Publications by authors named "Hanieh Yaghootkar"

77 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 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-021-05570-9DOI Listing
September 2021

Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.

Nat Genet 2021 09 2;53(9):1300-1310. Epub 2021 Sep 2.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00913-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432599PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab204DOI Listing
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db21-0129DOI Listing
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dme.14531DOI Listing
September 2021

Corrigendum to: "Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis" [J Hepatol (2020) 241-251].

J Hepatol 2020 Dec 18;73(6):1594-1595. Epub 2020 Sep 18.

Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK; Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK; Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055539PMC
December 2020

Ethnic Differences in Body Fat Deposition and Liver Fat Content in Two UK-Based Cohorts.

Obesity (Silver Spring) 2020 11 16;28(11):2142-2152. Epub 2020 Sep 16.

Research Centre for Optimal Health, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, London, UK.

Objective: Differences in the content and distribution of body fat and ectopic lipids may be responsible for ethnic variations in metabolic disease susceptibility. The aim of this study was to examine the ethnic distribution of body fat in two separate UK-based populations.

Methods: Anthropometry and body composition were assessed in two separate UK cohorts: the Hammersmith cohort and the UK Biobank, both comprising individuals of South Asian descent (SA), individuals of Afro-Caribbean descent (AC), and individuals of European descent (EUR). Regional adipose tissue stores and liver fat were measured by magnetic resonance techniques.

Results: The Hammersmith cohort (n = 747) had a mean (SD) age of 41.1 (14.5) years (EUR: 374 men, 240 women; SA: 68 men, 22 women; AC: 14 men, 29 women), and the UK Biobank (n = 9,533) had a mean (SD) age of 55.5 (7.5) years (EUR: 4,483 men, 4,873 women; SA: 80 men, 43 women, AC: 31 men, 25 women). Following adjustment for age and BMI, no significant differences in visceral adipose tissue or liver fat were observed between SA and EUR individuals in the either cohort.

Conclusions: Our data, consistent across two independent UK-based cohorts, present a limited number of ethnic differences in the distribution of body fat depots associated with metabolic disease. These results suggest that the ethnic variation in susceptibility to features of the metabolic syndrome may not arise from differences in body fat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.22948DOI Listing
November 2020

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes 2020 12 11;69(12):2806-2818. Epub 2020 Sep 11.

Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10, = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679778PMC
December 2020

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

J Hepatol 2021 01 31;74(1):20-30. Epub 2020 Aug 31.

MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK.

Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.

Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models.

Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], p = 4.8×10) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], p = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (p = 0.002) and lower serum triglycerides (p = 1.5×10). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD.

Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent.

Lay Summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755037PMC
January 2021

Machine Learning based histology phenotyping to investigate the epidemiologic and genetic basis of adipocyte morphology and cardiometabolic traits.

PLoS Comput Biol 2020 08 14;16(8):e1008044. Epub 2020 Aug 14.

Big Data Institute, University of Oxford, Oxford, United Kingdom.

Genetic studies have recently highlighted the importance of fat distribution, as well as overall adiposity, in the pathogenesis of obesity-associated diseases. Using a large study (n = 1,288) from 4 independent cohorts, we aimed to investigate the relationship between mean adipocyte area and obesity-related traits, and identify genetic factors associated with adipocyte cell size. To perform the first large-scale study of automatic adipocyte phenotyping using both histological and genetic data, we developed a deep learning-based method, the Adipocyte U-Net, to rapidly derive mean adipocyte area estimates from histology images. We validate our method using three state-of-the-art approaches; CellProfiler, Adiposoft and floating adipocytes fractions, all run blindly on two external cohorts. We observe high concordance between our method and the state-of-the-art approaches (Adipocyte U-net vs. CellProfiler: R2visceral = 0.94, P < 2.2 × 10-16, R2subcutaneous = 0.91, P < 2.2 × 10-16), and faster run times (10,000 images: 6mins vs 3.5hrs). We applied the Adipocyte U-Net to 4 cohorts with histology, genetic, and phenotypic data (total N = 820). After meta-analysis, we found that mean adipocyte area positively correlated with body mass index (BMI) (Psubq = 8.13 × 10-69, βsubq = 0.45; Pvisc = 2.5 × 10-55, βvisc = 0.49; average R2 across cohorts = 0.49) and that adipocytes in subcutaneous depots are larger than their visceral counterparts (Pmeta = 9.8 × 10-7). Lastly, we performed the largest GWAS and subsequent meta-analysis of mean adipocyte area and intra-individual adipocyte variation (N = 820). Despite having twice the number of samples than any similar study, we found no genome-wide significant associations, suggesting that larger sample sizes and a homogenous collection of adipose tissue are likely needed to identify robust genetic associations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1008044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449405PMC
August 2020

Using genetics to decipher the link between type 2 diabetes and cancer: shared aetiology or downstream consequence?

