Friday, April 19, 2019

Bottom line p-values now available in the CDKP

When genetic association analysis for a phenotype is performed in multiple studies, many different p-values representing the significance of that association are generated. How do we know which one is the most accurate?

To complicate things even further, the populations tested in different datasets often overlap with each other. How can we avoid double-counting associations?

Bottom line analysis provides an answer to both of these questions. It integrates results over multiple datasets and accounts for sample overlap between datasets to generate a single p-value representing the significance of the association between a variant and a phenotype.

Now, you can access bottom line p-values for individual variants on Variant pages in the Cerebrovascular Disease Knowledge Portal as well as in the other portals of the Knowledge Portal Network: Type 2 Diabetes KP, Cardiovascular Disease KP, and Sleep Disorder KP. To view bottom line p-values, open the "associations at a glance" section of the Variant page (see an example):



Choose to view "Bottom line analysis" in the PheWAS plot, and then mouse over a point to see the p-value:




We thank our colleagues at the University of Michigan, who developed the METAL method used in this analysis. Please note that this method as instantiated in the CDKP is experimental; be sure to compare the results with those from individual datasets, and contact us with any questions.

Thursday, April 18, 2019

GPS information for BMI and obesity now available

Genome-wide polygenic scores (GPS) have great potential for helping to advance research on complex diseases and traits. Not only can they help predict individual genetic risk, but they can also help us understand the physiology of disease, by identifying groups at the extremes of risk whose clinical profiles can be studied or who may be enrolled in clinical trials.

Following up on their previous work that generated GPSs for five complex diseases, co-lead authors Amit Khera and Mark Chaffin, along with senior author Sekar Kathiresan and colleagues, have now developed a GPS for body mass index (BMI) and obesity, published today in Cell. To help promote obesity research, the authors have provided an open-access file listing the variants and weights that comprise the GPS. That file is now available for download from the Data page of our sister Knowledge Portal, the Cardiovascular Disease Knowledge Portal.

To generate this GPS, Khera and colleagues started with a large, recently published genome-wide association study (GWAS) for BMI in more than 300,000 UK Biobank participants (Locke et al., 2015) and applied an algorithm that assigned a weight to each of 2.1 million variants, also taking into account factors such as the proportion of variants with non-zero effect size and the degree of correlation between a variant and its neighbors. They validated the GPS by applying it to nearly 120,000 additional UK Biobank participants, finding that the score was strongly correlated with measured BMI, and then applied it to four independent testing datasets.

We don't have space here to cover the many interesting details uncovered by the researchers, but overall, this work shows that a high GPS strongly predicts increased risk of severe obesity, cardiometabolic disease, and all-cause mortality. Those with the very highest GPS had a level of risk for obesity similar to that conferred by a rare monogenic mutation in the MC4R gene.

The GPS has the potential to be a powerful tool for people struggling with overweight and obesity. "Importantly, we are in the early days of identifying how we can best inform and empower patients to overcome health risks in their genetic background," said Khera in a press release from the Broad Institute. "We are incredibly excited about the potential to improve health outcomes."

We invite you to read the paper, take a look at the file of variants and weights freely available from the CVDKP Data page, and contact us with any questions!


Friday, March 1, 2019

Faster access to tools from the CDKP home page

We've rearranged some of the links on the Cerebrovascular Disease Knowledge Portal home page, as a first step towards offering a central location for analysis tools. The previous link to the Variant Finder tool has been replaced by a link to the new Analysis modules page:


The new page, shown below, offers access to two analysis tools.



  • The Interactive Manhattan plot allows you to choose a phenotype and view variant associations across the genome for that phenotype.  We've added phenotype selection options to both the Analysis modules page and the Manhattan plot page, making it easier to switch your view between phenotypes.  The default view on the Manhattan plot page shows the largest dataset for a phenotype, but when multiple datasets exist, you can select any one to display. For many datasets, LD clumping is available at several r2 thresholds. Clumping reduces redundancy due to association signals from linked variants, pinpointing the most strongly associated variant in a group.
  • The Variant Finder is a versatile tool that allows you to set multiple criteria (phenotype, p-value, size and direction of effect, and more) and retrieve the set of variants meeting those criteria.
The new Analysis Modules page will be the central access point for new analysis tools as they are developed, so check back often for updates!

The new Analysis Modules page will be the central access point for new analysis tools as they are developed, so check back often for updates!

Monday, January 28, 2019

New dataset added to the CDKP: WMHV GWAS

We are pleased to announce that a new dataset has been added to the Cerebrovascular Disease Knowledge Portal: Cerebral WMHV GWAS 2019, from the recently published study "Genetic variation in PLEKHG1 is associated with white matter hyperintensities" (Traylor et al. 2019). This genome-wide association study consisting of 11,226 individuals sparked the discovery of a locus at genome-wide significance in an intron of PLEKHG1.

Results from this study may be viewed and searched in the CDKP at these locations:

  • on Gene pages (view an example) for the "Cerebral white matter hyperintensities" phenotype
  • on Variant pages (view an example) in the Associations at a glance section, the Associations across all datasets graphic and table, and in LocusZoom static plots
LocusZoom plot of WMHV associations in the PLEKHG1 gene

  • from the View full genetic association results for a phenotype search on the home page: first select the cerebral white matter hyperintensities phenotype and then on the resulting page, select the Cerebral WMHV GWAS 2019 dataset.
Summary statistics may also be downloaded from the CDKP Downloads page.

