Monday, October 8, 2018

DIAMANTE GWAS dataset adds close to a million samples along with fine-mapping to the T2DKP

In a groundbreaking paper published today, Anubha Mahajan and colleagues (Mahajan et al., Nature Genetics 2018) report on a meta-analysis of unprecedented size for genetic associations with type 2 diabetes (T2D) along with fine-mapping analyses to identify causal variants that can suggest new therapeutic targets. We are pleased to provide access to the summary results as well as the results of the fine-mapping today in the T2D Knowledge Portal (T2DKP).

Working as part of the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) and DIAMANTE (DIAbetes Meta-ANalysis of Trans-Ethnic association studies) consortia, the researchers aggregated and meta-analyzed genome-wide association studies for about 900,000 individuals of European ancestry (about 74,000 T2D cases and 824,000 controls). The studies were imputed using the most comprehensive reference panels possible, and in all, the analysis considered about 27 million genotyped or imputed variants.

After performing T2D association analysis (both unadjusted and adjusted for body mass index) 243 loci were seen to be associated with T2D at genome-wide significance or better (p-value for association ≤ 5 x 10-8). Of these, 135 were novel--not detected previously in any T2D association analysis to date.

Within these loci, each of which included multiple significantly associated variants, the researchers performed approximate conditional analysis to determine whether the associations were independent of each other. They found surprising complexity within some loci; for example, the well-known TCF7L2 locus appears to include as many as 8 distinct association signals!

All of the T2D associations from this study may be viewed in the T2DKP. They are represented in two datasets, named "DIAMANTE (European) T2D GWAS" and "UK Biobank T2D GWAS (DIAMANTE-Europeans Sept 2018)."  Manhattan plots showing the distribution of the associations across the genome may be seen by selecting either the "Type 2 diabetes" or "Type 2 diabetes adj BMI" phenotypes from the phenotype selection menu on the T2DKP home page. On Gene pages of the T2DKP, the results may be viewed in tables of variant associations and in the interactive LocusZoom visualization (see below). Results from this study are also displayed on Variant pages of the T2DKP.

LocusZoom plot on the PPARG Gene page

The credible set analysis performed in this study is also incorporated into the T2DKP. On the "Credible sets" tab of Gene pages, you may choose to visualize any of the credible sets available for the region. Epigenomic annotations that overlap the positions of the variants in the credible set are presented in an interactive display that allows you to select particular chromatin states or tissues to view. In the example shown below, one of the credible sets in the TCF7L2 region includes just two variants, and the one with the highest posterior probability overlaps active enhancer regions in adipose and liver tissue--both of which are important for T2D.

Detail of the Credible sets tab of the TCF7L2 Gene page

The multiple causal variants identified in this study support previous investigations on the biological mechanisms behind T2D and suggest new hypotheses that will likely lead to therapeutic insights. After reading the paper and a blog post from the authors, we invite you to explore the results in the T2DKP and to contact us with any suggestions or questions!

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