1,721,582 research outputs found
Stress and glucocorticoid treatment during pregnancy, early growth and metabolic outcomes in childhood
Full text linkBackground: Variation in birth size has been linked to increased risk of a number of disorders later in life, including cardiovascular and metabolic disorders. However, less is known about other parameters of birth size, beyond birth weight, on later health. Moreover, the impact of the biological markers of stress, i.e. glucocorticoids, on various parameters of birth size remains understudied as well as their impact on later metabolic outcomes.
Aims and objectives: The aim of this study was to examine the influence of the HPA axis on birth size (birth weight, ponderal index, birth length, head circumference) and subsequent metabolic health in adolescence. The main predictor being exposure to glucocorticoids either administered clinically or inferred as a result of maternal social stress. The genetic environment interplay of birth weight lowering alleles near LEKR and CCNL1 and in ADCY5 was also examined.
Methods: Data came from the Northern Finland Birth Cohort (NFBC1986), and the National Finnish Medical Birth Registry (MBR) 2006-2010. Glucocorticoid treatment (sGC) to mature foetal lung in threatened preterm birth, social stress measures, and birth outcomes were obtained from medical records and via maternal report (in NFBC1986) during pregnancy. Data on NFBC1986 children at 16 years included anthropometry, blood pressure, blood sample for DNA, and metabolic outcomes. Results: The systematic literature review showed a dearth of information on the association of sGC on birth size, with the larger studies reporting smaller birth size in infants exposed to sGC. The NFBC1986 cohort showed only 17% (n=58) preterm infants had received sGC due to threatened preterm birth, with an association with smaller birth length of -0.18cm(95%CI -0.26, -0.10), but a larger birth weight of 116g(95%CI 98.9, 133.1) and head circumference of 0.75cm(95%CI 0.7, 0.81). In contrast, in the MBR (5090 exposed subjects) sGC treatment was consistently associated with lower birth weight of -207g(95%CI -220, -195), birth length of -1.26cm(95%CI -1.31, -1.20), head circumference of -0.94cm(95%CI -0.98, -0.90), and ponderal index of -0.91 (95%CI-1.02, -0.81). Maternal social stress during pregnancy and risk allele near LEKR and CCNL1 each was associated with smaller birth size. The association with stress was magnified with lower birth weight of -118g(95%CI -156, -79), birth length of -0.30cm(95%CI -0.46, -0.14), head circumference of -0.23cm(-0.35, -0.11), and ponderal index of -0.47(95%CI -0.67, -0.26) in the presence of risk allele. No robust association was found between maternal social stress during pregnancy and metabolic syndrome at 16 years. There was an association with more adverse lipid profile in particular with apolipoprotein B/A ratio (1.92% increase, 95%CI 0.34, 3.52, by maternal exposure to social stress).
Conclusion: Stress and exposure to sGC during pregnancy in addition to genetic risk are related to smaller birth size. In the NFBC1986 there was no evidence of longer term impact of in utero stress exposure on metabolic syndrome in adolescence, though there was a poorer lipid profile noted. To better understand the degree to which the HPA axis plays in foetal programming, maternal and foetal cortisol levels during pregnancy would be beneficial.Open Acces
Genetic and environmental correlates of growth patterns leading to obesity
Full text linkThe intrauterine period is a vulnerable period of development. Any adverse environment can permanently change the body’s organ structure and function, expressed as an increased disease risk later in life. Studies show that variability in growth patterns in early life is associated with obesity and other cardiovascular diseases in adulthood, but the genetic and environmental determinants of these processes are largely unknown.
The main objectives of this study were to identify genetic and environmental pre- and postnatal factors associated with early growth in infancy and childhood and later metabolic outcomes in adulthood from the Northern Finland Birth Cohorts (NFBCs).
Several maternal and paternal factors, such as height, smoking, parity and pre-eclampsia, had direct association with faster postnatal height growth, some of which had their association mediated by size-at-birth variables. It was observed that an obesogenic environment in utero and during a child’s growth exerts a ‘programming’ effect on the glucose-insulin axis as well as other cardio-vascular risk factors in adolescence. Moreover, the study shows that Leukocyte Telomere Length (LTL) at 31 years, a marker for aging, is inversely associated with multiple measures of adiposity in both men and women, and that a BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31. Two new genetic variants in/near SBNO1 and HMGA2 genes are associated with infant head circumference, which may indicate influence of brain growth and neurodevelopment via early life. Variants in/near LEPR-LEPROT, FTO, TFAP2B and GNPDA2 showed an age-dependent association with adiposity in early childhood, while three loci (FTO, TFAP2B and GNPDA2) had their effect on adult adiposity mediated by early growth phenotypes.
