Probability Of Causality Research Articles

Abstract 6145: A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer

Abstract Introduction: Cervical cancer is the second most common cause of cancer-related deaths among women worldwide. Genome-wide association studies (GWAS) have identified genetic variants associated with cervical cancer. However, these discoveries have been limited by the small sample sizes of the individual cohorts. To identify additional novel loci associated with cervical cancer, we performed a trans-ethnic meta-analysis. Methods: GWAS summary data for trans-ethic meta-analysis were identified in women of European ancestry from the UK Biobank, East Asian ancestry from Biobank Japan, and African ancestries from the pan-UK Biobank and Johannesburg cancer study. Meta-analyses were performed using fixed effect inverse variance weighted method implemented in GWAMA. To localize putative genomic loci associated with cervical cancer, we performed fine mapping using the Bayesian approach by calculating the marginal posterior probability of causality for each single nucleotide polymorphisms (SNPs) and 99% credible set size. Results: Our meta-analysis identified four additional novel genomic loci associated with cervical cancer. These loci include: rs147778467 (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.08-1.16, P-value = 3.12 x 10-08) in RGS21, rs53150478 (OR =1.03, 95%CI = 1.01-1.05, P-value = 4.48 x 10-08) in MAN1C1, rs113842373 (OR = 0.68, 95%CI = 0.56-0.81, P-value = 2.31 x 10-09) in LINCO1850 and rs75372437 (OR = 0.80, 95%CI = 0.72-0.88, P-value = 3.32 x 10-08) in RNU6-356P. These loci are implicated in carcinogenic pathways. Moreover, our Bayesian fine mapping identified five loci with a marginal posterior probability of causality > 1 and reduced the 99% credible set sizes. Conclusion: We identified additional novel loci associated with cervical cancer and our fine mapping identified loci with a high posterior probability of being causal. Citation Format: Abram Bunya Kamiza, Jean-Tristan Brandenburg, Michele Ramsay, Christopher Mathew. A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6145.

Causal relationships between Sjögren's syndrome and Parkinson's disease: A Mendelian randomization study.

Epidemiological and observational studies have indicated an association between Sjögren's syndrome (SS) and Parkinson's disease (PD). However, consistent conclusions have not been reached due to various limitations. In order to determine whether SS and PD are causally related, we conducted a Mendelian randomization study (MR) with two samples. Data for SS derived from the FinnGen consortium's R9 release (2495 cases and 365 533 controls). Moreover, data for PD were acquired from the publicly available GWAS of European ancestry, which involved 33 674 cases and 449 056 controls. The inverse variance weighted, along with four other effective methodologies, were employed to comprehensively infer the causal relationships between SS and PD. To assess the estimation's robustness, a number of sensitivity studies were performed. To determine the probability of reverse causality, we performed a reverse MR analysis. There was no evidence of a significant causal effect of SS on PD risks based on the MR [odds ratio (OR) = 1.03; 95% confidence interval (CI) = 0.95-1.11; p = .45]. Similarly, no evidence supported the causal effects of PD on SS (OR = 0.92; 95% CI = 0.81-1.04; p = .20). These findings held up under rigorous sensitivity analysis. MR bidirectional analysis did not reveal any cause-and-effect relationship between SS and PD, or vice versa. Further study of the mechanisms that may underlie the probable causal association between SS and PD is needed.

Multi-trait discovery and fine-mapping of lipid loci in 125,000 individuals of African ancestry

Most genome-wide association studies (GWAS) for lipid traits focus on the separate analysis of lipid traits. Moreover, there are limited GWASs evaluating the genetic variants associated with multiple lipid traits in African ancestry. To further identify and localize loci with pleiotropic effects on lipid traits, we conducted a genome-wide meta-analysis, multi-trait analysis of GWAS (MTAG), and multi-trait fine-mapping (flashfm) in 125,000 individuals of African ancestry. Our meta-analysis and MTAG identified four and 14 novel loci associated with lipid traits, respectively. flashfm yielded an 18% mean reduction in the 99% credible set size compared to single-trait fine-mapping with JAM. Moreover, we identified more genetic variants with a posterior probability of causality >0.9 with flashfm than with JAM. In conclusion, we identified additional novel loci associated with lipid traits, and flashfm reduced the 99% credible set size to identify causal genetic variants associated with multiple lipid traits in African ancestry.

