Publications by authors named "Robin N Beaumont"

53 Publications

Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile.

Diabetologia 2021 Sep 20. Epub 2021 Sep 20.

Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK.

Aims/hypothesis: Higher maternal BMI during pregnancy is associated with higher offspring birthweight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity, coupled with a favourable metabolic profile, in a Mendelian randomisation (MR) study comparing the effect of maternal 'metabolically favourable adiposity' on offspring birthweight with the effect of maternal general adiposity (as indexed by BMI).

Methods: To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birthweight, we performed two-sample MR. We used variants identified in large, published genetic-association studies as being associated with either higher adiposity and a favourable metabolic profile, or higher BMI (n = 442,278 and n = 322,154 for metabolically favourable adiposity and BMI, respectively). We then extracted data on the metabolically favourable adiposity and BMI variants from a large, published genetic-association study of maternal genotype and offspring birthweight controlling for fetal genetic effects (n = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total n = 9323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birthweight and cord-blood biomarkers.

Results: Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birthweight (-94 [95% CI -150, -38] g per 1 SD [6.5%] higher maternal metabolically favourable adiposity, p = 0.001). By contrast, higher maternal BMI was associated with higher offspring birthweight (35 [95% CI 16, 53] g per 1 SD [4 kg/m] higher maternal BMI, p = 0.0002). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures; their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that a higher maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels while a higher maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birthweight but the smaller sample sizes for these analyses meant that the effects were imprecisely estimated. We also found evidence to suggest that higher maternal metabolically favourable adiposity decreases cord-blood leptin while higher maternal BMI increases it.

Conclusions/interpretation: Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birthweight. Higher maternal adiposity can lead to lower offspring birthweight if accompanied by a favourable metabolic profile.

Data Availability: The data for the genome-wide association studies (GWAS) of BMI are available at https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files . The data for the GWAS of body fat percentage are available at https://walker05.u.hpc.mssm.edu .
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http://dx.doi.org/10.1007/s00125-021-05570-9DOI Listing
September 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

Higher adiposity and mental health: Causal inference using Mendelian randomisation.

Hum Mol Genet 2021 Jul 16. Epub 2021 Jul 16.

Genetics of Complex Traits, The College of Medicine and Health, University of Exeter, The RILD Building, RD&E Hospital, Exeter, EX2 5DW.

Higher adiposity is an established risk factor for psychiatric diseases including depression and anxiety. The associations between adiposity and depression may be explained by the metabolic consequences and/or by the psychosocial impact of higher adiposity. We performed one- and two- sample Mendelian Randomisation(MR) in up to 145 668 European participants from the UK Biobank to test for a causal effect of higher adiposity on ten well-validated mental health and wellbeing outcomes derived using the Mental Health Questionnaire (MHQ). We used three sets of adiposity genetic instruments: a) a set of 72 BMI genetic variants, b) a set of 36 favourable adiposity variants and c) a set of 38 unfavourable adiposity variants. We additionally tested causal relationships (1) in men and women separately, (2) in a subset of individuals not taking antidepressants and (3) in non-linear MR models. Two-sample MR provided evidence that a genetically determined one standard deviation (1-SD) higher BMI (4.6 kg/m2) was associated with higher odds of current depression [OR: 1.50, 95%CI: 1.15, 1.95] and lower wellbeing [ß: -0.15, 95%CI: -0.26, -0.04]. Findings were similar when using the metabolically favourable and unfavourable adiposity variants, with higher adiposity associated with higher odds of depression and lower wellbeing scores. Our study provides further evidence that higher BMI causes higher odds of depression and lowers wellbeing. Using genetics to separate out metabolic and psychosocial effects, our study suggests that in the absence of adverse metabolic effects higher adiposity remains causal to depression and lowers wellbeing.
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http://dx.doi.org/10.1093/hmg/ddab204DOI Listing
July 2021

A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor.

PLoS Genet 2021 06 10;17(6):e1009577. Epub 2021 Jun 10.

