Lower-Order Effects Adjustment in Quantitative Traits Model-Based Multifactor Dimensionality Reduction

Identifying gene-gene interactions or gene-environment interactions in studies of human complex diseases remains a big challenge in genetic epidemiology. An additional challenge, often forgotten, is to account for important lower-order genetic effects. These may hamper the identification of genuine epistasis. If lower-order genetic effects contribute to the genetic variance of a trait, identified statistical interactions may simply be due to a signal boost of these effects. In this study, we restrict attention to quantitative traits and bi-allelic SNPs as genetic markers. Moreover, our interaction study focuses on 2-way SNP-SNP interactions. Via simulations, we assess the performance of different corrective measures for lower-order genetic effects in Model-Based Multifactor Dimensionality Reduction epistasis detection, using additive and co-dominant coding schemes. Performance is evaluated in terms of power and familywise error rate. Our simulations indicate that empirical power estimates are reduced with correction of lower-order effects, likewise familywise error rates. Easy-to-use automatic SNP selection procedures, SNP selection based on “top” findings, or SNP selection based on p-value criterion for interesting main effects result in reduced power but also almost zero false positive rates. Always accounting for main effects in the SNP-SNP pair under investigation during Model-Based Multifactor Dimensionality Reduction analysis adequately controls false positive epistasis findings. This is particularly true when adopting a co-dominant corrective coding scheme. In conclusion, automatic search procedures to identify lower-order effects to correct for during epistasis screening should be avoided. The same is true for procedures that adjust for lower-order effects prior to Model-Based Multifactor Dimensionality Reduction and involve using residuals as the new trait. We advocate using “on-the-fly” lower-order effects adjusting when screening for SNP-SNP interactions using Model-Based Multifactor Dimensionality Reduction analysis

Performance of model-based multifactor dimensionality reduction methods for epistasis detection by controlling population structure

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Multiple Epistasis Interactions Within MHC Are Associated With Ulcerative Colitis

Successful searching for epistasis is much challenging, which generally requires very large sample sizes and/or very dense marker information. We exploited the largest Crohn's disease (CD) dataset (18,000 cases + 34,000 controls) and ulcerative colitis (UC) dataset (14,000 cases + 34,000 controls) to date. Leveraging its dense marker information and the large sample size of this IBD dataset, we employed a two-step approach to exhaustively search for epistasis. We detected abundant genome-wide significant (p < 1 × 10−13) epistatic signals, all within the MHC region. These signals were reduced substantially when conditional on the additive background, but still nine pairs remained significant at the Immunochip-wide level (P < 1.1 × 10−8) in conditional tests for UC. All these nine epistatic interactions come from the MHC region, and each explains on average 0.15% of the phenotypic variance. Eight of them were replicated in a replication cohort. There are multiple but relatively weak interactions independent of the additive effects within the MHC region for UC. Our promising results warrant the search for epistasis in large data sets with dense markers, exploiting dependencies between markers

ОСОБЕННОСТИ ПАТОМОРФОЗА ПРИ СОНОДИНАМИЧЕСКОЙ ХИМИОТЕРАПИИ НА ЭТАПАХ ЛУЧЕВОГО ЛЕЧЕНИЯ РАКА СЛИЗИСТОЙ ОБОЛОЧКИ ПОЛОСТИ РТА

Abstract.Morphological response of the tumor was investigated after sonodynamic chemotherapy during distal gamma-therapy (DGT) in patients with cancer of the oral cavity. Sixty-one patients were divided into two groups: group 1 (n=31) received DGT and local ultrasound treatment (0,88 MHz±0,33% and I=1,0Вm/cm2) with 5 mg of platidiam  and group 2 (n=30) received only DGT. Biopsies were investigated by standard morphological and immunohistochemical analysis after achieving total dose of radiation 40 Gy. In the main group the mass of stroma increased 1,9 times after starting of treatment and 1,6 times in comparison with the control group, mitotic activity of the cells decreased 3,9 and 1,9 times respectively, and index of parenchymal damage was 2,4 times higher in the main group than in the control. There was fibrosis and focuses of cells with “cells – shadows” with dystrophic changes of the nucleus and cytoplasma.There was a high index of Ki-67 proliferating activity (60-75%) and high apoptotic index (50-65%) of all cell layers.  The rate of Ki-67 and gene p53 decreased 1,3 and 1,5 times respectively after treatment. In specimens of the main group basal layer cells expressed Ki-67 and p53 in 10-15% of area and didn’t differ from normal values. The rate of KI-67 and expression of p53 gene decreased 7.1 and 6.5 after treatment. Sonodynamic chemotherapy contributes to the suppression of the biological aggressiveness of the tumor, provides a much more pronounced antitumor effect compared to the effect of ionizing radiation alone.Исследовали  морфологический  ответ опухоли на воздействие,  включающее проведение  сонодинамической химиотерапии при дистанционной гамматерапии (ДГТ) рака  слизистой  оболочки  полости  рта (РСПР). 61 больной РПСР были разделены  на основную (31 больному  при ДГТ проводилась   локально  на очаг  опухоли 5 мг платидиама  с помощью  ультразвукового  воздействия  частотой  0,88 МГц±0,33%, и I=1,0Вm/см2) и контрольную (30 больным, сопоставимым по клиническим параметрам,  проводилась  только аналогичная ДГТ) группы. До лечения и после планового перерыва на дозе 40 Гр исследовались  биоптаты опухолей по стандартным морфологическим и иммуногистохимическим методикам. В основной группе доля стромы опухоли увеличилась в 1,9 раз, чем до лечения и в 1,6 раз против контроля, митотическая активность клеток снизилась  в 3,9 и 1,9 раз соответственно, а индекс повреждения паренхимы был выше в 2,4 раза чем в контрольной. Определялся  выраженный фиброз,  наблюдались фокусы клеток, представленные  «клетками — тенями», с выраженными дистрофическими изменениями ядра и цитоплазмыВ контрольной группе было отмечено  сохранение  высокого индекса  пролиферации  Ki-67 (60–75%)  и высокий апоптотический индекс (50–65%)  всех клеточных слоев опухоли. Уровень маркера  Ki-67 и экспрессия мутагенного гена р53 по сравнению с исходными данными снизилась лишь в 1,3 и в 1,5 раз соответственно. В образцах опухоли основной группы клетки базального слоя плоского эпителия вокруг опухоли экспрессировали  Ki-67, p53 в 10–15%  площади и не отличались от нормальных показателей. Уровень маркера  Ki-67 и экспрессия мутагенного гена р53 по сравнению с исходными данными снизились в 7,1 и 6,5 раз соответственно. Таким образом,  сонодинамическая химиотерапия способствует подавлению биологической агрессивности опухоли, обеспечивает существенно более выраженный противоопухолевый эффект по сравнению с действием только ионизирующего излучения

High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.

This is the author accepted manuscript. The final version is available from NPG at http://www.nature.com/ng/journal/v47/n2/full/ng.3176.html#acknowledgmentsGenome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.We would like to thank the International PSC study group (http://www.ipscsg.org/) for sharing data. We are grateful to B.A. Lie and K. Holm for helpful discussions. J.D.R. holds a Canada Research Chair, and this work was supported by a US National Institute of Diabetes and Digestive and Kidney Diseases grant (NIDDK; R01 DK064869 and U01 DK062432). The laboratory of A.F. is supported by the German Ministry of Education and Research (BMBF) grant program e:Med (sysINFLAME). A.F. receives infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence 'Inflammation at Interfaces' and holds an endowment professorship (Peter Hans Hofschneider Professorship) of the Foundation for Experimental Biomedicine (Zurich, Switzerland). Grant support for T.H.K. and A.F. was received from the European Union Seventh Framework Programme (FP7/2007-2013, grant number 262055, ESGI). M.N.C. is supported by the Intramural Research Program of the US National Institutes of Health (NIH), Frederick National Laboratory, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. J.C.B. was supported by a Wellcome Trust grant (WT098051). D.M. and V.K. are supported by the NIHR Cambridge Biomedical Research Centre. L.P.S. is supported by an NIDDK grant (U01 DK062429-14). J.A.T. is supported by the UK Medical Research Council. D.P.B.M. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, the European Union (305479) and by grants from the NIDDK (U01 DK062413, P01 DK046763-19, U54 DE023789-01), the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI067068) and the Agency for Healthcare Research and Quality (AHRQ; HS021747). R.H.D. holds the Inflammatory Bowel Disease Genetic Research endowed chair at the University of Pittsburgh and was supported by an NIDDK grant (U01 DK062420) and a US National Cancer Institute grant (CA141743). S.L.H. and J.R.O. would like to also acknowledge the support of the US NIH (R01 NS049477 and 1U19 A1067152) and the National Multiple Sclerosis Society (RG 2899-D11). S.L. wishes to acknowledge support from the Australian National Health and Medical Research Council (R.D. Wright Career Development Fellowship, APP1053756)

Analiza družbene odgovornosti podjetja BTC

Large-scale epistasis studies can give new clues to system-level genetic mechanisms and a better understanding of the underlying biology of human complex disease traits. Though many novel methods have been proposed to carry out such studies, so far only a few of them have demonstrated replicable results. Here, we propose a minimal protocol for genome-wide association interaction (GWAI) analysis to identify gene-gene interactions from large-scale genomic data. The different steps of the developed protocol are discussed and motivated, and encompass interaction screening in a hypothesis-free and hypothesis-driven manner. In particular, we examine a wide range of aspects related to epistasis discovery in the context of complex traits in humans, hereby giving practical recommendations for data quality control, variant selection or prioritization strategies and analytic tools, replication and meta-analysis, biological validation of statistical findings and other related aspects. The minimal protocol provides guidelines and attention points for anyone involved in GWAI analysis and aims to enhance the biological relevance of GWAI findings. At the same time, the protocol improves a better assessment of strengths and weaknesses of published GWAI methodologies

A cautionary note on the impact of protocol changes for genome-wide association SNP × SNP interaction studies: an example on ankylosing spondylitis

Genome-wide association interaction (GWAI) studies have increased in popularity. Yet to date, no standard protocol exists. In practice, any GWAI workflow involves making choices about quality control strategy, SNP filtering, linkage disequilibrium (LD) pruning, analytic tool to model or to test for genetic interactions. Each of these can have an impact on the final epistasis findings and may affect their reproducibility in follow-up analyses. Choosing an analytic tool is not straightforward, as different tools exist and current understanding about their performance is based on often very particular simulation settings. In the present study, we wish to create awareness for the impact of (minor) changes in a GWAI analysis protocol can have on final epistasis findings. In particular, we investigate the influence of marker selection and marker prioritization strategies, LD pruning and the choice of epistasis detection analytics on study results, giving rise to 8 GWAI protocols. Discussions are made in the context of the ankylosing spondylitis (AS) data obtained via the Wellcome Trust Case Control Consortium (WTCCC2). As expected, the largest impact on AS epistasis findings is caused by the choice of marker selection criterion, followed by marker coding and LD pruning. In MB-MDR, co-dominant coding of main effects is more robust to the effects of LD pruning than additive coding. We were able to reproduce previously reported epistasis involvement of HLA-B and ERAP1 in AS pathology. In addition, our results suggest involvement of MAGI3 and PARK2, responsible for cell adhesion and cellular trafficking. Gene ontology biological function enrichment analysis across the 8 considered GWAI protocols also suggested that AS could be associated to the central nervous system malfunctions, specifically, in nerve impulse propagation and in neurotransmitters metabolic processes.status: publishe

A robustness study of parametric and non-parametric tests in model-based multifactor dimensionality reduction for epistasis detection

Applying a statistical method implies identifying underlying (model) assumptions and checking their validity in the particular context. One of these contexts is association modeling for epistasis detection. Here, depending on the technique used, violation of model assumptions may result in increased type I error, power loss, or biased parameter estimates. Remedial measures for violated underlying conditions or assumptions include data transformation or selecting a more relaxed modeling or testing strategy. Model-Based Multifactor Dimensionality Reduction (MB-MDR) for epistasis detection relies on association testing between a trait and a factor consisting of multilocus genotype information. For quantitative traits, the framework is essentially Analysis of Variance (ANOVA) that decomposes the variability in the trait amongst the different factors. In this study, we assess through simulations, the cumulative effect of deviations from normality and homoscedasticity on the overall performance of quantitative Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect 2-locus epistasis signals in the absence of main effects.status: publishe

Population-specific adaptation in malaria-endemic regions of Asia

Evolutionary mechanisms of adaptation to malaria are understudied in Asian endemic regions despite a high prevalence of malaria in the region. In our research, we performed genome-wide screening for footprints of natural selection against malaria by comparing eight Asian population groups from malaria-endemic regions with two non-endemic population groups from Europe and Mongolia. We identified 285 adaptive genes showing robust selection signals across three statistical methods, iHS, XP-EHH, and PBS. Interestingly, most of the identified genes (82%) were found to be under selection in a single population group, while adaptive genes shared across populations were rare. This is likely due to the independent adaptation history in different endemic populations. The gene ontology analysis for the 285 adaptive genes highlighted their functional processes linked to neuronal organizations or nervous system development. These genes could be related to cerebral malaria and may reduce the inflammatory response and the severity of malaria symptoms. Remarkably, our novel population genomic approach identified population-specific adaptive genes potentially against malaria infection without the need for patient samples or individual medical records.Ministry of Education (MOE)Published versionThis research was supported by the Singapore Ministry of Education, Academic Research Fund Tier 1 (2017-T1-001-046). The computational work for this article was performed in part on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg) supported by Project 12000454