Please check out these new results and let us know if you have comments or questions!

Wednesday, November 7, 2018

Meet the Knowledge Portal team at AHA

This weekend, cardiovascular researchers from around the globe will be meeting in Chicago for the 2018 Scientific Sessions of the American Heart Association. Members of the Knowledge Portal Network team will be there to meet and talk with geneticists and biologists who use the Portals and get your input on how we can improve them.

Please come visit us at booth #2249 in the Exhibit Hall! We'll be there on Saturday, Nov. 10 from 11am-5pm; on Sunday, Nov. 11 from 10am-4:30pm; and on Monday, Nov. 12 from 10am-3pm.

Friday, October 26, 2018

New features in the CDKP

Today the Cerebrovascular Disease Knowledge Portal has several new features that help bring meaning to genetic association results.

Calculated credible sets

Credible sets are useful because they assign to individual variants in a locus a probability of being causal for a phenotype. On Gene Pages, when viewing the type 2 diabetes (T2D) phenotype, the Credible sets tab displays credible sets generated by the MAGIC consortium. However, credible sets have not been generated by researchers for phenotypes in the CDKP other than T2D.

Now, the CDKP provides calculated credible sets for all phenotypes. When viewing a phenotype other than T2D on the Gene page, the Credible sets tab is replaced by a Calculated credible set tab. This LocusZoom module, developed by researchers at the University of Michigan, automatically calculates posterior probabilities from p-values. Calculated credible sets include up to 10 variants; the credible interval covered by the set may vary, depending on the strength of associations across the region.

UK Biobank PheWAS

The PheWAS display in the "Associations at a glance" section of Variant pages (see an example) is another LocusZoom module for displaying phenome-wide associations. The default PheWAS plot on the Variant page shows associations for a variant across all of the phenotypes included in the CDKP.

Now, by checking the "Use UKBB data" box, you can view associations for a variant across about 1,400 UK Biobank phenotypes from an analysis performed at the University of Michigan.


New LocusZoom visualization shows variant associations across UK Biobank phenotypes


Forest plot visualization of variant associations

We provide yet another LocusZoom visualization on a separate tab of the "Associations at a glance" section of the Variant page. The Forest plot is an alternative way to visualize phenotypic associations for a variant. In addition to displaying the significance of variant associations, the Forest plot also shows their direction of effect and confidence interval.

Forest plot on the Variant page


Check out a new portal!

We've just launched a new member of the Knowledge Portal Network: the Sleep Disorder Knowledge Portal for the genetics of sleep and circadian traits. Find a link to it on the CDKP home page:




We hope you enjoy the new data and features in the CDKP. Please contact us any time with suggestions or questions!


Monday, October 15, 2018

Connect with the Knowledge Portal Network team at ASHG!

Next week, the human genetics research community will come together in San Diego for one of the most important conferences of the year: the annual American Society of Human Genetics meeting. The Knowledge Portal Network team will be there, and in addition to presenting all the new data and features in the Type 2 DiabetesCerebrovascular Disease, and Cardiovascular Disease Knowledge Portals (KPs), we'll be launching an entirely new Portal for the genetics of sleep disorders!

We'll also present an interactive workshop on Friday that will go over the basics of navigating the Knowledge Portal Network. Download the flyer here, and find more details below.

Here's the schedule of events for the week:

Tuesday, October 16
2:05-2:30 pm: Jason Flannick will present a talk, "Infrastructure for analyzing and disseminating large-scale genetic data for type 2 diabetes and other complex diseases," in the ASHG/IGES/ISCB Joint Symposium.
Room 6C - Upper Level/San Diego Convention Center

Wednesday, October 17
The Knowledge Portal team will be at our booth, #219, in the exhibit hall from 10am-4:30pm.
We'll also be at the Broad Institute Genomic Services booth, #1634, from 10:30-11:30am.

Thursday, October 18
The team will again be at our booth, #219, in the exhibit hall from 10am-4:30pm.

Friday, October 19
We'll again be at our booth, #219, in the exhibit hall from 10am- 4:30pm, but today the booth will be closed around lunchtime so that we can present a special tutorial session on the Knowledge Portals. See details and sign up below. After the session, we'll be back at our booth until 4:30pm and will also be at the Broad Institute Genomic Services booth, #1634, from 2:30 - 3:30pm.

At lunchtime on Friday, grab your laptop and come to a workshop on the Knowledge Portals:

Navigating complex disease genetics: using the Knowledge Portal Network to move from SNPs to functional insights
12:30-1:45pm
Room 28C, Upper Level, San Diego Convention Center

We'll go over some basics, illustrate workflows, and answer questions about how you can use KPs to investigate SNPs, genes, or regions of interest and turn genetic data into insights about complex diseases.

Please sign up so we can plan for refreshments. We'll send you a reminder a few days beforehand. We look forward to seeing you there! Please contact us with any questions or suggestions for topics you'd like to discuss.