Effects of increased body mass index on employment status: a Mendelian randomisation study.

BACKGROUND: 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. DATASET/METHODS: 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. RESULTS: 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/m2 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. DISCUSSION: 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.

Multifactorial disease risk calculator: Risk prediction for multifactorial disease pedigrees.

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.

Salt stress in the renal tubules is linked to TAL-specific expression of uromodulin and an upregulation of heat shock genes.

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-12) and Hspa1b (Log2 fold change 4.05, P = 2.48 e-12). 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.

Sacral agenesis: a pilot whole exome sequencing and copy number study.

BACKGROUND: Caudal regression syndrome (CRS) or sacral agenesis is a rare congenital disorder characterized by a constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. CRS is a complex condition, attributed to an abnormal development of the caudal mesoderm, likely caused by the effect of interacting genetic and environmental factors. A well-known risk factor is maternal type 1 diabetes. METHOD: Whole exome sequencing and copy number variation (CNV) analyses were conducted on 4 Caucasian trios to identify de novo and inherited rare mutations. RESULTS: In this pilot study, exome sequencing and copy number variation (CNV) analyses implicate a number of candidate genes, including SPTBN5, MORN1, ZNF330, CLTCL1 and PDZD2. De novo mutations were found in SPTBN5, MORN1 and ZNF330 and inherited predicted damaging mutations in PDZD2 (homozygous) and CLTCL1 (compound heterozygous). Importantly, predicted damaging mutations in PTEN (heterozygous), in its direct regulator GLTSCR2 (compound heterozygous) and in VANGL1 (heterozygous) were identified. These genes had previously been linked with the CRS phenotype. Two CNV deletions, one de novo (chr3q13.13) and one homozygous (chr8p23.2), were detected in one of our CRS patients. These deletions overlapped with CNVs previously reported in patients with similar phenotype. CONCLUSION: Despite the genetic diversity and the complexity of the phenotype, this pilot study identified genetic features common across CRS patients.

Software for generating liability distributions for pedigrees conditional on their observed disease states and covariates.

For many multifactorial diseases, aetiology is poorly understood. A major research aim is the identification of disease predictors (environmental, biological, and genetic markers). In order to achieve this, a two-stage approach is proposed. The initial or synthesis stage combines observed pedigree data with previous genetic epidemiological research findings, to produce estimates of pedigree members' disease risk and predictions of their disease liability. A further analysis stage uses the latter as inputs to look for associations with potential disease markers. The incorporation of previous research findings into an analysis should lead to power gains. It also allows separate predictions for environmental and genetic liabilities to be generated. This should increase power for detecting disease predictors that are environmental or genetic in nature. Finally, the approach brings pragmatic benefits in terms of data reduction and synthesis, improving comprehensibility, and facilitating the use of existing statistical genetics tools. In this article we present a statistical model and Gibbs sampling approach to generate liability predictions for multifactorial disease for the synthesis stage. We have implemented the approach in a software program. We apply this program to a specimen disease pedigree, and discuss the results produced, comparing its results with those generated under a more naïve model. We also detail simulation studies that validate the software's operation.

Interplay between Schizophrenia Polygenic Risk Score and Childhood Adversity in First-Presentation Psychotic Disorder: A Pilot Study.

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.

Two subtypes of intervertebral disc degeneration distinguished by large-scale population-based study.

BACKGROUND CONTEXT: Lumbar disc degeneration (LDD) is a major cause of low back pain, and is a common and disabling condition worldwide. It has been defined and measured by multiple spine magnetic resonance imaging (MRI) features, but the heterogeneity among them has never been fully addressed. PURPOSE: This study examined the intercorrelations, risk factor associations, and single nucleotide polymorphism (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: 15-55 years; 59.6% women). OUTCOME MEASURES: The outcome measures were 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 to S1 was assessed. The MRI features of lumbar intervertebral disc changes, such as disc signal intensity loss and disc bulges or extrusions, as well as additional imaging phenotypes of end plate changes, high-intensity zones, and bone marrow changes, were evaluated. Blood samples were taken for genotyping using the HumanOmni-ZhongHua-8 BeadChip. Subject demographics, environmental, and lifestyle factors were assessed by questionnaires. Multivariate statistical techniques were used for phenotype 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 the 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 end plate 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 body mass index. 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 epidemiologic studies. In addition, such insights may have direct clinical implications in the prevention, therapeutics, and prognostics of patients with disc degeneration.

Cost effective assay choice for rare disease study designs.

High throughput assays tend to be expensive per subject. Often studies are limited not so much by the number of subjects available as by assay costs, making assay choice a critical issue. We have developed a framework for assay choice that maximises the number of true disease causing mechanisms 'seen', given limited resources. Although straightforward, some of the ramifications of our methodology run counter to received wisdom on study design. We illustrate our methodology with examples, and have built a website allowing calculation of quantities of interest to those designing rare disease studies.

Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.

OBJECTIVE: Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. METHOD: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. RESULTS: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). CONCLUSIONS: Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Cognitive impairment among children at-risk for schizophrenia.

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: FHx(H)); (2) 14 with ≥1 affected second-degree relative (lower familial loading: FHx(L)); (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 FHx(H) and ASz children exhibited significantly poorer verbal comprehension, scholastic achievement, and verbal working memory, while FHx(H) 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, FHx(L) 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.

CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.

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.

Amerind ancestry, socioeconomic status and the genetics of type 2 diabetes in a Colombian population.

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).