A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed ...individuals go on to develop psychosis. One possibility is pre-existing genetic vulnerability. Research on gene-environment interaction in psychosis has primarily focused on candidate genes, although the genetic effects are now known to be polygenic. This pilot study investigated whether the effect of childhood adversity on psychosis is moderated by the polygenic risk score for schizophrenia (PRS). Data were utilised from the Genes and Psychosis (GAP) study set in South London, UK. The GAP sample comprises 285 first-presentation psychosis cases and 256 unaffected controls with information on childhood adversity. We studied only white subjects (80 cases and 110 controls) with PRS data, as the PRS has limited predictive ability in patients of African ancestry. The occurrence of childhood adversity was assessed with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and the PRS was based on genome-wide meta-analysis results for schizophrenia from the Psychiatric Genomics Consortium. Higher schizophrenia PRS and childhood adversities each predicted psychosis status. Nevertheless, no evidence was found for interaction as departure from additivity, indicating that the effect of polygenic risk scores on psychosis was not increased in the presence of a history of childhood adversity. These findings are compatible with a multifactorial threshold model in which both genetic liability and exposure to environmental risk contribute independently to the etiology of psychosis.
The "thrifty genotype" hypothesis proposes that the high prevalence of type 2 diabetes (T2D) in Native Americans and admixed Latin Americans has a genetic basis and reflects an evolutionary ...adaptation to a past low calorie/high exercise lifestyle. However, identification of the gene variants underpinning this hypothesis remains elusive. Here we assessed the role of Native American ancestry, socioeconomic status (SES) and 21 candidate gene loci in susceptibility to T2D in a sample of 876 T2D cases and 399 controls from Antioquia (Colombia). Although mean Native American ancestry is significantly higher in T2D cases than in controls (32% v 29%), this difference is confounded by the correlation of ancestry with SES, which is a stronger predictor of disease status. Nominally significant association (P<0.05) was observed for markers in: TCF7L2, RBMS1, CDKAL1, ZNF239, KCNQ1 and TCF1 and a significant bias (P<0.05) towards OR>1 was observed for markers selected from previous T2D genome-wide association studies, consistent with a role for Old World variants in susceptibility to T2D in Latin Americans. No association was found to the only known Native American-specific gene variant previously associated with T2D in a Mexican sample (rs9282541 in ABCA1). An admixture mapping scan with 1,536 ancestry informative markers (AIMs) did not identify genome regions with significant deviation of ancestry in Antioquia. Exclusion analysis indicates that this scan rules out ~95% of the genome as harboring loci with ancestry risk ratios >1.22 (at P < 0.05).
Abstract Adults with schizophrenia present cognitive impairments, as do individuals at ultra-high risk for the disorder, youth with relatives with schizophrenia spectrum disorders, and children with ...antecedents of schizophrenia. The present study aimed to determine if impairments in childhood differed depending on the definition of risk and/or on the degree of relatedness to an affected individual, and if impairments were explained by IQ. Four groups of children aged 9–12 years were studied: (1) 13 children with ≥1 first-degree or ≥2 second-degree affected relatives (high familial loading: FHxH ); (2) 14 with ≥1 affected second-degree relative (lower familial loading: FHxL ); (3) 32 with well-replicated antecedents of schizophrenia (ASz); and (4) 45 typically-developing (TD) children with neither a positive family history nor antecedents. Compared to TD children, both FHxH and ASz children exhibited significantly poorer verbal comprehension, scholastic achievement, and verbal working memory, while FHxH children additionally displayed significantly lower full-scale IQ, and verbal memory and executive function impairments. After adjusting statistical analyses for IQ, group differences were attenuated. Relative to TD children, FHxL children showed no significant differences in performance. The results imply that impairments in verbal comprehension, scholastic achievement, and verbal working memory may index vulnerability for schizophrenia among children with affected relatives with the disorder and among those with multiple antecedents of the disorder who have no affected relatives. More accurate identification of children at-risk for schizophrenia and the specific deficits that they present provides opportunities for interventions such as cognitive remediation that may impact the development of the illness.
