Accurate Liability Estimation Improves Power in Ascertained Case Control Studies

Linear mixed models (LMMs) have emerged as the method of choice for confounded genome-wide association studies. However, the performance of LMMs in non-randomly ascertained case-control studies deteriorates with increasing sample size. We propose a framework called LEAP (Liability Estimator As a Phenotype, https://github.com/omerwe/LEAP) that tests for association with estimated latent values corresponding to severity of phenotype, and demonstrate that this can lead to a substantial power increase

eGIFT: Mining Gene Information from the Literature

<p>Abstract</p> <p>Background</p> <p>With the biomedical literature continually expanding, searching PubMed for information about specific genes becomes increasingly difficult. Not only can thousands of results be returned, but gene name ambiguity leads to many irrelevant hits. As a result, it is difficult for life scientists and gene curators to rapidly get an overall picture about a specific gene from documents that mention its names and synonyms.</p> <p>Results</p> <p>In this paper, we present eGIFT (<url>http://biotm.cis.udel.edu/eGIFT</url>), a web-based tool that associates informative terms, called <it>i</it>Terms, and sentences containing them, with genes. To associate <it>i</it>Terms with a gene, eGIFT ranks <it>i</it>Terms about the gene, based on a score which compares the frequency of occurrence of a term in the gene's literature to its frequency of occurrence in documents about genes in general. To retrieve a gene's documents (Medline abstracts), eGIFT considers all gene names, aliases, and synonyms. Since many of the gene names can be ambiguous, eGIFT applies a disambiguation step to remove matches that do not correspond to this gene. Another additional filtering process is applied to retain those abstracts that focus on the gene rather than mention it in passing. eGIFT's information for a gene is pre-computed and users of eGIFT can search for genes by using a name or an EntrezGene identifier. <it>i</it>Terms are grouped into different categories to facilitate a quick inspection. eGIFT also links an <it>i</it>Term to sentences mentioning the term to allow users to see the relation between the <it>i</it>Term and the gene. We evaluated the precision and recall of eGIFT's <it>i</it>Terms for 40 genes; between 88% and 94% of the <it>i</it>Terms were marked as salient by our evaluators, and 94% of the UniProtKB keywords for these genes were also identified by eGIFT as <it>i</it>Terms.</p> <p>Conclusions</p> <p>Our evaluations suggest that <it>i</it>Terms capture highly-relevant aspects of genes. Furthermore, by showing sentences containing these terms, eGIFT can provide a quick description of a specific gene. eGIFT helps not only life scientists survey results of high-throughput experiments, but also annotators to find articles describing gene aspects and functions.</p

Increasing uptake of colorectal cancer screening in Korea: a population-based study

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer (CRC) screening rates are low in most Asian countries and remain largely unknown. This study examined trends in CRC screening rates after the introduction of the Korean National Cancer Screening Programme (NCSP) and determined the factors associated with uptake of CRC screening by test modality over time.</p> <p>Methods</p> <p>An annual population-based survey conducted through nationally representative random sampling from 2005-2008. In total, 3,699 participants from the 2005-2008 surveys were selected as study subjects. Face-to-face interviews were performed to assess the utilization rate of CRC screening by each screening modality.</p> <p>Results</p> <p>Overall, CRC screening within the recommended time interval increased significantly from 22.9% in 2005 to 36.6% in 2008 (<it>p </it>< 0.001). The proportion of subjects receiving a fecal occult blood test (FOBT) test within the previous year increased significantly from 7.2% in 2005 to 21.3% in 2008 (<it>p </it>< 0.001). Increases in FOBT testing were highest among those who had a lower income status (relative difference = 511.9%) and women (relative difference = 266.1%). Endoscopy use also increased from 18.0% in 2005 to 20.5% in 2008, albeit not significant. Overall, those who were male, non-smokers, 60-69 years old, and had a higher income status were more likely to have undergone up-to-date endoscopy and CRC screening.</p> <p>Conclusions</p> <p>This study revealed a substantial increase in up-to-date CRC screening in the general population from 2005 to 2008. However, more than half of adults in Korea are still not up-to-date with their CRC tests. It will be important to continue to investigate factors associated with up-to-date CRC screening by each modality.</p

Association of Toll-like receptor 4 (TLR4) with chronic plaque type psoriasis and psoriatic arthritis.

Family studies have provided overwhelming evidence for an underlying genetic component to psoriasis. Toll-like receptors (TLRs) are key transmembrane proteins in both the innate and adaptive immune responses which are known to be integral processes in psoriasis. Recent functional studies support this notion having suggested a role for TLR4 in the pathogenesis of psoriasis. Furthermore a missense polymorphism in the TLR4 gene has been associated with a number of autoimmune conditions, including Crohn diseases, making TLR4 a viable candidate gene for investigation. The aim of this study was to investigate polymorphisms across the TLR4 region with a high-density single nucleotide polymorphism (SNP) panel in a large cohort of patients with chronic plaque type psoriasis. Twenty SNPs were successfully genotyped using Sequenom iPLEX Gold platform in 2826 UK chronic plaque type psoriasis patients including subgroup data on presence of confirmed psoriatic arthritis (n = 1839) and early-onset psoriasis (n = 1466) was available. Allele frequencies for psoriasis patients were compared against imputed Wellcome Trust Case Control Consortium controls (n = 4861). Significant association was observed between a missense variant rs4986790 of TLR4 (Asp229Gly) and plaque type psoriasis (p = 2 × 10(-4)) which was also notable in those with psoriatic arthritis (p = 2 × 10(-4)) and early-onset psoriasis (p = 8 × 10(-4)). We present data suggestive of an association between a functional variant and an intronic variant of TLR4 and chronic plaque type psoriasis and psoriatic arthritis. However, validation of this association in independent cohorts will be necessary

Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation

This is the final version. Available from eLife Science Publications via the DOI in this record. Data availability: GWAS data from the outcome diseases studied is available from links published in the original studies (Supplementary File 1ci). FinnGen data is available at: https://finngen.gitbook.io/documentation/, and the list of disease outcomes used is in Supplementary File 1cii. Individual-level UK Biobank data cannot be provided, but it is available by application to the UK Biobank: https://www.ukbiobank.ac. uk, and a list of the traits used is in Supplementary File 1ciii. Code used to conduct this analysis will be made available on GitHub after removing any sensitive information (https://github.com/susiemartin/ uncoupling-bmi, copy archived at swh:1:rev:f3472762ad6cb7f313656f684e07c14b8735efe5).Background: Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases. Methods: We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically ‘favourable adiposity’ (FA) and ‘unfavourable adiposity’ (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases. Results: MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism. Conclusions: Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthyMedical Research Council (MRC)Diabetes UKWorld Cancer Research FundMedical Research CouncilDiabetes UKWorld Cancer Research FundCancer Research UKUniversity of Bristo

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes