergy explain international variation in prevalence of wheeze in childhood?

Eur J Epidemiol 2019 May 11;34(5):509-520. Epub 2018 Nov 11.

Population Health Research Institute, St George's, University of London, London, UK.

Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8-12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence.
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http://dx.doi.org/10.1007/s10654-018-0463-zDOI Listing
May 2019

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Am J Hum Genet 2018 11;103(5):691-706

Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC
November 2018

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Nat Genet 2018 10 17;50(10):1412-1425. Epub 2018 Sep 17.

Laboratory of Genetics and Genomics, NIA/NIH, Baltimore, MD, USA.

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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http://dx.doi.org/10.1038/s41588-018-0205-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284793PMC
October 2018

Are noise and air pollution related to the incidence of dementia? A cohort study in London, England.

BMJ Open 2018 09 11;8(9):e022404. Epub 2018 Sep 11.

MRC-PHE Centre for Environment and Health, King's College London, London, UK.

Objective: To investigate whether the incidence of dementia is related to residential levels of air and noise pollution in London.

Design: Retrospective cohort study using primary care data.

Setting: 75 Greater London practices.

Participants: 130 978 adults aged 50-79 years registered with their general practices on 1 January 2005, with no recorded history of dementia or care home residence.

Primary And Secondary Outcome Measures: A first recorded diagnosis of dementia and, where specified, subgroups of Alzheimer's disease and vascular dementia during 2005-2013. The average annual concentrations during 2004 of nitrogen dioxide (NO), particulate matter with a median aerodynamic diameter ≤2.5 µm (PM) and ozone (O) were estimated at 20×20 m resolution from dispersion models. Traffic intensity, distance from major road and night-time noise levels (L) were estimated at the postcode level. All exposure measures were linked anonymously to clinical data via residential postcode. HRs from Cox models were adjusted for age, sex, ethnicity, smoking and body mass index, with further adjustments explored for area deprivation and comorbidity.

Results: 2181 subjects (1.7%) received an incident diagnosis of dementia (39% mentioning Alzheimer's disease, 29% vascular dementia). There was a positive exposure response relationship between dementia and all measures of air pollution except O, which was not readily explained by further adjustment. Adults living in areas with the highest fifth of NO concentration (>41.5 µg/m) versus the lowest fifth (<31.9 µg/m) were at a higher risk of dementia (HR=1.40, 95% CI 1.12 to 1.74). Increases in dementia risk were also observed with PM, PM specifically from primary traffic sources only and L, but only NO and PM remained statistically significant in multipollutant models. Associations were more consistent for Alzheimer's disease than vascular dementia.

Conclusions: We have found evidence of a positive association between residential levels of air pollution across London and being diagnosed with dementia, which is unexplained by known confounding factors.
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http://dx.doi.org/10.1136/bmjopen-2018-022404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144407PMC
September 2018

Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Wellcome Open Res 2018 12;3. Epub 2018 Jan 12.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC 27514, USA.

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
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http://dx.doi.org/10.12688/wellcomeopenres.12583.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081985PMC
January 2018

Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 09;50(9):1343

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0197-6DOI Listing
September 2018

Retinal Vasculometry Associations with Cardiometabolic Risk Factors in the European Prospective Investigation of Cancer-Norfolk Study.

Ophthalmology 2019 01 1;126(1):96-106. Epub 2018 Aug 1.

Integrative Epidemiology Research Group, UCL Institute of Ophthalmology, London, United Kingdom; NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, United Kingdom.

Purpose: To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women.

Design: Retinal imaging examination as part of the European Prospective Investigation into Cancer-Norfolk Eye Study.

Participants: Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry.

Methods: Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width.

Main Outcomes Measures: Retinal arteriolar and venular tortuosity and width.

Results: In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%-3.3% per 5 kg/m), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%-3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%-10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2-2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3-0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4-1.0 per 5 kg/m), HbA1c level (0.4 μm; 95% CI, -0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7-4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3-2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7-2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%-7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%-1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%-6.4%), and in those with prevalent stroke (8.3%; 95% CI, -0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6-1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4-0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0-0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7-1.6 μm per 1 mmol/l).

Conclusions: Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.
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http://dx.doi.org/10.1016/j.ophtha.2018.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302796PMC
January 2019

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 08 16;50(8):1072-1080. Epub 2018 Jul 16.

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.
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http://dx.doi.org/10.1038/s41588-018-0157-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068780PMC
August 2018

Persistent variations in national asthma mortality, hospital admissions and prevalence by socioeconomic status and region in England.

Thorax 2018 08 14;73(8):706-712. Epub 2018 May 14.

Population Health Research Institute, St George's, University of London, London, UK.

Background: The UK-wide National Review of Asthma Deaths sought to identify avoidable factors from the high numbers of deaths, but did not examine variation by socioeconomic status (SES) or region.

