Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues

Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.

With the goal of providing a comprehensive, high-quality resource for both plant transcription factors (TFs) and their regulatory interactions with target genes, we upgraded plant TF database PlantTFDB to version 4.0 (http://planttfdb.cbi.pku.edu.cn/). In the new version, we identified 320 370 TFs from 165 species, presenting a more comprehensive genomic TF repertoires of green plants. Besides updating the pre-existing abundant functional and evolutionary annotation for identified TFs, we generated three new types of annotation which provide more directly clues to investigate functional mechanisms underlying: (i) a set of high-quality, non-redundant TF binding motifs derived from experiments; (ii) multiple types of regulatory elements identified from high-throughput sequencing data; (iii) regulatory interactions curated from literature and inferred by combining TF binding motifs and regulatory elements. In addition, we upgraded previous TF prediction server, and set up four novel tools for regulation prediction and functional enrichment analyses. Finally, we set up a novel companion portal PlantRegMap (http://plantregmap.cbi.pku.edu.cn) for users to access the regulation resource and analysis tools conveniently.

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid β-peptide (Aβ) in Alzheimer's Disease (AD). We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset AD. These variants, which occur in at least two different clusters of intronic sequences may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways, and that when SORL1 is under-expressed, APP is sorted into Aβ-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing AD.

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 × 10-9) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 × 10-8, rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.