Diabetologia 2020 09 23;63(9):1706-1717. Epub 2020 Jul 23.

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

Recent developments in the field of genetics have accelerated our understanding of the aetiology of complex diseases. Type 2 diabetes mellitus and cancer are no exception, with large-scale genome-wide association studies (GWAS) facilitating exploration of the underlying pathology. Here, we discuss how genetics studies can be used to investigate the relationship between these complex diseases. Observational epidemiological studies consistently report that people with type 2 diabetes have a higher risk of several types of cancer. Indeed, type 2 diabetes and cancer share many common risk factors, such as obesity, ageing, poor diet and low levels of physical activity. However, questions remain regarding the biological mechanisms that link these two diseases. Large-scale GWAS of type 2 diabetes and cancer allow us to consider the evidence for shared genetic architecture. Several shared susceptibility genes have been identified, yet tissue specificity and direction of effect must be taken into account when considering common genetic aetiology. We also consider how GWAS, and associated techniques such as Mendelian randomisation, allow us to dissect the link between the two diseases and address questions such as 'Does type 2 diabetes cause cancer or is the increased risk observed driven by higher adiposity or another associated metabolic feature?' Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-020-05228-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406536PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyaa082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750946PMC
August 2020

Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis.

J Hepatol 2020 08 2;73(2):241-251. Epub 2020 Apr 2.

Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK; Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK; Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden. Electronic address:

Background & Aims: MRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases.

Methods: First, we performed a genome-wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures.

Results: We identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10). Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective.

Conclusion: The association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at-risk individuals.

Lay Summary: We estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2020.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372222PMC
August 2020

A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.

Diabetes 2020 05 8;69(5):1072-1082. Epub 2020 Jan 8.

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

Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically "favorable adiposity" phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db19-0862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611011PMC
May 2020

The Māori and Pacific specific CREBRF variant and adult height.

Int J Obes (Lond) 2020 03 22;44(3):748-752. Epub 2019 Sep 22.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Background: The CREBRF missense variant (p.Arg457Gln) is paradoxically associated with lower risk of type 2 diabetes, yet higher body mass index (BMI). Here we sought to determine whether this CREBRF variant might be associated with adult height.

Methods: Linear regression was used to analyse the association of the CREBRF minor (A) allele with height in 2286 Māori and Pacific adults living in Aotearoa/New Zealand. A potential type 2 diabetes index event was corrected to account for a bias that may be the cause of paradoxical association between the CREBRF diabetes-protective allele and higher BMI and height.

Results: The CREBRF protective allele was associated with increased adult height (ß = 1.25 cm, P = 3.9 × 10), with the effect being more pronounced in males. The lower odds of diabetes remained similar when analyses were adjusted for height (OR = 0.67-0.65). We found no evidence of a diabetes index event bias to explain the paradoxical effect of CREBRF with either BMI or height and diabetes. The orthologous CREBRF p.Arg457Gln variant was created in knock-in mice to independently assess the effect of the variant, and length was found to be greater in male mice at 8 weeks of age.

Conclusion: These data taken together indicate that CREBRF p.Arg457Gln is associated with taller stature in Māori and Pacific adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-019-0437-6DOI Listing
March 2020

Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration.

J Hepatol 2019 09 19;71(3):594-602. Epub 2019 Jun 19.

Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, UK; Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK. Electronic address:

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases.

Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes.

Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease.

Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases.

Lay Summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2019.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694204PMC
September 2019

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Am J Hum Genet 2019 07 6;105(1):15-28. Epub 2019 Jun 6.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612516PMC
July 2019

Wolcott-Rallison syndrome in Iran: a common cause of neonatal diabetes.

J Pediatr Endocrinol Metab 2019 Jun;32(6):607-613

Genetics of Complex Traits, University of Exeter Medical School, Medical Research - Level 3, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK.

Background Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by neonatal/early-onset non-autoimmune insulin-dependent diabetes, multiple epiphyseal dysphasia and growth retardation. It is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3). We aimed to study the clinical characteristics and frequency of the disease in the Iranian population. Methods We recruited 42 patients who referred to the endocrine and metabolism clinic at Mashhad Imam Reza Hospital with neonatal diabetes. Molecular screening of KCNJ11, INS, ABCC8 and EIF2AK3 was performed at the Exeter Molecular Genetics Laboratory, UK. We calculated the frequency of the disease in 124 patients referred from Iran to the Exeter Molecular Genetics Laboratory for genetic screening and compared it to other countries worldwide. Results We identified seven patients as having Wolcott-Rallison syndrome. Genetic testing confirmed the clinical diagnosis and indicated five novel mutations. Only two patients developed clinical features of the syndrome by 6 months of age. Of all 124 cases of Iranian neonatal diabetes referred to the Exeter Molecular Genetics Laboratory for genetic screening, 28 patients (22.58%) had a recessive mutation in EIF2AK3. Conclusions The results of this study raises awareness of the condition and provides further accurate data on the genetic and clinical presentation of Wolcott-Rallison syndrome in the Iranian population. Our study highlights the importance of genetic testing in patients from consanguineous families with diabetes diagnosed within the first 6 months of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem-2018-0434DOI Listing
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour.