This study emphasises the clinical importance of early growth markers as they may inform public health policy aimed at improving the pre-pregnancy environment and to monitor childhood growth during the first few years of development.Open Acces
Investigation of Alexithymia and related psychological factors in relation to body mass index and obesity
Full text linkCommon obesity is thought to be the result of genetic variations influencing susceptibility to environmental circumstances related to food intake, mediated by appetite-regulating pathways, and also affected by emotional processing and other behavioural traits. Alexithymia is a psychological construct for emotional processing deficits, characterised by impaired identification and description of feelings, and externally-oriented thinking.
Here, I investigate the relationship between alexithymia, measured by the 20-item Toronto Alexithymia scale (TAS-20), and adiposity in two Northern Finland Birth Cohorts (NFBC1966 and NFBC1986) and in severely-obese adults seeking bariatric surgery in the UK (PMMO clinical trial). Analysis of depression as a possible contributing factor in the relationship between alexithymia and obesity was also conducted in the NFBC1966. Consistent associations between BMI and TAS-20 total scores were observed among adult and adolescent general populations and in severely-obese adults (pre- and post-surgery, assessed longitudinally). Males with clinically-relevant alexithymia status (TAS-20≥ 61) and history of depression diagnosis had higher BMI than males without, at age of 31 years in NFBC1966. In the severe obesity clinical trial cohort (PMMO), participants with history of clinical depression diagnosis had higher TAS-20 total scores and weight at baseline than those who had no clinical depression history. Depression and bariatric surgery type were also moderately associated with TAS-20 total scores after surgery.
A genome-wide association study was conducted to identify genetic variants influencing psychological measures (TAS-20 and HSCL-13 scores) in the general adult and adolescent populations. In the NFBC1966 dataset, one SNP, rs2242223 (p= 8.10 x 10-8) in the Parkinson’s disease gene SNCAIP (synuclein alpha interacting protein) was associated with TAS-20 score. There were also significant sex and genotype interactions.
These findings raise intriguing questions regarding the direction of causal mechanisms between emotional processing and obesity. Design of treatment strategies for complex conditions, such as obesity, would benefit from enhanced understanding of underlying psychological/behavioural components in the general population and clinical patients.Open Acces
Statistical association networks as complex phenotypes : new methods and applications
Full text linkRecent advances in ’omics technologies and the development of new computational techniques have greatly contributed to the identification of factors influencing the onset and progression of many common diseases. Yet, despite this great success, it is unlikely that the independent analysis of these data
will elucidate the complex web of mechanisms involved in disease development. To enhance our knowledge of disease aetiology, new approaches for linking the large amount of available data need to be developed.
As a step towards this goal, the aim of this thesis is to investigate and develop novel statistical methods for the integrative analysis of ’omic data. In particular, in this project we analyse genomic and metabolomic data in relation to the health outcomes in three study populations. To investigate
how genetic and metabolic variables act as risk factors in the development of complex disorders, we have developed three novel analytical methodologies, namely ’Differential Network’, ’GEMINi: GEnome Metabolome Integrated Network analysis’ and ’Variance and Covariance regression’ and illustrate
their use on real data sets.
