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Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.
We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).
One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.
Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
Molecular pathways underlying carcinogenesis: signal transduction
Alexandra K. Gardino, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA,
Michael B. Yaffe, David H. Koch Institute for Integrative Cancer Research and Department of Biological Engineering,Massachusetts Institute of Technology, Cambridge, MA, USA
14-3-3 proteins constitute a family of acidic α-helical cup-shaped dimers that are ubiquitously expressed in all eukaryotic cells. Well over 200 proteins have been identified as 14-3-3-binding ligands, and many of these proteins have established roles in cell-cycle control, DNA damage responses, growth-factor receptor signaling, regulation of gene expression, metabolism, and apoptosis (1–5; Figure 24.1). Early work that hinted at a connection between protein phosphorylation and 14-3-3 binding came from work on tryptophan hydroxylase (6), an enzyme involved in neurotransmitter biosynthesis, and Raf, the upstream activator of the classical MAP kinase pathway (7). Work from the Shaw lab (8), building on detailed phosphorylation studies of Raf by Debbie Morrison's group, revealed that 14-3-3 proteins specifically bound to phosphoserine-containing sequences. That work, together with oriented peptide library screening on all mammalian 14-3-3 proteins by Yaffe and colleagues (9), led to the identification of two optimal phosphoserine/threonine-containing motifs – RSx[pS/pT]xP (mode-1) and Rxxx[pS/pT]xP (mode-2) – that are recognized by all 14-3-3 isotypes (9). Pro in the pS/pT+2 position is not absolutely required (9–11), and an additional motif (mode-3) has been found in proteins where the pS/pT residue is the final or next to the last residue at the C-terminus (12). Although there are clear examples of proteins and peptides that differ from these motifs, or that do not require phosphorylation at all for binding, most 14-3-3 ligands use phosphorylated sequences that closely resemble the optimal 14-3-3 consensus motifs for binding. This ability of 14-3-3 proteins to bind to large numbers of ligands in a phospho-regulated manner provides a mechanism for cytoplasmic Ser/Thr kinases, including kinases that are misregulated in cancer, such as mTor, AKT, and PKC family members, to broadly exert control over many key signaling events required for tumor cell survival.
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