Shoulder Unit, Princess Elizabeth Orthopaedic Centre, Royal Devon and Exeter Hospital, Exeter, United Kingdom.

Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16-1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren's disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02-1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren's disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.
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http://dx.doi.org/10.1371/journal.pgen.1009577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191964PMC
June 2021

Understanding Factors That Cause Tinnitus: A Mendelian Randomization Study in the UK Biobank.

Ear Hear 2021 Jun 8. Epub 2021 Jun 8.

Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, United Kingdom Genetics of Complex Traits, University of Exeter Medical School, RILD building, Royal Devon and Exeter Hospital, Exeter, United Kingdom Torbay and South Devon NHS Foundation Trust, Newton Road, Torquay, United Kingdom.

Objectives: To investigate the causal role of established risk factors and associated conditions to tinnitus and tinnitus severity in the UK Biobank.

Design: The prospective cohort study with large dataset of >500,000 individuals. The analytical sample of 129,731 individuals in the UK Biobank of European descent. Participants were recruited from National Health Service registries, baseline age range between 37 and 73 years, response rate to baseline survey 6%. Participants were asked subjective questions about tinnitus and its severity. Previously observed associations (n = 23) were confirmed in the UK Biobank using logistic and ordinal regression models. Two-sample Mendelian randomization approaches were then used to test causal relationships between the 23 predictors and tinnitus and tinnitus severity. The main outcome measures were observational and genetic association between key demographics and determinants and two tinnitus outcomes (current tinnitus and tinnitus severity).

Results: Prevalence of tinnitus was 20% and severe tinnitus 3.8%. The observational results are consistent with the previous literature, with hearing loss, older age, male gender, high BMI, higher deprivation, higher blood pressure, smoking history, as well as numerous comorbidities being associated with higher odds of current tinnitus. Mendelian randomization results showed causal correlations with tinnitus. Current tinnitus was predicted by genetically instrumented hearing loss (odds ratio [OR]: 8.65 [95% confidence interval (CI): 6.12 to 12.23]), major depression (OR: 1.26 [95% CI: 1.06 to 1.50]), neuroticism (OR: 1.48 [95% CI: 1.28 to 1.71]), and higher systolic blood pressure (OR: 1.01 [95% CI:1.00 to 1.02]). Lower odds of tinnitus were associated with longer duration in education (OR: 0.74 [95% CI: 0.63 to 0.88]), higher caffeine intake (OR: 0.89 [95% CI: 0.83 to 0.95]) and being a morning person (OR: 0.94 [95% CI: 0.90 to 0.98]). Tinnitus severity was predicted by a higher genetic liability to neuroticism (OR: 1.15 [95% CI: 1.06 to 1.26]) and schizophrenia (OR: 1.02 [95% CI: 1.00 to 1.04]).

Conclusions: Tinnitus data from the UK Biobank confirm established associated factors in the literature. Genetic analysis determined causal relationships with several factors that expand the understanding of the etiology of tinnitus and can direct future pathways of clinical care and research.
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http://dx.doi.org/10.1097/AUD.0000000000001074DOI Listing
June 2021

Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health.

Mol Psychiatry 2021 Jun 8. Epub 2021 Jun 8.

Genetics of Complex Traits, The College of Medicine and Health, University of Exeter, The RILD Building, RD&E Hospital, Exeter, UK.

Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preference on mental health outcomes, including anxiety, depression and general wellbeing and test the hypothesis that more misaligned individuals have poorer mental health and wellbeing using an actigraphy-based measure of circadian misalignment. Multiple Mendelian Randomisation (MR) approaches were used to test causal pathways between diurnal preference and seven well-validated mental health and wellbeing outcomes in up to 451,025 individuals. In addition, observational analyses tested the association between a novel, objective measure of behavioural misalignment (Composite Phase Deviation, CPD) and seven mental health and wellbeing outcomes. Using genetic instruments identified in the largest GWAS for diurnal preference, we provide robust evidence that early diurnal preference is protective for depression and improves wellbeing. For example, using one-sample MR, a twofold higher genetic liability of morningness was associated with lower odds of depressive symptoms (OR: 0.92, 95% CI: 0.88, 0.97). It is possible that behavioural factors including circadian misalignment may contribute in the chronotype depression relationship, but further work is needed to confirm these findings.
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http://dx.doi.org/10.1038/s41380-021-01157-3DOI Listing
June 2021

Genetic Evidence for Different Adiposity Phenotypes and Their Opposing Influences on Ectopic Fat and Risk of Cardiometabolic Disease.

