Providing visualisation support for the analysis of anatomy ontology data

BACKGROUND: Improvements in technology have been accompanied by the generation of large amounts of complex data. This same technology must be harnessed effectively if the knowledge stored within the data is to be retrieved. Storing data in ontologies aids its management; ontologies serve as controlled vocabularies that promote data exchange and re-use, improving analysis. The Edinburgh Mouse Atlas Project stores the developmental stages of the mouse embryo in anatomy ontologies. This project is looking at the use of visual data overviews for intuitive analysis of the ontology data. RESULTS: A prototype has been developed that visualises the ontologies using directed acyclic graphs in two dimensions, with the ability to study detail in regions of interest in isolation or within the context of the overview. This is followed by the development of a technique that layers individual anatomy ontologies in three-dimensional space, so that relationships across multiple data sets may be mapped using physical links drawn along the third axis. CONCLUSION: Usability evaluations of the applications confirmed advantages in visual analysis of complex data. This project will look next at data input from multiple sources, and continue to develop the techniques presented to provide intuitive identification of relationships that span multiple ontologies

Sequence variants with large effects on cardiac electrophysiology and disease.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadFeatures of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease

Understanding genetic architecture of kidney function through analysis of genome-wide arrays

Chronic kidney disease (CKD) is a worldwide public health problem. In the United States, both incidence and prevalence of CKD are rising, leading to increasing morbidity, mortality, and medical costs. Kidney function, such as estimated glomerular filtration rate (eGFR), is heritable. Previous genome-wide association studies (GWAS) have identified 29 genetic loci for eGFR. However, most of the published variants are non-coding and explain a small proportion of eGFR heritability. Moreover, the vast majority of these studies were conducted in European ancestry populations, thus leaving even more unexplained heritability in African Americans. Our objective is to identify additional loci for eGFR in both the European ancestry and African American populations. We conducted a meta-analysis of genome-wide association studies for eGFR with data from up to 133,413 European ancestry individuals from 48 studies. We identified 24 novel genomic loci for kidney function and confirmed association at 29 previously identified ones. In addition, I combined the data from 133,413 European ancestry participants and 16,840 African American participants with trans-ethnic meta-analysis. All previously published loci and more than half of the newly identified loci in European ancestry participants were genome-wide significant in the trans-ethnic meta-analysis. The results from trans-ethnic meta-analysis suggest that some of the genetic loci of eGFR can be generalized across different ancestry groups and we were able to fine-map several of them by leveraging the linkage disequilibrium (LD) structure in African Americans. These observations highlight the importance of large-scale genomic studies in different ancestry groups for identifying kidney function susceptibility loci. Exonic genetic variants with minor allele frequency (MAF) < 5% had not been represented well in existing GWAS. We meta-analyzed the association result from 24 European ancestry studies and 5 African American studies between eGFR and the genetic variants genotyped on the Illumina HumanExome Beadchip (“Exome Array”). In European ancestry, we identified 8 novel loci associated with eGFR that achieved exome array wide significance. The lowest frequency variant that achieved exome array wide significance is at EDEM3 (MAF=2%, p=5.25*10-8), which is involved in endoplasmic reticulum-associated degradation. We also identified a novel gene-based association with eGFR in SOS2 gene using gene-based statistical tests. In African American, we identified 4 novel loci with eGFR and 1 novel gene enriched with rare variants. Our findings suggest there are additional associations to be discovered by leveraging data from coding regions and low frequency variants. Copy number variants (CNVs) have not been explicitly examined in the current GWAS pipeline. To increase our understanding of the role of CNVs in influencing eGFR, we identified 226 and 256 copy number polymorphisms (CNPs) in the European ancestry and African American cohorts in the ARIC study from high-throughput Affymetix arrays using a hidden Markov model and performed genome-wide association analysis of the CNPs and eGFR in each ancestry group separately. We identified a CNP in the European ancestry population on chromosome 5 located in a gene desert approaching Bonferroni statistical significance. The region appears to have transcription factor binding sites as measured from chip-seq experiments in human kidney cell lines. Lastly, this work showed that common CNVs detectable with these methods do not contribute substantially to the heritability of eGFR and further investigations in low-frequency CNVs and other types of CNVs are needed. With these new genotyping technologies and new statistical tools, we were able to look at the association of kidney function with various genetic data. We were able to confirm the known eGFR loci and discovered new loci associated with eGFR that may shed light on new biological pathway related to kidney function and potentially influence targets for treatment of CKD. These results indicate that the genetic architecture of kidney function is more complicated and require further investigation