Nat Commun 2019 04 5;10(1):1585. Epub 2019 Apr 5.

Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, EX2 5DW, UK.

Sleep is an essential human function but its regulation is poorly understood. Using accelerometer data from 85,670 UK Biobank participants, we perform a genome-wide association study of 8 derived sleep traits representing sleep quality, quantity and timing, and validate our findings in 5,819 individuals. We identify 47 genetic associations at P < 5 × 10, of which 20 reach a stricter threshold of P < 8 × 10. These include 26 novel associations with measures of sleep quality and 10 with nocturnal sleep duration. The majority of identified variants associate with a single sleep trait, except for variants previously associated with restless legs syndrome. For sleep duration we identify a missense variant (p.Tyr727Cys) in PDE11A as the likely causal variant. As a group, sleep quality loci are enriched for serotonin processing genes. Although accelerometer-derived measures of sleep are imperfect and may be affected by restless legs syndrome, these findings provide new biological insights into sleep compared to previous efforts based on self-report sleep measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09576-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451011PMC
April 2019

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms.

Nat Commun 2019 01 29;10(1):343. Epub 2019 Jan 29.

23andMe Inc., 899W. Evelyn Avenue, Mountain View, CA, 94041, USA.

Being a morning person is a behavioural indicator of a person's underlying circadian rhythm. Using genome-wide data from 697,828 UK Biobank and 23andMe participants we increase the number of genetic loci associated with being a morning person from 24 to 351. Using data from 85,760 individuals with activity-monitor derived measures of sleep timing we find that the chronotype loci associate with sleep timing: the mean sleep timing of the 5% of individuals carrying the most morningness alleles is 25 min earlier than the 5% carrying the fewest. The loci are enriched for genes involved in circadian regulation, cAMP, glutamate and insulin signalling pathways, and those expressed in the retina, hindbrain, hypothalamus, and pituitary. Using Mendelian Randomisation, we show that being a morning person is causally associated with better mental health but does not affect BMI or risk of Type 2 diabetes. This study offers insights into circadian biology and its links to disease in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-08259-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351539PMC
January 2019

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Mol Psychiatry 2020 10 7;25(10):2392-2409. Epub 2019 Jan 7.

Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-018-0313-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515840PMC
October 2020

Using genetics to understand the causal influence of higher BMI on depression.

Int J Epidemiol 2019 06;48(3):834-848

Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, SA, Australia.

Background: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women.

Methods: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways.

Results: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence.

Conclusions: Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ije/dyy223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659462PMC
June 2019

Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype Is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension.

Diabetes 2019 01 23;68(1):207-219. Epub 2018 Oct 23.

Section of Investigative Medicine, Imperial College London, London, U.K.

Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to-subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in , , and , whereas the allele in was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db18-0708DOI Listing
January 2019

Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.

Hum Mol Genet 2019 01;28(1):166-174

Big Data Institute, Li Ka Shing Center for Health Information and Discovery, Oxford University, Oxford, UK.

More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddy327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298238PMC
January 2019

Mosaic Turner syndrome shows reduced penetrance in an adult population study.

Genet Med 2019 04 5;21(4):877-886. Epub 2018 Sep 5.

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

Purpose: Many women with X chromosome aneuploidy undergo lifetime clinical monitoring for possible complications. However, ascertainment of cases in the clinic may mean that the penetrance has been overestimated.

Methods: We characterized the prevalence and phenotypic consequences of X chromosome aneuploidy in a population of 244,848 women over 40 years of age from UK Biobank, using single-nucleotide polymorphism (SNP) array data.

Results: We detected 30 women with 45,X; 186 with mosaic 45,X/46,XX; and 110 with 47,XXX. The prevalence of nonmosaic 45,X (12/100,000) and 47,XXX (45/100,000) was lower than expected, but was higher for mosaic 45,X/46,XX (76/100,000). The characteristics of women with 45,X were consistent with the characteristics of a clinically recognized Turner syndrome phenotype, including short stature and primary amenorrhea. In contrast, women with mosaic 45,X/46,XX were less short, had a normal reproductive lifespan and birth rate, and no reported cardiovascular complications. The phenotype of women with 47,XXX included taller stature (5.3 cm; SD = 5.52 cm; P = 5.8 × 10) and earlier menopause age (5.12 years; SD = 5.1 years; P = 1.2 × 10).

Conclusion: Our results suggest that the clinical management of women with 45,X/46,XX mosaicism should be minimal, particularly those identified incidentally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0271-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752315PMC
April 2019
-->