Diabetes 2021 08 12;70(8):1843-1856. Epub 2021 May 12.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Royal Devon & Exeter Hospital, Exeter, U.K.

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants: one with "adverse" metabolic effects (UFA) and the other with, paradoxically, "favorable" metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, and higher fat in subcutaneous and visceral adipose tissue, liver, and pancreas for UFA and a favorable metabolic profile, lower risk of disease, higher CRP and higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for a risk-increasing effect of UFA and protective effect of FA for type 2 diabetes, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting, and treating cardiometabolic diseases.
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http://dx.doi.org/10.2337/db21-0129DOI Listing
August 2021

Common genetic variants with fetal effects on birth weight are enriched for proximity to genes implicated in rare developmental disorders.

Hum Mol Genet 2021 May;30(11):1057-1066

Birth weight is an important factor in newborn survival; both low and high birth weights are associated with adverse later-life health outcomes. Genome-wide association studies (GWAS) have identified 190 loci associated with maternal or fetal effects on birth weight. Knowledge of the underlying causal genes is crucial to understand how these loci influence birth weight and the links between infant and adult morbidity. Numerous monogenic developmental syndromes are associated with birth weights at the extreme ends of the distribution. Genes implicated in those syndromes may provide valuable information to prioritize candidate genes at the GWAS loci. We examined the proximity of genes implicated in developmental disorders (DDs) to birth weight GWAS loci using simulations to test whether they fall disproportionately close to the GWAS loci. We found birth weight GWAS single nucleotide polymorphisms (SNPs) fall closer to such genes than expected both when the DD gene is the nearest gene to the birth weight SNP and also when examining all genes within 258 kb of the SNP. This enrichment was driven by genes causing monogenic DDs with dominant modes of inheritance. We found examples of SNPs in the intron of one gene marking plausible effects via different nearby genes, highlighting the closest gene to the SNP not necessarily being the functionally relevant gene. This is the first application of this approach to birth weight, which has helped identify GWAS loci likely to have direct fetal effects on birth weight, which could not previously be classified as fetal or maternal owing to insufficient statistical power.
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http://dx.doi.org/10.1093/hmg/ddab060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355446PMC
May 2021

Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile.

Diabet Med 2021 Sep 11;38(9):e14531. Epub 2021 Feb 11.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, RILD Level 3, Royal Devon & Exeter Hospital, Exeter, UK.

Aims: Change in weight, HbA , lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression.

Methods: We involved people with type 2 diabetes from two UK-based cohorts: 11,914 individuals with GP follow-up data from the UK Biobank and 723 from Salford. We generated a 'favourable adiposity' genetic score and conducted cross-sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow-up time points with 1-year intervals.

Results: The 'favourable adiposity' genetic score was cross-sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m [0.19,0.40]), but higher high-density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (-0.04 mmol/L [-0.07, -0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow-up. There was a trend for participants with higher 'favourable adiposity' genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid-lowering (0.91 [0.86, 0.97]) and anti-hypertensive medication (0.95 [0.91, 0.99]).

Conclusions: In individuals with type 2 diabetes, having more 'favourable adiposity' alleles is associated with a marginally better lipid profile long-term and having lower odds of requiring lipid-lowering or anti-hypertensive medication in spite of relatively higher adiposity.
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http://dx.doi.org/10.1111/dme.14531DOI Listing
September 2021

Investigating the causal effect of maternal vitamin B12 and folate levels on offspring birthweight.

Int J Epidemiol 2021 03;50(1):179-189

University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia.

Background: Lower maternal serum vitamin B12 (B12) and folate levels have been associated with lower offspring birthweight, in observational studies. The aim of this study was to investigate whether this relationship is causal.

Methods: We performed two-sample Mendelian randomization (MR) using summary data on associations between genotype-B12 (10 genetic variants) or genotype-folate (four genetic variants) levels from: a genome-wide association study of 45 576 individuals (sample 1); and both maternal- and fetal-specific genetic effects on offspring birthweight from the latest Early Growth Genetics consortium meta-analysis with 297 356 individuals reporting their own birthweight and 210 248 women reporting their offspring's birthweight (sample 2). We used the inverse variance weighted method, and sensitivity analyses to account for pleiotropy, in addition to excluding a potentially pleiotropic variant in the FUT2 gene for B12 levels.

Results: We did not find evidence for a causal effect of maternal or fetal B12 levels on offspring birthweight. The results were consistent across the different methods. We found a positive causal effect of maternal folate levels on offspring birthweight [0.146 (0.065, 0.227), which corresponds to an increase in birthweight of 71 g per 1 standard deviation higher folate]. We found some evidence for a small inverse effect of fetal folate levels on their own birthweight [-0.051 (-0.100, -0.003)].

Conclusions: Our results are consistent with evidence from randomized controlled trials that higher maternal folate levels increase offspring birthweight. We did not find evidence for a causal effect of B12 levels on offspring birthweight, suggesting previous observational studies may have been confounded.
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http://dx.doi.org/10.1093/ije/dyaa256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938507PMC
March 2021

Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies.

PLoS Genet 2020 12 7;16(12):e1009191. Epub 2020 Dec 7.

Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom.

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.
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http://dx.doi.org/10.1371/journal.pgen.1009191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721187PMC
December 2020

Telomere length and risk of idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease: a mendelian randomisation study.

Lancet Respir Med 2021 03 13;9(3):285-294. Epub 2020 Nov 13.

Institute of Biomedical & Clinical Science, College of Medicine & Health, University of Exeter, Exeter, UK; Exeter Patients in Collaboration for PF, Exeter, UK. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in about 30% of cases, and a majority of these causal genes are associated with telomere maintenance. Prematurely shortened leukocyte telomere length is associated with IPF and chronic obstructive pulmonary disease (COPD), a disease with similar demographics and shared risk factors. Using mendelian randomisation, we investigated evidence supporting a causal role for short telomeres in IPF and COPD.

Methods: Mendelian randomisation inference of telomere length causality was done for IPF (up to 1369 cases) and COPD (13 538 cases) against 435 866 controls of European ancestry in UK Biobank. Polygenic risk scores were calculated and two-sample mendelian randomisation analyses were done using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort (2668 cases vs 8591 controls) and COPD cohort (15 256 cases vs 47 936 controls).

Findings: In the UK Biobank, a genetically instrumented one-SD shorter telomere length was associated with higher odds of IPF (odds ratio [OR] 4·19, 95% CI 2·33-7·55; p=0·0031) but not COPD (1·07, 0·88-1·30; p=0·51). Similarly, an association was found in the IPF replication cohort (12·3, 5·05-30·1; p=0·0015) and not in the COPD replication cohort (1·04, 0·71-1·53; p=0·83). Meta-analysis of the two-sample mendelian randomisation results provided evidence inferring that shorter telomeres cause IPF (5·81 higher odds of IPF, 95% CI 3·56-9·50; p=2·19 × 10). There was no evidence to infer that telomere length caused COPD (OR 1·07, 95% CI 0·90-1·27; p=0·46).

Interpretation: Cellular senescence is hypothesised as a major driving force in IPF and COPD; telomere shortening might be a contributory factor in IPF, suggesting divergent mechanisms in COPD. Defining a key role for telomere shortening enables greater focus in telomere-related diagnostics, treatments, and the search for a cure in IPF. Investigation of therapies that improve telomere length is warranted.