Genome-wide association analysis of cystatin-C kidney function in continental Africa

Chronic kidney disease is becoming more prevalent in Africa, and its genetic determinants are poorly understood. Creatinine-based estimated glomerular filtration rate (eGFR) is commonly used to estimate kidney function, modelling the excretion of the endogenous biomarker (creatinine). However, eGFR based on creatinine has been shown to inadequately detect individuals with low kidney function in Sub-Saharan Africa, with eGFR based on cystatin-C (eGFRcys) exhibiting significantly superior performance. Therefore, we opted to conduct a GWAS for eGFRcys. Using the Uganda Genomic Resource, we performed a genome-wide association study (GWAS) of eGFRcys in 5877 Ugandans and evaluated replication in independent studies. Subsequently, putative causal variants were screened through Bayesian fine-mapping. Functional annotation of the GWAS loci was performed using Functional Mapping and Annotation (FUMA). Three independent lead single nucleotide polymorphisms (SNPs) (P-value <5×10-8 (based on likelihood ratio test (LRT))) were identified; rs59288815 (ANK3), rs4277141 (OR51B5) and rs911119 (CST3). From fine-mapping, rs59288815 and rs911119 each had a posterior probability of causality of >99%. The rs911119 SNP maps to the cystatin C gene and has been previously associated with eGFRcys among Europeans. With gene-set enrichment analyses of the olfactory receptor family 51 overlapping genes, we identified an association with the G-alpha-S signalling events. Our study found two previously unreported associated SNPs for eGFRcys in continental Africans (rs59288815 and rs4277141) and validated a previously well-established SNP (rs911119) for eGFRcys. The identified gene-set enrichment for the G-protein signalling pathways relates to the capacity of the kidney to readily adapt to an ever-changing environment. Additional GWASs are required to represent the diverse regions in Africa. Wellcome (220740/Z/20/Z).

Identification of potential genetic causal variants for obesity-related traits using statistical fine mapping.

Obesity is highly influenced by heritability and variant effects. While previous genome-wide association studies (GWASs) have successfully identified numerous genetic loci associated with obesity-related traits [body mass index (BMI) and waist-to-hip ratio (WHR)], most causal variants remain unidentified. The high degree of linkage disequilibrium (LD) throughout the genome makes it extremely difficult to distinguish the GWAS-associated SNPs that exert a true biological effect. This study was to identify the potential causal variants having a biological effect on obesity-related traits. We used Probabilistic Annotation INTegratOR, a Bayesian fine-mapping method, which incorporated genetic association data (GWAS summary statistics), LD structure, and functional annotations to calculate a posterior probability of causality for SNPs across all loci of interest. Moreover, we performed gene expression analysis using the available public transcriptomic data to validate the corresponding genes of the potential causal SNPs partially. We identified 96 SNPs for BMI and 43 SNPs for WHR with a high posterior probability of causality (> 99%), including 49 BMI SNPs and 24 WHR SNPs which did not reach genome-wide significance in the original GWAS. Finally, we partially validated some genes corresponding to the potential causal SNPs. Using a statistical fine-mapping approach, we identified a set of potential causal variants to be prioritized for future functional validation and also detected some novel trait-associated variants. These results provided novel insight into our understanding of the genetics of obesity and also demonstrated that fine mapping may improve upon the results identified by the original GWASs.

Intensive care drug therapy and its potential adverse effects on blood pressure and heart rate in critically ill children