Proceedings of the RESOLVE Workshop 2002

Proceedings of the RESOLVE Workshop 200

The effects of sequence variants on cardiac function and disease

Introduction and aims: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and its complex pathophysiology is incompletely understood. At the time of beginning of this work, genome-wide association studies (GWAS) on AF had yielded about 30 associations, mostly with common variants in the non-coding genome that affect AF risk through unknown mechanisms. Recently, rare coding variants in the sarcomere genes MYH6 and MYL4 associated with increased risk of AF, representing a novel implication of the sarcomere in arrhythmogenesis in the absence of cardiomyopathy. The aim of this doctoral research was to perform GWASs on AF and search for novel associations. Furthermore, to gain insights into the mechanisms by which novel and published variants affect AF risk by assessing their effects on other cardiovascular diseases and on normal cardiac conduction, using electrocardiogram (ECG) measurements. Through association analysis we observed that one of the strongest AF variants, in MYH6, accounts for 20% of Icelandic cases of coarctation of the aorta (CoA), thus we decided to explore this variant and its effects on structural heart disease in detail resulting in a separate paper. The overall purpose of identifying novel associations of sequence variants with AF is to further the understanding of underlying pathogenesis and facilitate advances in treatment. Methods: We conducted four GWASs. In all cases, genotype information of Icelandic participants was based on whole-genome sequencing of 15,220 and chip-typing of 151,677 individuals performed at deCODE genetics. We tested AF variants for association with measurements in 289,297 sinus rhythm ECGs from 62,974 individuals. Three GWASs on AF and one on CoA were performed: i) A GWAS among 13,471 AF cases and 374,939 controls from Iceland with additional follow up in samples from the US. ii) A meta-analysis of GWAS on AF among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants. Analysis of 167 RNA samples from the right atrium were used to assess the effects of a novel AF variant at the transcript level. iii) A multi-center meta-analysis of GWASs on AF including >1,000,000 participants from six contributing cohorts, including 60,620 AF cases. iv) A GWAS on CoA among 120 cases and 355,166 controls in Iceland. Detailed phenotyping of carriers of a novel variant was performed. Results: We identified novel AF associations with coding variants in three genes which have a role in maintaining cardiac structure; PLEC, RPL3L and MYZAP. Analysis of RNA samples from the right atrium revealed that a splice-donor variant in RPL3L results in exon skipping. Through a meta-analysis involving >1,000,000 participants from six contributing cohorts, 80 novel AF loci were identified. Pathway and functional enrichment analysis suggested variable mechanisms underlying the associations, including effects on structural remodeling. Assessing variants associations with ECG measurements showed diverse effects of AF variants on normal cardiac conduction. We found that one of the strongest AF variants, a missense variant, p.Arg721Trp, in the sarcomere gene MYH6 was found to explain approximately 20% of CoA cases in Iceland. This variant was previously reported to associate with sick sinus syndrome through GWAS and has strong effects on AF risk and ECG measurements in the current study. Conclusion: The results highlight the important role of myocardial structure in the pathogenesis of AF. Furthermore, they support speculations of a role for subclinical atrial cardiomyopathy in the development of arrhythmia. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF and might help inform on underlying biology of specific AF loci in future studies. We demonstrate a pleiotropic effect of p.Arg721Trp in MYH6 on cardiac function and disease. The variant explains a large proportion of CoA cases in Iceland which may be a relevant fact for genetic counseling. The association with MYH6, that encodes a part of the cardiac contractile unit, complies with the hemodynamic theory of CoA development. Combined the results increase understanding of the pathophysiology of both AF and CoA, thus providing knowledge that will hopefully translate into advances in treatment.nngangur og markmið: Gáttatif er algengast viðvarandi hjartsláttartruflana en núverandi skilningur á flókinni meingerð sjúkdómsins er takmarkaður. Við upphaf þessarar vinnu höfðu víðtækar erfðamengisleitir sýnt fram á tengsl milli um 30 erfðabreytileika og gáttatifs. Flestir eru algengir og staðsettir utan útraða gena og tengjast því sjúkdómnum með óþekktum hætti. Nýlega var sýnt fram á að tveir sjaldgæfir erfðabreytileikar í útröðum vöðvaliðagenanna MYH6 og MYL4 auka áhættu á gáttatifi en slík tenging vöðvaliðunnar við hartsláttartruflanir þegar hjartavöðvakvilli var ekki til staðar var nýmæli. Tilgangur þessa doktorsverkefnis var að framkvæma víðtæka erfðamengisleit með það að markmiði að bera kennsl á áður óþekkt tengsl milli erfðabreytileika og gáttatifs. Jafnframt var markmiðið að öðlast innsýn í með hvaða hætti erfðabreytileikar hafa áhrif með því að kanna tengsl þeirra við aðra hjartasjúkdóma og hjartalínuritsbreytur. Í verkefninu skoðuðum við einnig áhrif MYH6 breytileikans á aðra hjartasjúkdóma og reyndist hann einnig auka líkur á meðfæddum ósæðarþrengslum. Þess vegna var einnig framkvæmd víðtæk erfðamengisleit á þeim meðfædda hjartagalla. Megintilgangur þess að finna áður óþekkt tengsl milli erfðabreytileika og áhættu á gáttatifi er að auka skilning á meingerð sjúkdómsins og stuðla með því að framförum í meðhöndlun hans. Aðferðir: Við framkvæmdum fjórar rannsóknir byggðar á víðtækri erfðamengisleit. Í öllum tilvikum byggðust erfðaupplýsingar Íslendinga á heilraðgreiningu 15.220 einstaklinga og örflögugreiningu 151.677 sem framkvæmdar voru hjá Íslenskri erfðagreiningu. Við könnuðum erfðabreytileika sem fundust og tengdust sjúkdómum nánar með því að meta áhrif þeirra á hjartalínuritsbreytur úr 289.297 hjartalínuritum frá 62.974 einstaklingum sem ekki höfðu greinst með gáttatif eða fengið gangráð. Þrjár rannsóknanna fjölluðu fyrst og fremst um gáttatif og sú fjórða um meðfædd ósæðarþrengsli: i) Víðtæk erfðamengisleit meðal 13.471 tilfella gáttatifs og 374.939 viðmiða frá Íslandi. Niðurstöðum var fylgt eftir í bandarískum gögnum. ii) Safnrannsókn víðtækra erfðamengisleita á gáttatifi meðal 29.502 tilfella og 767.760 viðmiða frá Íslandi og Bretlandi (UK Biobank). Niðurstöðum var fylgt eftir í sýnum frá Noregi og Bandaríkjunum. Áhrif tiltekinnar stökkbreytingar á umritun var metin í 167 RNA sýnum úr hægri gátt. iii) Safnrannsókn víðtækra erfðamengisleita meðal >1.000.000 þátttakenda frá sex rannsóknarverkefnum, þ.m.t. 60.620 tilfelli gáttatifs. iv) Víðtæk erfðamengisleit á meðfæddum ósæðarþrengslum meðal 120 tilfella og 355.166 viðmiða frá Íslandi. Nákvæm svipgerðargreining bera tiltekins erfðabreytileika var framkvæmd. Niðurstöður: Við fundum áður óþekkt tengsl milli gáttatifs og erfðabreytileika í útröðum þriggja gena sem öll gegna hlutverki í viðhaldi eðlilegrar byggingar hjartans; PLEC, RPL3L og MYZAP. Greining RNA sýna úr hjarta leiddi í ljós að erfðabreytileiki í RPL3L olli því að ein útröð gensins var ekki umrituð. Stór safnrannsókn meðal rúmlega milljón þátttakenda leiddi í ljós áður óþekkt tengsl á milli 80 erfðabreytileika og gáttatifs og þau gen sem þóttu líklegust til að útskýra tengslin reyndust hafa áhrif á marga ferla, m.a. byggingu hjartans. Erfðabreytileikar sem auka líkur á gáttatifi höfðu fjölbreytt áhrif á hjartalínuritsbreytur. Víðtæk erfðamengisleit á meðfæddum ósæðarþrengslum fann einungis mislestursstökkbreytinguna p.Arg721Trp í MYH6 en hún ein útskýrir um 20% tilfella hjartagallans á Íslandi. Sami erfðabreytileiki hafði áður verið tengdur aukinni áhættu á sjúkum sínushnút og gáttatifi, auk þess að hafa hér víðtæk og sterk áhrif á hjartalínuritsbreytur. Ályktanir: Niðurstöðurnar benda til mikilvægis byggingareininga hjartans í meingerð gáttatifs og styðja kenningar um að hartavöðvakvilli í gáttum hafi þýðingu í þróun sjúkdómsins. Erfðabreytileikar sem auka líkur gáttatifs höfðu fjölbreytt áhrif á rafleiðni í hjartanu sem bendir til að þeir auki líkur á gáttatifi með ólíkum hætti. Kortlagning á tengslum þeirra við hjartalínuritsbreytur gæti gagnast við frekari rannsóknir á með hvaða hætti einstakir erfðabreytileikar tengjast gáttatifi. Fjölbreytt og víðtæk áhrif p.Arg721Trp í MYH6 á hjartasjúkdóma og starfsemi hjartans benda til að þessi breytileiki tengist gáttatifi ekki eingöngu gegnum sterk tengsl við sjúkan sínushnút. Tengsl meðfæddra ósæðarþrengsla við samdráttareiningu hjartans samræmast kenningum um að skert blóðflæði gegnum ósæðina á fósturstigi stuðli að myndun hjartagallans. Erfðabreytileikinn í MYH6 útskýrir stóran hluta tilfella meðfæddra ósæðarþrengsla á Íslandi og gæti sú vitneskja komið að notum í erfðaráðgjöf. Samanlagt veita niðurstöðurnar aukinn skilning á meingerð bæði gáttatifs og meðfæddra ósæðarþrengsla, en slík innsýn er nauðsynlegt skref í átt að bættum meðferðarúrræðum