Funding: Medical Research Council.
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http://dx.doi.org/10.1016/S2213-2600(20)30364-7DOI Listing
March 2021

Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.

Int J Epidemiol 2021 07;50(3):817-828

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

Background: It is established that Alzheimer's disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD.

Methods: We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk.

Results: Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50-0.99). Some other sleep traits (accelerometer-measured 'eveningness' and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated.

Conclusions: Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.
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http://dx.doi.org/10.1093/ije/dyaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271193PMC
July 2021

RETRACTION: Mendelian randomization supports a causative effect of TSH on thyroid carcinoma.

Endocr Relat Cancer 2020 11;27(11):Z1

Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

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http://dx.doi.org/10.1530/ERC-20-0067rDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439130PMC
November 2020

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

A single nucleotide polymorphism genetic risk score to aid diagnosis of coeliac disease: a pilot study in clinical care.

Aliment Pharmacol Ther 2020 10 13;52(7):1165-1173. Epub 2020 Aug 13.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

Background: Single nucleotide polymorphism-based genetic risk scores (GRS) model genetic risk as a continuum and can discriminate coeliac disease but have not been validated in clinic. Human leukocyte antigen (HLA) DQ gene testing is available in clinic but does not include non-HLA attributed risk and is limited by discrete risk stratification.

Aims: To accurately characterise both HLA and non-HLA coeliac disease genetic risk as a single nucleotide polymorphism-based GRS and evaluate diagnostic utility.

Methods: We developed a 42 single nucleotide polymorphism coeliac disease GRS from a European case-control study (12 041 cases vs 12 228 controls) using HLA-DQ imputation and published genome-wide association studies. We validated the GRS in UK Biobank (1237 cases) and developed direct genotyping assays. We tested the coeliac disease GRS in a pilot clinical cohort of 128 children presenting with suspected coeliac disease.

Results: The GRS was more discriminative of coeliac disease than HLA-DQ stratification in UK Biobank (receiver operating characteristic area under the curve [ROC-AUC] = 0.88 [95% CIs: 0.87-0.89] vs 0.82 [95% CIs: 0.80-0.83]). We demonstrated similar discrimination in the pilot clinical cohort (114 cases vs 40 controls, ROC-AUC = 0.84 [95% CIs: 0.76-0.91]). As a rule-out test, no children with coeliac disease in the clinical cohort had a GRS below 38th population centile.

Conclusions: A single nucleotide polymorphism-based GRS may offer more effective and cost-efficient testing of coeliac disease genetic risk in comparison to HLA-DQ stratification. As a comparatively inexpensive test it could facilitate non-invasive coeliac disease diagnosis but needs detailed assessment in the context of other diagnostic tests and against current diagnostic algorithms.
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http://dx.doi.org/10.1111/apt.15826DOI Listing
October 2020

Mendelian randomization supports a causative effect of TSH on thyroid carcinoma.

Endocr Relat Cancer 2020 10;27(10):551-559

Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

Evidence from observational studies suggest a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause-effect relationship is poorly understood and these studies are susceptible to bias and confounding. This study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 UK Biobank participants, using a genetic technique, known as Mendelian randomization (MR). Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. Mendelian randomization provided evidence of a causal link between TSH and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that a 1 s.d. higher genetically instrumented TSH (approximately 0.8 mIU/L) resulted in 4.96-fold higher odds of benign nodular disease (95% CI 2.46-9.99) and 2.00-fold higher odds of thyroid cancer (95% CI 1.09-3.70). Our results thus support a causal role for TSH in both benign nodular thyroid disease and thyroid cancer.
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http://dx.doi.org/10.1530/ERC-20-0067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497356PMC
October 2020

Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study.

Int J Epidemiol 2020 08;49(4):1270-1281

Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.

Background: Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD.

Methods: We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist-hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption.

Results: Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference.

Conclusions: These results provide strong evidence that a higher waist-hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.
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http://dx.doi.org/10.1093/ije/dyaa082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750946PMC
August 2020

Large Copy-Number Variants in UK Biobank Caused by Clonal Hematopoiesis May Confound Penetrance Estimates.

Am J Hum Genet 2020 08 22;107(2):325-329. Epub 2020 Jun 22.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Royal Devon & Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK. Electronic address:

Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413842PMC
August 2020

Clinical features and genetic risk of demyelination following anti-TNF treatment.

J Crohns Colitis 2020 Jun 4. Epub 2020 Jun 4.

IBD Pharmacogenetics Group, University of Exeter, Exeter, UK.

Background: Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and test whether affected patients were genetically predisposed to multiple sclerosis (MS).

Methods: We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF. We compared genetic risk scores (GRS), calculated using carriage of 43 susceptibility loci for MS, in 48 cases to 1219 patients exposed to anti-TNF who did not develop demyelination.

Results: Overall, 39 (74%) cases were female. The median age (range) of patients at time of demyelination was 41.5 years (20.7 - 63.2). The median duration of anti-TNF treatment was 21.3 months (0.5 - 99.4) and 19 (36%) patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord or both. Complete recovery was reported in 12 (23%) patients after a median time of 6.8 months (0.1 - 28.7). After 33.0 months of follow-up partial recovery was observed in 29 (55%) patients, relapsing and remitting episodes in 9 (17%), progressive symptoms in 3 (6%): 2 (4%) patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 x 10-4, SD 0.0039) and controls (mean -1.1×10-3, SD 0.0042) (p=0.23).

Conclusions: Patients who experienced demyelination events following anti-TNF were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa104DOI Listing
June 2020

Does Obesity Cause Thyroid Cancer? A Mendelian Randomization Study.

J Clin Endocrinol Metab 2020 07;105(7)

Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK.

Background: The incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer.

Methods: We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships.

Results: Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90).

Conclusions: Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.
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http://dx.doi.org/10.1210/clinem/dgaa250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274488PMC
July 2020

The influence of transmitted and non-transmitted parental BMI-associated alleles on the risk of overweight in childhood.

Sci Rep 2020 03 16;10(1):4806. Epub 2020 Mar 16.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Overweight in children is strongly associated with parental body mass index (BMI) and overweight. We assessed parental transmitted and non-transmitted genetic contributions to overweight in children from the Danish National Birth Cohort by constructing genetic risk scores (GRSs) from 941 common genetic variants associated with adult BMI and estimating associations of transmitted maternal/paternal and non-transmitted maternal GRS with child overweight. Maternal and paternal BMI (standard deviation (SD) units) had a strong association with childhood overweight [Odds ratio (OR): 2.01 (95% confidence interval (CI) 1.74; 2.34) and 1.64 (95% CI 1.43; 1.89)]. Maternal and paternal transmitted GRSs (SD-units) increased odds for child overweight equally [OR: 1.30 (95% CI 1.16; 1.46) and 1.30 (95% CI 1.16; 1.47)]. However, both the parental phenotypic and the GRS associations may depend on maternal BMI, being weaker among mothers with overweight. Maternal non-transmitted GRS was not associated with child overweight [OR 0.98 (95% CI 0.88; 1.10)] suggesting no specific influence of maternal adiposity as such. In conclusion, parental transmitted GRSs, based on adult BMI, contribute to child overweight, but in overweight mothers other genetic and environmental factors may play a greater role.
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http://dx.doi.org/10.1038/s41598-020-61719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075975PMC
March 2020

Using human genetics to understand the disease impacts of testosterone in men and women.

Nat Med 2020 02 10;26(2):252-258. Epub 2020 Feb 10.

Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
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http://dx.doi.org/10.1038/s41591-020-0751-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025895PMC
February 2020

Effects of body mass index on relationship status, social contact and socio-economic position: Mendelian randomization and within-sibling study in UK Biobank.