The results demonstrate the applicability of the new methodologies to identify key molecular changes undetectable with standard approaches. The approaches introduce here have the potential of providing insight into the biological basis of phenotypic variation and aid the generation of new hypotheses about molecular control and regulation in the context of systems biology.Open Acces
The genetic and life course epidemiology of familial adiposity
Full text linkThe developmental overnutrition hypothesis proposes that prenatal exposure to maternal obesity causes increased risk of obesity and cardiometabolic disease in the offspring in subsequent adult life. Maternal body mass index (BMI) before or during pregnancy is positively associated with offspring adiposity from birth to adulthood, and with adult cardiometabolic disease incidence and mortality, but whether these associations are causal remains uncertain. This thesis aimed to investigate whether greater maternal BMI before or during pregnancy causes greater offspring adiposity in childhood and adolescence, and whether maternal BMI is associated with an adverse offspring cardiometabolic risk factor profile in adulthood. I analysed data from five European prospective birth cohorts: the Northern Finland Birth Cohorts (NFBCs) 1966 and 1986, the Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB) and Generation R, as well as the UK Biobank. I applied polygenic risk scoring (PRS), intergenerational Mendelian randomization (MR), bivariate Genomic Restricted Maximum Likelihood implemented in the GCTA software package (bivariate GCTA-GREML) and maternal GCTA-GREML. In NFBC1966, greater maternal BMI was associated with greater offspring adiposity and insulin resistance in adulthood, but these associations were somewhat attenuated on adjustment for a PRS partially capturing the offspring’s genetic predisposition to increased BMI. In ALSPAC and BiB, MR analyses suggested that maternal BMI does not have a large causal effect on offspring adiposity in late childhood and adolescence. Bivariate GCTA-GREML analyses in five cohorts showed that imputed offspring single nucleotide polymorphisms (SNPs) explained up to half of the phenotypic covariance between maternal BMI and offspring child and adolescent adiposity. Maternal GCTA-GREML analyses in ALSPAC and BiB showed that genetic confounding (the direct effects of maternal alleles inherited by the offspring) is an important explanation for this. My findings suggest that interventions aimed at reducing pre-conceptional adiposity in women are of uncertain effectiveness as a means to reduce offspring obesity risk.Open Acces
Robust approaches for performing meta-analysis of genome-wide association studies to identify single nucleotide polymorphisms and copy number variations associated with complex traits
Full text linkFrom 2007, there has been a huge proliferation in the discovery of genetic variants affecting human traits and diseases, achieved largely by the integration of multiple genome-wide association studies (GWAS) via meta-analysis. The principal objective of this thesis is to develop robust approaches for meta-analysis GWAS in order to reduce false positive findings and optimise statistical power. I consider both Single Nucleotide Polymorphism (SNP) and Copy Number Variant (CNV) GWAS. First, to gain background knowledge in GWAS and meta-analysis, I was involved in a large-scale meta-analysis GWAS to identify genetic variants associated with alcohol consumption, as the main statistical analyst. This study provided me with the opportunity to investigate ways of reducing the probability of false positive findings, via quality control procedures. The main discovery from the study was the identification of the Autism susceptibility candidate 2 gene (AUTS2) as associated with alcohol consumption at genome-wide significance. In the alcohol study, different phenotype transformations were applied to the data according to the inclusion or exclusion of non-drinkers, which led to questioning which transformation of skewed continuous phenotypes optimises statistical power in GWAS in general, forming the second major investigation in my thesis. It was shown that while the inverse normal transformation (INT) may not be the preferable choice of transformation in many epidemiological studies where effect sizes are large, its application to non-normal phenotypes in GWAS, where effect sizes are small and the priority is discovery over interpretability, may lead to an increase in the discovery of genetic variants affecting continuous traits. Finally, as knowledge about CNVs has accumulated in recent years, the meta-analysis of GWAS on CNVs has become a natural next step forward in the field. Therefore, I investigated and developed an approach to enable CNV meta-analysis to proceed in a similar way as SNP meta-analyses. This approach was developed into a software package, cnvPipe, which was applied to investigate CNVs associated with height and weight in the meta-analysis setting.Open Acces
Worldwide trends in body-mass index by urban and rural place of residence