Methods: We used asthma deaths in England over the period 2002-2015 obtained from national deaths registers, summarised by quintiles of Index of Multiple Deprivation (IMD) and Government Office Region. Emergency asthma admissions were obtained from Hospital Episode Statistics for England 2001-2011. The prevalence of asthma was derived from the Health Survey for England 2010. Associations of mortality, admissions and prevalence with IMD quintile and region were estimated cross-sectionally using incidence rate ratios (IRRs) adjusted for age and sex and, where possible, smoking.

Results: Asthma mortality decreased among more deprived groups at younger ages. Among 5-44 year olds, those in the most deprived quintile, mortality was 19% lower than those in the least deprived quintile (IRR 0.81 (95% CI 0.69 to 0.96). In older adults, this pattern was reversed (45-74 years: IRR 1.37 (1.24-1.52), ≥75 years: IRR 1.30 (1.22-1.39)). In 5-44 year olds the inverse trend with asthma mortality contrasted with large positive associations for admissions (IRR 3.34 (3.30-3.38)) and prevalence of severe symptoms (IRR 2.38 (1.70-3.33)). Prevalence trends remained after adjustment for smoking. IRRs for asthma mortality, admissions and prevalence showed significant heterogeneity between English regions.

Conclusions: Despite asthma mortality, emergency admissions and prevalence decreasing over recent decades, England still experiences significant SES and regional variations. The previously undocumented inverse relation between deprivation and mortality in the young requires further investigation.
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http://dx.doi.org/10.1136/thoraxjnl-2017-210714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204968PMC
August 2018

Molecular genetic overlap between migraine and major depressive disorder.

Eur J Hum Genet 2018 08 11;26(8):1202-1216. Epub 2018 Jul 11.

Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.

Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h = 12%) and MDD (h = 19%), and a significant cross-disorder genetic correlation (r = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (P ≤ 5 × 10) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (P ≤ 0.05) with both migraine and MDD (P = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher's combined gene-based P values that surpassed the genome-wide significance threshold (P ≤ 3.6 × 10). Pathway analysis of genes with P ≤ 1 × 10 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD.
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http://dx.doi.org/10.1038/s41431-018-0150-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057914PMC
August 2018

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

Nat Genet 2018 01 22;50(1):42-53. Epub 2017 Dec 22.

Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
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http://dx.doi.org/10.1038/s41588-017-0014-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901974PMC
January 2018

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

Nat Commun 2017 09 29;8(1):744. Epub 2017 Sep 29.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m for each Mb of total deletion burden (P = 2.5 × 10, 6.0 × 10, and 2.9 × 10). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
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http://dx.doi.org/10.1038/s41467-017-00556-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622064PMC
September 2017

Effect of Early-Life Geohelminth Infections on the Development of Wheezing at 5 Years of Age.

Am J Respir Crit Care Med 2018 02;197(3):364-372

6 Population Health Research Institute, St. George's University of London, London, United Kingdom.

Rationale: Exposures to geohelminths during gestation or early childhood may reduce risk of wheezing illness/asthma and atopy during childhood in tropical regions.

Objectives: To investigate the effect of maternal and early childhood geohelminths on development of wheeze/asthma and atopy during the first 5 years of life.

Methods: A cohort of 2,404 neonates was followed to 5 years of age in a rural district in coastal Ecuador. Data on wheeze were collected by questionnaire and atopy was measured by allergen skin prick test reactivity to 10 allergens at 5 years. Stool samples from mothers and children were examined for geohelminths by microscopy.

Measurements And Main Results: A total of 2,090 (86.9%) children were evaluated at 5 years. Geohelminths were observed in 45.5% of mothers and in 34.1% of children by 3 years. Wheeze and asthma were reported for 12.6% and 5.7% of children, respectively, whereas 14.0% had skin test reactivity at 5 years. Maternal geohelminths were associated with an increased risk of wheeze (adjusted odds ratio, 1.41; 95% confidence interval, 1.06-1.88), whereas childhood geohelminths over the first 3 years of life were associated with reduced risk of wheeze (adjusted odds ratio, 0.70; 95% confidence interval, 0.52-0.96) and asthma (adjusted odds ratio, 0.60; 95% confidence interval, 0.38-0.94) but not skin prick test reactivity. The effects on wheeze/asthma were greatest with later age of first infection, were observed only in skin test-negative children, but were not associated with parasite burden or specific geohelminths.

Conclusions: Although maternal exposures to geohelminths may increase childhood wheeze, childhood geohelminths during the first 3 years may provide protection through a nonallergic mechanism. Registered as an observational study (ISRCTN41239086).
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http://dx.doi.org/10.1164/rccm.201706-1222OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811953PMC
February 2018
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