Int J Epidemiol 2020 08;49(4):1173-1184

Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Exeter, UK.

Background: We assessed whether body mass index (BMI) affects social and socio-economic outcomes.

Methods: We used Mendelian randomization (MR), non-linear MR and non-genetic and MR within-sibling analyses, to estimate relationships of BMI with six socio-economic and four social outcomes in 378 244 people of European ancestry in UK Biobank.

Results: In MR of minimally related individuals, higher BMI was related to higher deprivation, lower income, fewer years of education, lower odds of degree-level education and skilled employment. Non-linear MR suggested both low (bottom decile, <22 kg/m2) and high (top seven deciles, >24.6 kg/m2) BMI, increased deprivation and reduced income. Non-genetic within-sibling analysis supported an effect of BMI on socio-economic position (SEP); precision in within-sibling MR was too low to draw inference about effects of BMI on SEP. There was some evidence of pleiotropy, with MR Egger suggesting limited effects of BMI on deprivation, although precision of these estimates is also low. Non-linear MR suggested that low BMI (bottom three deciles, <23.5 kg/m2) reduces the odds of cohabiting with a partner or spouse in men, whereas high BMI (top two deciles, >30.7 kg/m2) reduces the odds of cohabitation in women. Both non-genetic and MR within-sibling analyses supported this sex-specific effect of BMI on cohabitation. In men only, higher BMI was related to lower participation in leisure and social activities. There was little evidence that BMI affects visits from friends and family or having someone to confide in.

Conclusions: BMI may affect social and socio-economic outcomes, with both high and low BMI being detrimental for SEP, although larger within-family MR studies may help to test the robustness of MR results in unrelated individuals. Triangulation of evidence across MR and within-family analyses supports evidence of a sex-specific effect of BMI on cohabitation.
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http://dx.doi.org/10.1093/ije/dyz240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750981PMC
August 2020

A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.

Hum Mol Genet 2019 12;28(24):4197-4207

Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK.

Raised albumin-creatinine ratio (ACR) is an indicator of microvascular damage and renal disease. We aimed to identify genetic variants associated with raised ACR and study the implications of carrying multiple ACR-raising alleles with metabolic and vascular-related disease. We performed a genome-wide association study of ACR using 437 027 individuals from the UK Biobank in the discovery phase, 54 527 more than previous studies, and followed up our findings in independent studies. We identified 62 independent associations with ACR across 56 loci (P < 5 × 10-8), of which 20 were not previously reported. Pathway analyses and the identification of 20 of the 62 variants (at r2 > 0.8) coinciding with signals for at least 16 related metabolic and vascular traits, suggested multiple pathways leading to raised ACR levels. After excluding variants at the CUBN locus, known to alter ACR via effects on renal absorption, an ACR genetic risk score was associated with a higher risk of hypertension, and less strongly, type 2 diabetes and stroke. For some rare genotype combinations at the CUBN locus, most individuals had ACR levels above the microalbuminuria clinical threshold. Contrary to our hypothesis, individuals carrying more CUBN ACR-raising alleles, and above the clinical threshold, had a higher frequency of vascular disease. The CUBN allele effects on ACR were twice as strong in people with diabetes-a result robust to an optimization-algorithm approach to simulating interactions, validating previously reported gene-diabetes interactions (P ≤ 4 × 10-5). In conclusion, a variety of genetic mechanisms and traits contribute to variation in ACR.
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http://dx.doi.org/10.1093/hmg/ddz243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246045PMC
December 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

The Effect of Genetic Variation on the Placental Transcriptome in Humans.

Front Genet 2019 11;10:550. Epub 2019 Jun 11.

Human Genetics Research Group, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.