Full text linkMore than one half of the global population lives in urban areas. Urbanisation is often implicated as a driver of the global obesity epidemic. The empirical basis for this claim, however, is often limited data in one or a small number of countries and in limited age and sex groups. My thesis aimed to systematically quantify body-mass index (BMI) trends for children, adolescents and adults in the urban and rural areas of 200 countries and territories. Data on BMI were collated, via the NCD Risk Factor Collaboration (NCD-RisC) network, from population-based surveys that measured height and weight. Data were pooled from 1,154 surveys for the analysis of trends in children and adolescents from 1990 to 2016, and 1,842 surveys for the analysis of trends in adults from 1985 to 2016. I used a Bayesian hierarchical model to estimate urban and rural population mean BMI in each country and year, by sex and age-group. In 2016, mean BMI of children and adolescents living in urban areas was higher than that of their rural peers in almost all countries. The rise in mean BMI from 1990 to 2016 was steeper among urban than among rural boys and girls in all regions, except sub-Saharan Africa and South Asia. By contrast, mean BMI of urban and rural adults in low- and middle-income regions, particularly women, converged from 1985 to 2016, driven by a steeper rise in rural areas. Sub-Saharan Africa was the exception, where urban excess grew for women. In high-income and industrialised regions there was a rural excess in mean BMI for adults in 2016. The rise in mean BMI of rural populations was the largest contributor to the overall rise in BMI in low- and middle-income regions, and the world as a whole. Whereas, the contribution of urbanisation to the rise was at most 17% across all regions. My findings thus challenge the current paradigm that urbanisation is driving the global obesity epidemic and motivate a focus on rural populations if the worldwide BMI rise is to be curtailed. The availability, affordability and accessibility of healthy versus unhealthy foods must be confronted and action taken to create environments that promote healthy diets.Open Acces
Investigating the role of nuclear encoded mitochondrial genes in the onset of type 2 diabetes
Full text linkMitochondrial dysfunction has long been implicated in Type 2 diabetes (T2D). This rela- tionship appears to be bidirectional, with evidence that mitochondrial dysfunction is both caused by and causal of T2D-related phenotypes. A potential causal role in T2D onset would be supported by evidence of a genetic predisposition to mitochondrial dysfunction, since inherited genetic risk factors precede and contribute to disease onset. Here, a genetic study design is used to investigate the potential role of T2D-associated genetic risk loci (T2D loci) in disrupting mitochondrial function through the altered expression of nuclear- encoded mitochondrial genes (NEMGs). The mitochondria are targeted by multiple T2D drugs and therefore such loci may be informative for effective treatment and prevention measures. The functional cis–genes regulated by T2D loci were identified based on the co-location of T2D loci with adipose tissue expression quantitative trait (eQTL) within a genetic distance of 1 LDU. T2D loci and eQTL were previously mapped using LDU- based gene mapping, which is compared and contrasted in this thesis to other popular tests of association. 50 of the identified T2D cis–genes were NEMGs and implicated a number of pathways in the inherited risk of T2D, including the relevant pathway of branched-chain amino acid catabolism. These same 50 genes were enriched for decreased expression in T2D cases compared to controls in independent gene expression datasets. Compared to the total known NEMGs, the 50 cis-NEMGs showed further enrichment for decreased expression, suggesting that T2D-eQTL co-location may identify specific subsets of causal genes. Finally, a candidate T2D locus associated with the cis–NEMG ACAD11 was fine-mapped using targeted sequence data for 94 T2D cases and 94 controls. Sev- eral candidate causal variants were identified, including two low-frequency haplotypes, one of which contained both an ACAD11 splicing mutation and a mutation predicted to disrupt the observed binding of HNF4A and COUP-TFII within the ACAD11 promoter region.Open Acces
The genetic basis of urinary incontinence in women
Full text linkBackground: Both urgency and stress urinary incontinence are heritable, with genetic factors contributing approximately half of total susceptibility.
Aims: The overall aim of this project is to identify known and novel genetic polymorphisms associated with urgency and stress incontinence in women.
Design: We systematically reviewed prior genetic association studies of incontinence, and other pelvic floor disorders. We then conducted a two stage GWAS, using women enrolled in NFBC1966, UK Twins, and ALSPAC for discovery, and women in six separate cohorts for replication. To prioritise likely susceptibility genes we measured gene expression in bladder biopsies, using whole genome microarrays, and PCR using custom microfluidic plates.
Results: From prior studies of incontinence, and the related condition of prolapse among women, we conducted 13 meta-analyses for different polymorphisms, finding a single moderately credible association for a common variant in the ADRB3 gene associated with overactive bladder. From prior studies of lower urinary tract symptoms in men, we conducted 35 meta-analyses for different polymorphisms, finding a single moderately credible association for a common variant in the VDR gene associated with a composite of symptoms.
For the GWAS discovery phase 8,997 women provided both incontinence phenotypes and genome wide genotypes. In meta-analysis, five loci included at least one genome-wide significant variant (p<5x10-8). Twelve loci were taken forward for replication, with two demonstrating robust replication. In bladder biopsies we identified 1,115 significantly differentially expressed genes between stress and urgency incontinence. In the context of the previous literature, these results suggested EN1 and EDN1 as the most likely causal genes within the two replicated GWAS significant loci.
Conclusions: This work highlights many of the challenges of identification of risk variants for complex conditions such as incontinence. The discovery of two novel risk loci for incontinence represents a significant advance in understanding the pathophysiology of these conditions.Open Acces
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