BackgroundOwing to complex treatment, critically ill children may experience alterations in their vital parameters. We investigated whether such hemodynamic alterations were temporally and causally related to drug therapy.MethodsIn a university pediatric intensive care unit, we retrospectively analyzed hemodynamic alterations defined as values exceeding the limits set for heart rate (HR) and blood pressure (BP). For causality assessment, we used the World Health Organization–Uppsala Monitoring Center (WHO–UMC) system, which categorizes the probability of causality as “certain,” “probable,” “possible,” and “unlikely.”ResultsOf 315 analyzed patients with 43,200 drug prescriptions, 59.7% experienced at least one hemodynamic alteration; 39.0% were affected by increased HR, 19.0% by decreased HR, 18.1% by increased BP, and 16.2% by decreased BP. According to drug information databases, 83.9% of administered drugs potentially lead to hemodynamic alterations. Overall, 88.3% of the observed hemodynamic alterations had a temporal relation to the administration of drugs; in 80.2%, more than one drug was involved. Based on the WHO–UMC system, a drug was rated as a “probable” causing factor for only 1.4% of hemodynamic alterations. For the remaining alterations, the probability ratings were lower because of multiple potential causes, e.g., several drugs.ConclusionsCritically ill children were frequently affected by hemodynamic alterations. The administration of drugs with potentially adverse effects on hemodynamic parameters is often temporally related to hemodynamic alterations. Hemodynamic alterations are often multifactorial, e.g., due to administering multiple drugs in rapid succession; thus, the influence of individual drugs cannot easily be captured with the WHO–UMC system.

Dynamic causality between oil prices and stock market indexes in Russia and China: does US financial instability matter?

PurposeThis study aims to examine the dynamic bidirectional causality between oil price (OIL) and stock market indexes in net oil-exporting (Russia) and net oil-importing (China) countries.Design/methodology/approachThe authors use monthly data for the period starting from October 1995 to October 2021. In this study, the bootstrap rolling-window Granger causality approach introduced by Balcilar et al. (2010) and the probit regression model are performed in order to identify the bidirectional causality.FindingsThe results show that the causal periods mainly occur during economic, financial and health crises. For oil-exporting country, the results suggest that any increase (decrease) in the OIL leads to an appreciation (depreciation) in the stock market index. The effect of the stock market on OIL is more relevant for the oil-importing country than that for the oil-exporting one. The COVID-19 consequences are demonstrated in the impact of oil on the Russian stock market. The probit regression shows that the US financial instabilities increase the probability of causality between OIL and stock market indexes in Russia and China.Practical implicationsThe dynamic relationship between the variables must be taken into account in investment decisions. As financial instabilities in the USA drive the relationship between oil and stocks, investors should consider geopolitical, economic and financial elements when constructing their portfolios. Shareholders are required to include other assets in their portfolios since oil–stock relationship is highly risky.Originality/valueThis study provides further evidence of the bidirectional oil–stock causal link. Additionally, it examines the impact of financial instabilities on the probability that the OIL and the stock market index cause each other through the Granger effect.

Decision Support Techniques for determination of the causal relationship between health problems of workers and their work activities.

Reflecting on the complexity and impacts of determination of the causal relationship between health problems of workers and the exercise of their work activities, there is a need to learn about scientific articles that expose techniques to determine this type of causal relationship. There is also a need to reveal whether any article exposes multicriteria decision analysis technique. The aim is to quantify the techniques used to determine the causal relationship between health problems of workers and the exercise of their work activities. Bibliometric analysis was performed, searching for articles in Portuguese, Spanish and English. An advanced search was performed on the website of the ministerial journals portal and then on the Gale Academic OneFile, SciVerse Scopus, Scientific Electronic Library Online (SciELO) and PubMed Central collections. In summary, 38 articles were selected from portal, 50 from Gale Academic OneFile, 20 from SciVerse Scopus, 37 from SciELO and 5 from PubMed Central, totaling 150 articles of interest for analysis of their contents. Among these 150 articles, 33.33% addressed the causal relationship between illness and work, 3.33% described some process related to occupational diagnostic investigation and 0.66%, which represents only one article, exhibited a technique to determine this type of causal relationship: the probability of causality in neoplastic diseases. No article described multicriteria decision analysis method as a technique for determine this type of causal relationship. Therefore, there is a need to carry out and disseminate scientific research on methods to help determine a causal relationship between illness and work.

A novel fuzzy dynamic Bayesian network for dynamic risk assessment and uncertainty propagation quantification in uncertainty environment

Risk assessment (RA) plays a vital role in safety engineering. The conventional RA approaches have limited capabilities in handling time dependence and data uncertainty. Although dynamic Bayesian network (DBN) is robust in inference under uncertainty due to its flexible structure and capability of modeling the interdependencies of variables, it still has some defects in quantifying the uncertainty (probability range) propagation over time, and dealing with inaccurate or insufficient data (data uncertainty). This study is aimed to propose a novel fuzzy dynamic Bayesian network (FDBN) methodology to improve the ability of dynamic risk assessment (DRA) methods to quantify and propagate uncertainty arise from inaccurate or insufficient data. The methodology incorporates the fuzzy set theory (FST) with DBN to conduct DRA under data uncertainty while quantifying the uncertainty propagation over time. The proposed methodology represents the causality of variables in the time dimension and adopts expert elicitation and FST to determine the probability of causality. Triangular fuzzy numbers are used throughout the entire dynamic modeling process of DBN to completely retain the uncertainty information. A comparison between the proposed novel FDBN and crisp value based DBN verifies the credibility, rationality and robustness of the proposed methodology. A multi-variable risk assessment of the cotton warehouse is presented here to illustrate the potential of the proposed methodology in dealing with dynamic risk with uncertainty.

Discovery and fine-mapping of kidney function loci in first genome-wide association study in Africans.

Genome-wide association studies (GWAS) of kidney function have uncovered hundreds of loci, primarily in populations of European ancestry. We have undertaken the first continental African GWAS of estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We conducted GWAS of eGFR in 3288 East Africans from the Uganda General Population Cohort (GPC) and replicated in 8224 African Americans from the Women’s Health Initiative. Loci attaining genome-wide significant evidence for association (P < 5 × 10−8) were followed up with Bayesian fine-mapping to localize potential causal variants. The predictive power of a genetic risk score (GRS) constructed from previously reported trans-ancestry eGFR lead single nucleotide polymorphism (SNPs) was evaluated in the Uganda GPC. We identified and validated two eGFR loci. At the glycine amidinotransferase (GATM) locus, the association signal (lead SNP rs2433603, P = 1.0 × 10−8) in the Uganda GPC GWAS was distinct from previously reported signals at this locus. At the haemoglobin beta (HBB) locus, the association signal (lead SNP rs141845179, P = 3.0 × 10−8) has been previously reported. The lead SNP at the HBB locus accounted for 88% of the posterior probability of causality after fine-mapping, but did not colocalise with kidney expression quantitative trait loci. The trans-ancestry GRS of eGFR was not significantly predictive into the Ugandan population. In the first GWAS of eGFR in continental Africa, we validated two previously reported loci at GATM and HBB. At the GATM locus, the association signal was distinct from that previously reported. These results demonstrate the value of performing GWAS in continental Africans, providing a rich genomic resource to larger consortia for further discovery and fine-mapping. The study emphasizes that additional large-scale efforts in Africa are warranted to gain further insight into the genetic architecture of CKD.

Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians.

Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality.At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue.Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.

A quantitative weight of evidence assessment of Hill's guidelines for causal inference for cosmetic talc as a cause of mesothelioma

Cosmetic talc has been suggested to cause mesothelioma. To assess a potential causal relationship between cosmetic talc and mesothelioma, a quantitative weight of evidence analysis was performed in accordance with Hill's nine original guidelines for causal inference using a published empirical model to weight each respective guideline. Various epidemiological, toxicological, and exposure studies related to cosmetic talc and risk of mesothelioma were included in an evaluation of each of Hill's guidelines. Probabilities that the guidelines were true were assigned based on expert judgment. We applied a sensitivity analysis to evaluate the variability of our probability estimates. The overall probability of causality for cosmetic talc and mesothelioma was approximately 1.29% (range: 0.73%–3.96%). This low probability of causality supports the conclusion that cosmetic talc is not related to the development of mesothelioma.

The utility of the Laplace effect size prior distribution in Bayesian fine-mapping studies.

The Gaussian distribution is usually the default causal single-nucleotide polymorphism (SNP) effect size prior in Bayesian population-based fine-mapping association studies, but a recent study showed that the heavier-tailed Laplace prior distribution provided a better fit to breast cancer top hits identified in genome-wide association studies. We investigate the utility of the Laplace prior as an effect size prior in univariate fine-mapping studies. We consider ranking SNPs using Bayes factors and other summaries of the effect size posterior distribution, the effect of prior choice on credible set size based on the posterior probability of causality, and on the noteworthiness of SNPs in univariate analyses. Across a wide range of fine-mapping scenarios the Laplace prior generally leads to larger 90% credible sets than the Gaussian prior. These larger credible sets for the Laplace prior are due to relatively high prior mass around zero which can yield many noncausal SNPs with relatively large Bayes factors. If using conventional credible sets, the Gaussian prior generally yields a better trade off between including the causal SNP with high probability and keeping the set size reasonable. Interestingly when using the less well utilised measure of noteworthiness, the Laplace prior performs well, leading to causal SNPs being declared noteworthy with high probability, whilst generally declaring fewer than 5% of noncausal SNPs as being noteworthy. In contrast, the Gaussian prior leads to the causal SNP being declared noteworthy with very low probability.

Fine genetic mapping of the chromosome 11q23.3 region in a Han Chinese population: insights into the apolipoprotein genes underlying the blood lipid-lipoprotein variances

The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases. However, its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed. We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing, association analyses, genetic fine mapping, and functional interpretation. The present study identified new meaningful genetic associations that were not simply determined by statistical significance. In addition to the APOA5 gene, we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids. Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses. rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediate APOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility. Similarly, multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol. Our findings provided novel insights into this genomic locus in the Chinese population.

Narrative of time and sign in the Film Ode to My Father

본고에서는 영화 <국제시장>에 나타난 서사구조를 시간과 기호로 나누어 살폈다. 시간을 중심으로 할 때 서사가 어떤 식으로 전개되고 어떻게 재구조화될 수 있는지, 들뢰즈의 기호를 중심으로 살피게 되면 서사가 또한 어떤 식으로 확장될 수 있는지를 분석해보았다. 우선 시간의 서사에서는 담화의 시간과 스토리의 시간을 구분하여 설명했다. 담화의 시간은 현재적 시간을 의미하는데, 관객이 스크린을 통해 현재적으로 서사를 바라본다는 얘기다. 이때의 서사는 시간의 흐름에 따라 전개되는 것이 아니라, 서사체 내부 사건들의 재-배열을 통해서 진행된다. 따라서 담화의 시간은 비연대기적이며, 이러한 구조를 통해서 감독은 자신의 이데올로기나 궁극의 메시지를 관객에게 전달할 수가 있게 된다. 아울러 스토리의 시간은 서사체 내부의 사건들을 연대기적으로 또는 인과관계를 따져서 재배치할 수 있는 동력이 된다. 서사의 재구성 내지는 재배열이 중요한 이유는 사건의 인과관계 및 주인공의 현재적 삶이라는 결과에 대한 개연성과 핍진성을 높일 수가 있기 때문이다. 곧 사건과 시간의 관계가 명확한 틀 안에서 인과적으로 구현이 되어야 만이 관객은 서사를 통해 객관성을 확보할 수가 있게 된다. 마지막으로 기호의 시간에서는 <국제시장> 중 기호가 발생한 부분을 크게 여섯 장면으로 포착하여 살펴보았다. 기호는 장면의 변화를 가져오는 것을 넘어서서, 우연히 마주친 것들 속에 의미가 담겨있는 것을 말한다. 단순하게 기억이나 추억의 되새김을 의미하는 것이 아니라 기억을 가능하게 하는 매개체로 기호는 쓰이는 것이다. 감독은 (무)의식적으로 나타나는 기억들의 의미를 기호로 추적하고 이를 형상화해서 또 다른 이야기에 도달하고자 했다.This writing divided the narrative structure of the movie Ode to My Father into time and sign. This writing analyzed how narratives can be developed and re-structured when centered on time, and how narratives can also be extended when focused on the sign of the Gilles Deleuze. First of all, the narrative of time explains the time of the discourse and the time of the story. The time of the discourse means the present time. In other words, the audience looks at the narrative currently through the screen. In this situation, this narrative is not go according to the time, but through re-arrangement of events in the narration. Therefore, the time of discourse is non-chronic, and this structure allows the director to convey his ideology or ultimate message to the audience. In addition, the time of the story is the driving force to relocate events within the narration chronologically or according to causality. The reason why reconstruction or rearrangement of narratives is important is that probability and verisimilitude of causality of events and the outcome of the present life of the main character can be increased. Soon, the relationship between events and time must be causal within a clear framework so that the audience can secure objectivity through the narrative. Finally, in the time of the sign, this writing captured six scenes of the sign in the Ode to My Father. Sign is meant to be something which happens by chance, beyond bringing about a change in the scene. Sign is used as memory-capable medium, not just reminder of memories. The director tried to trace the meaning of the unconscious memories with sign and shape them to reach the truth.

Behind Every High Earning Man is a Conscientious Woman: The Impact of Spousal Personality on Earnings and Marriage

Using three waves (2005, 2009 and 2013) of the Household, Income and Labour Dynamics in Australia Survey (HILDA), and linear regression and probit analyses, we examined the relationship between personality and own earnings, spousal earnings, and marriage. Specifically, we were interested in whether an individual’s personality traits re predictive of these three outcomes. As part of these analyses, we first established that adult personality was stable diminishing the probability of reverse causality. Our empirical results confirmed previous findings on the effect of own personality on own earnings. We then turned to the effect of spousal personality on earnings, the first study to examine this by gender. Regression estimates indicated that for men, having a conscientious wife was positively correlated with his earnings. There was some evidence that having an extraverted husband complement a woman’s earnings. These results highlight the importance of non-cognitive skills on earnings and emphasize the value of looking separately by gender. We also found that personality traits played an important factor in how people match in the marriage market, underscoring an important link between the marriage market and the labor market.

1642-P: Colocalization Analyses of Genetic Associations of Type 2 Diabetes with DNA Methylation on Chromosome 11p in American Indians

Our recent genome-wide association study (GWAS) identified variants strongly associated with type 2 diabetes (T2D) on chromosome 11p15 in American Indians at KCNQ1 (index variant rs2237895, P=2.5×10-8) and TH (rs11564707, P=3.8×10-8). To assess whether these variants influence epigenetic variation we analyzed associations with DNA methylation. Participants included 7659 American Indians (33% with T2D) who had participated in the GWAS, 842 of whom had DNA methylation measured in peripheral blood. Methylation was measured with the Infinium 450k array (Illumina, San Diego, CA). To identify local CpG sites associated with index variants, we analyzed associations for sites within 1 Mb of each gene (2162 sites for KCNQ1, 2325 for TH). Strong associations were identified: the diabetes risk allele at rs2237895 associated with decreased methylation at cg14637411 (β= 1.35 SD per copy, P=2.6×10-169), and the risk allele at rs11564707 associated with increased methylation at cg19878200 (β=0.46 SD, P=1.1×10-21). We further conducted Bayesian functional fine-mapping association of T2D and statistical colocalization of association of methylation at these sites with T2D using CAVIAR- including 1943 variants for KCNQ1 and 2954 variants for TH. Potentially causal variants for T2D were identified for each gene (30 for KCNQ1 and 33 for TH with posterior probability of causality &amp;gt;0.01); all were in strong linkage disequilibrium with the index variant. Strong evidence for colocalization of the association of T2D with methylation at cg14637411 (colocalization posterior probability &amp;gt;0.01, suggesting both traits are influenced by the same causal variants) was seen with 4 KCNQ1 variants: rs60808706, rs2299620, rs2237896 and rs2237897. Evidence for colocalization was weak for cg19878200 and T2D at TH variants. These results support the notion that KCNQ1 variants may influence T2D risk via an epigenetic effect, and they identify candidate functional variants. Disclosure R.L. Hanson: None. S. Kobes: None. W. Hsueh: None. Y.L. Muller: None. W.C. Knowler: None. L. Baier: None. Funding American Diabetes Association (1-12-DNP-01 to R.L.H.)