The knowledge of genetic variants shaping human placental transcriptome is limited and they are not cataloged in the Genotype-Tissue Expression project. So far, only one whole genome analysis of placental expression quantitative trait loci (eQTLs) has been published by Peng et al. (2017) with no external independent validation. We report the second study on the landscape of placental eQTLs. The study aimed to generate a high-confidence list of placental -eQTLs and to investigate their potential functional implications. Analysis of -eQTLs (±100 kbp from the gene) utilized 40 placental RNA sequencing and respective whole genome genotyping datasets. The identified 199 placental -eSNPs represented 88 independent eQTL signals (FDR < 5%). The most significant placental eQTLs (FDR < 10) modulated the expression of ribosomal protein RPL9, transcription factor ZSCAN9 and aminopeptidase ERAP2. The analysis confirmed 50 eSNP-eGenes pairs reported by Peng et al. (2017) and thus, can be claimed as robust placental eQTL signals. The study identified also 13 novel placental eGenes. Among these, is modulated by several eSNPs (experimentally validated: rs1150707) that have been also shown to affect the methylation level of genes variably escaping X-chromosomal inactivation. The identified 63 placental eGenes exhibited mostly mixed or ubiquitous expression. Functional enrichment analysis highlighted 35 Gene Ontology categories with the top ranking pathways "ruffle membrane" (FDR = 1.81 × 10) contributing to the formation of motile cell surface and "ATPase activity, coupled" (FDR = 2.88 × 10), critical for the membrane transport. Placental eGenes were also significantly enriched in pathways implicated in development, signaling and immune function. However, this study was not able to confirm a significant overrepresentation of genome-wide association studies top hits among the placental eSNP and eGenes, reported by Peng et al. (2017). The identified eSNPs were further analyzed in association with newborn and pregnancy traits. In the discovery step, a suggestive association was detected between the eQTL of (rs11678251) and reduced placental, newborn's and infant's weight. Meta-analysis across REPROMETA, HAPPY PREGNANCY, ALSPAC cohorts ( = 6830) did not replicate these findings. In summary, the study emphasizes the role of genetic variation in driving the transcriptome profile of the human placenta and the importance to explore further its functional implications.
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http://dx.doi.org/10.3389/fgene.2019.00550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581026PMC
June 2019

Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis.

PLoS Med 2019 06 18;16(6):e1002828. Epub 2019 Jun 18.

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

Background: Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.

Methods And Findings: We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.

Conclusions: Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.
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http://dx.doi.org/10.1371/journal.pmed.1002828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581250PMC
June 2019

Genome-Wide Association Study of Microscopic Colitis in the UK Biobank Confirms Immune-Related Pathogenesis.

J Crohns Colitis 2019 Dec;13(12):1578-1582

Genetics of Complex Traits, University of Exeter Medical School, Exeter, UK.

Background And Aims: The causes of microscopic colitis are currently poorly understood. Previous reports have found clinical associations with coeliac disease and genetic associations at the human leukocyte antigen [HLA] locus on the ancestral 8.1 haplotype. We investigated pharmacological and genetic factors associated with microscopic colitis in the UK Biobank.

Methods: In total, 483 European UK Biobank participants were identified by ICD10 coding, and a genome-wide association study was performed using BOLT-LMM, with a sensitivity analysis performed excluding potential confounders. The HLA*IMP:02 algorithm was used to estimate allele frequency at 11 classical HLA genes, and downstream analysis was performed using FUMA. Genetic overlap with inflammatory bowel disease [Crohn's disease and ulcerative colitis] was investigated using genetic risk scores.

Results: We found significant phenotypic associations with smoking status, coeliac disease and the use of proton-pump inhibitors but not with other commonly reported pharmacological risk factors. Using the largest sample size to date, we confirmed a recently reported association with the MHC Ancestral 8.1 Haplotype. Downstream analysis suggests association with digestive tract morphogenesis. By calculating genetic risk scores, we also report suggestive evidence of shared genetic risk with Crohn's disease, but not with ulcerative colitis.

Conclusions: This report confirms the role of genetic determinants in the HLA in the pathogenesis of microscopic colitis. The genetic overlap with Crohn's disease suggests a common underlying mechanism of disease.
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http://dx.doi.org/10.1093/ecco-jcc/jjz104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903793PMC
December 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019
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