ABSTRACT
Construction of multifactorial disease models from epidemiological findings and their application to disease pedigrees for risk prediction is nontrivial for all but the simplest of cases. ...Multifactorial Disease Risk Calculator is a web tool facilitating this. It provides a user‐friendly interface, extending a reported methodology based on a liability‐threshold model. Multifactorial disease models incorporating all the following features in combination are handled: quantitative risk factors (including polygenic scores), categorical risk factors (including major genetic risk loci), stratified age of onset curves, and the partition of the population variance in disease liability into genetic, shared, and unique environment effects. It allows the application of such models to disease pedigrees. Pedigree‐related outputs are (i) individual disease risk for pedigree members, (ii) n year risk for unaffected pedigree members, and (iii) the disease pedigree's joint liability distribution. Risk prediction for each pedigree member is based on using the constructed disease model to appropriately weigh evidence on disease risk available from personal attributes and family history. Evidence is used to construct the disease pedigree's joint liability distribution. From this, lifetime and n year risk can be predicted. Example disease models and pedigrees are provided at the website and are used in accompanying tutorials to illustrate the features available. The website is built on an R package which provides the functionality for pedigree validation, disease model construction, and risk prediction. Website: http://grass.cgs.hku.hk:3838/mdrc/current
The obesity epidemic may have substantial implications for the global workforce, including causal effects on employment, but clear evidence is lacking. Obesity may prevent people from being in paid ...work through poor health or through social discrimination. We studied genetic variants robustly associated with body mass index (BMI) to investigate its causal effects on employment.
White UK ethnicity participants of working age (men 40-64 years, women 40-59 years), with suitable genetic data were selected in the UK Biobank study (N = 230,791). Employment status was categorised in two ways: first, contrasting being in paid employment with any other status; and second, contrasting being in paid employment with sickness/disability, unemployment, early retirement and caring for home/family. Socioeconomic indicators also investigated were hours worked, household income, educational attainment and Townsend deprivation index (TDI). We conducted observational and two-sample Mendelian randomisation (MR) analyses to investigate the effect of increased BMI on employment-related outcomes.
Regressions showed BMI associated with all the employment-related outcomes investigated. MR analyses provided evidence for higher BMI causing increased risk of sickness/disability (OR 1.08, 95% CI 1.04, 1.11, per 1 Kg/m
BMI increase) and decreased caring for home/family (OR 0.96, 95% CI 0.93, 0.99), higher TDI (Beta 0.038, 95% CI 0.018, 0.059), and lower household income (OR 0.98, 95% CI 0.96, 0.99). In contrast, MR provided evidence for no causal effect of BMI on unemployment, early retirement, non-employment, hours worked or educational attainment. There was little evidence for causal effects differing by sex or age. Robustness tests yielded consistent results.
BMI appears to exert a causal effect on employment status, largely by affecting an individual's health rather than through increased unemployment arising from social discrimination. The obesity epidemic may be contributing to increased worklessness and therefore could impose a substantial societal burden.
Abstract Background Lumbar disc degeneration (LDD) is a major cause of low back pain, and is a common and disabling condition worldwide. LDD has been defined and measured by multiple spine MRI ...features, but the heterogeneity among them has never been fully addressed. Purpose This study examined the inter-correlations, risk factor associations, and SNP-heritabilities of lumbar disc MRI features, in a large-scale sample to classify the different intervertebral disc phenotypes associated with LDD. Study Design A cross-sectional study was conducted consisting of 2,943 volunteers of Southern Chinese origin (mean age, 41.1 years; range, 15 to 55 years; 59.6% females). Outcome Measures Magnetic resonance imaging (MRI) phenotypic spinal patterns and their risk factor profiles in relation to developmental or degenerative origins of disc degeneration. Methods Sagittal T2-weighted MRI of the lumbar spine from L1-S1 was assessed. MRI features of lumbar intervertebral disc changes, such as disc signal intensity loss, disc bulges or extrusions, as well as additional imaging phenotypes of endplate changes, high-intensity zones, and bone marrow changes were evaluated. Blood samples were taken for genotyping using the Human Omni-ZhongHua-8 Bead Chip. Subject demographics, environmental and lifestyle factors were assessed by questionnaires. Multivariate statistical techniques were used for phenotypes evaluation. Polychoric correlations and local regression statistical analyses were performed. The genetic components contributed by common SNPs were estimated by comparing genetic correlations and phenotypic correlations using Genome-wide Complex Trait Analysis (GCTA) tool. Results The study noted that lumbar disc MRI features separated into two groups with differential patterns of risk factor associations. A subset of lumbar disc abnormalities including endplate changes but also upper lumbar disc bulging and signal intensity loss may have a developmental origin. Subsequent degenerative changes, typically affecting the lower lumbar discs, then emerge as individuals age and are associated with BMI. Conclusions This is the first large-scale study to identify two distinct patterns of lumbar disc alterations, noting degenerative changes and a possible developmental component affecting the lumbar spine. This new classification provides a starting point for a more homogeneous phenotype definition, which may provide greater statistical power and precision in future genetic and epidemiological studies. In addition, such insights may have direct clinical implications in the prevention, therapeutics and prognostics of patients with disc degeneration.
Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to ...contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (>500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with ∼400 kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions.
Semi-quantitative image analysis methods in Alzheimer's Disease (AD) require normalization of positron emission tomography (PET) images. However, recent studies have found variabilities associated ...with reference region selection of amyloid PET images. Haralick features (HFs) generated from the Gray Level Co-occurrence Matrix (GLCM) quantify spatial characteristics of amyloid PET radiotracer uptake without the need for intensity normalization. The objective of this study is to calculate several HFs in different diagnostic groups and determine the group differences.
All image and metadata were acquired through the Alzheimer's Disease Neuroimaging Initiative database. Subjects were grouped in three ways: by clinical diagnosis, by APOE e4 allele, and by Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score. Several GLCM matrices were calculated for different direction and distances (1-4 mm) from multiple regions on PET images. The HFs, contrast, correlation, dissimilarity, energy, entropy, and homogeneity, were calculated from these GLCMs. Wilcoxon tests and Student
-tests were performed on Haralick features and standardized uptake value ratio (SUVR) values, respectively, to determine group differences. In addition to statistical testing, receiver operating characteristic (ROC) curves were generated to determine the discrimination performance of the selected regional HFs and the SUVR values.
Preliminary results from statistical testing indicate that HFs were capable of distinguishing groups at baseline and follow-up (false discovery rate corrected
<0.05) in particular regions at much higher occurrences than SUVR (81 of 252). Conversely, we observed nearly no significant differences between all groups within ROIs at baseline or follow-up utilizing SUVR. From the ROC analysis, we found that the Energy and Entropy offered the best performance to distinguish Normal versus mild cognitive impairment and ADAS-Cog negative versus ADAS-Cog positive groups.
These results suggest that this technique could improve subject stratification in AD drug trials and help to evaluate the disease progression and treatment effects longitudinally without the disadvantages associated with intensity normalization.
Previously, our comprehensive cardiovascular characterization study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesized at the thick ascending limb of ...the loop of Henle and is encoded by the Umod gene. Umod
mice have significantly lower blood pressure than Umod
mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed use RNA-Seq to delineate salt stress pathways in tubules isolated from Umod
mice (a model of sodium retention) and Umod
mice (a model of sodium depletion) ± 300 mosmol sodium chloride ( n = 3 per group). In response to salt stress, the tubules of Umod
mice displayed an upregulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, P = 2.48 e
) and Hspa1b (Log2 fold change 4.05, P = 2.48 e
). This response was absent in tubules of Umod
mice. Interestingly, seven of the genes discordantly expressed in the Umod
tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod
tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress.
Error in sample size formula Campbell, Desmond
Journal of human reproductive sciences
7, Številka:
2
Journal Article
Recenzirano
Odprti dostop
In the section titled "sample size estimation with two means" they state the minimum required sample size for detecting a mean difference between two groups is: INLINE:1 Where α is the false ...positive rate β is the false negative rate N is the sample size required to detect an inter-group mean difference of d with specified α and power of 1-β δ2 is the variance in each group (both groups having the same variance) r is the ratio of size (n1 and n2 ) of the two groups, that is, r = n1 /n2 Z is the standard normal distribution deviate, note this is the absolute of the z-score, as in (Suresh and Chandrashekara, 2012) Table 2 and Table 3.