HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

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Background Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary Molecular Tumor Board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU). Methods We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based upon next-generation sequencing results of individual patient’s tumor tissue. Clinical and molecular information, previous therapy regimens and outcome parameters were collected. Results Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32 - 536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), EGFR amplification (19/73; 26%) and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization. Conclusion In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable anti-tumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.

The original version of this Article contained a typographical error in the spelling of the author Martin H. de Borst, which was incorrectly given as Martin de Borst. This has now been corrected in both the PDF and HTML versions of the Article.