GWAS and fine-mapping of livability and six disease traits in Holstein cattle

BackgroundHealth traits are of significant economic importance to the dairy industry due to their effects on milk production and associated treatment costs. Genome-wide association studies (GWAS) provide a means to identify associated genomic variants and thus reveal insights into the genetic architecture of complex traits and diseases. The objective of this study is to investigate the genetic basis of seven health traits in dairy cattle and to identify potential candidate genes associated with cattle health using GWAS, fine mapping, and analyses of multi-tissue transcriptome data.ResultsWe studied cow livability and six direct disease traits, mastitis, ketosis, hypocalcemia, displaced abomasum, metritis, and retained placenta, using de-regressed breeding values and more than three million imputed DNA sequence variants. After data edits and filtering on reliability, the number of bulls included in the analyses ranged from 11,880 (hypocalcemia) to 24,699 (livability). GWAS was performed using a mixed-model association test, and a Bayesian fine-mapping procedure was conducted to calculate a posterior probability of causality to each variant and gene in the candidate regions. The GWAS detected a total of eight genome-wide significant associations for three traits, cow livability, ketosis, and hypocalcemia, including the bovine Major Histocompatibility Complex (MHC) region associated with livability. Our fine-mapping of associated regions reported 20 candidate genes with the highest posterior probabilities of causality for cattle health. Combined with transcriptome data across multiple tissues in cattle, we further exploited these candidate genes to identify specific expression patterns in disease-related tissues and relevant biological explanations such as the expression of Group-specific Component (GC) in the liver and association with mastitis as well as the Coiled-Coil Domain Containing 88C (CCDC88C) expression in CD8 cells and association with cow livability.ConclusionsCollectively, our analyses report six significant associations and 20 candidate genes of cattle health. With the integration of multi-tissue transcriptome data, our results provide useful information for future functional studies and better understanding of the biological relationship between genetics and disease susceptibility in cattle.

Сила связи. Сообщение 1. Градации относительного риска

Purpose: To summarize data on graduation of the effect size on the base of Hill’s first causality criterion ‘Strength of association’ on relative risk parameters (RR). Material and methods: Survey of published sources: monographs, handbooks, papers, educational material on statistics in various disciplines (including on-line), etc. (128 references; of which about 30 handbooks on epidemiology, carcinogenesis and medical statistics). Results: For the RR value, the collected data summary (1980–2018) implies non-homogeneity in concepts. The most common references are to the Monson scale (two editions of the monograph on the epidemiology of occupational exposures Monson R.R., 1980; 1990). In our opinion, the optimal graduation can be developed on the basis of this scale, and it should include both the range of no effect (RR = 0.9–1.2) and the weak (RR = 1.2–1.5, or 0.7–0.9), moderate (RR = 1.5–3.0, or 0.4–0.7), strong (RR = 3.0–10.0; or 0.1–0.4) and very strong’(RR = 10.0–40.0; or 0.0–0.1) ranges. Examples of epidemiological effects with overwhelming strength of association are presented (RR &gt; 40.0). For the effects of thalidomide, RR reached thousands, for diethylstilbestrol, conditional infinity, and when irradiated in childhood, the frequency of some cancers increased tens and even hundreds of times. The juristic aspects of compensation payment based on RR are briefly reviewed. According to the Daubert rule (Daubert ruling, Daubert standard) on the 1993 precedent in the United States, risks are recognized only at RR &gt; 2.0, when the probability of causality is more than 50 %. Conclusions: To estimate the RR value, one should use the most common and officially established Monson scale, albeit with an expansion in the range of dramatic or overhelming risks. This study can be used as a reference guide on the graduations of effect size on RR (OR) for a wide variety of observed disciplines.

A statistical approach to fine-mapping for the identification of potential causal variants related to human intelligence.

Genome-wide association studies (GWASs) have identified >20 genetic loci associated with human intelligence. However, due to correlations between the trait-associated SNPs, only a few of the loci are confirmed to have a true biological effect. In order to distinguish the SNPs that have a causal effect on human intelligence, we must eliminate the noise from the high degree of linkage disequilibrium that persists throughout the genome. In this study, we apply a novel PAINTOR fine-mapping method, which uses a Bayesian approach to determine the SNPs with the highest probability of causality. This technique incorporates the GWAS summary statistics, linkage disequilibrium structure, and functional annotations to compute the posterior probability of causality for all SNPs in the GWAS-associated regions. We found five SNPs (rs6002620, rs41352752, rs6568547, rs138592330, and rs28371699) with a high probability of causality, three of which have posterior probabilities >0.60. The SNP rs6002620 (NDUFA6), which is involved in mitochondrial function, has the highest likelihood of causality. These findings provide important insight into the genetic determinants contributing to human intelligence.