Mineralocorticoid receptor haplotypes sex-dependently moderate depression susceptibility following childhood maltreatment
PSYCHONEUROENDOCRINOLOGY
Authors: Vinkers, Christiaan H.; Joels, Marian; Milaneschi, Yuri; Gerritsen, Lotte; Kahn, Rene S.; Penninx, Brenda W. J. H.; Boks, Marco P. M.
Abstract
The MR is an important regulator of the hypothalamic-pituitary-adrenal (HPA) axis and a prime target for corticosteroids. There is increasing evidence from both clinical and preclinical studies that the MR has different effects on behavior and mood in males and females. To investigate the hypothesis that the MR sex-dependently influences the relation between childhood maltreatment and depression, we investigated three common and functional MR haplotypes (GA, CA, and CG haplotype, based on rs5522 and rs2070951) in a population-based cohort (N=665) and an independent clinical cohort from the Netherlands Study of Depression and Anxiety (NESDA) (N=1639). The CA haplotype sex-dependently moderated the relation between childhood maltreatment and depressive symptoms both in the population-based sample (sex x maltreatment x haplotype: beta=-4.07, P=0.029) and in the clinical sample (sex x maltreatment x haplotype, beta=-2.40, P=0.011). Specifically, female individuals in the population-based sample were protected (beta = -4.58, P=2.0e(-5)), whereas males in the clinical sample were at increased risk (beta=2.54, P=0.0022). In line with these results, female GA haplotype carriers displayed increased vulnerability in the population-based sample (beta=4.58, P=7.5e(-5)) whereas male CG-carriers showed increased resilience in the clinical sample (beta=-2.71, P=0.016). Consistently, we found a decreased lifetime MDD risk for male GA haplotype carriers following childhood maltreatment but an increased risk for male CA haplotype carriers in the clinical sample. In both samples, sex-dependent effects were observed for GA-GA diplotype carriers. In summary, sex plays an important role in determining whether functional genetic variation in MR is beneficial or detrimental, with an apparent female advantage for the CA haplotype but male advantage for the GA and CG haplotype. These sex-dependent effects of MR on depression susceptibility following childhood maltreatment are relevant in light of the increased prevalence of mood disorders in women and point to a sex-specific role of MR in the etiology of depression following childhood maltreatment. (C) 2015 Elsevier Ltd. All rights reserved.
Gene expression-based biomarkers for discriminating early and late stage of clear cell renal cancer
SCIENTIFIC REPORTS
Authors: Bhalla, Sherry; Chaudhary, Kumardeep; Kumar, Ritesh; Sehgal, Manika; Kaur, Harpreet; Sharma, Suresh; Raghava, Gajendra P. S.
Abstract
In this study, an attempt has been made to identify expression-based gene biomarkers that can discriminate early and late stage of clear cell renal cell carcinoma (ccRCC) patients. We have analyzed the gene expression of 523 samples to identify genes that are differentially expressed in the early and late stage of ccRCC. First, a threshold-based method has been developed, which attained a maximum accuracy of 71.12% with ROC 0.67 using single gene NR3C2. To improve the performance of thresholdbased method, we combined two or more genes and achieved maximum accuracy of 70.19% with ROC of 0.74 using eight genes on the validation dataset. These eight genes include four underexpressed (NR3C2, ENAM, DNASE1L3, FRMPD2) and four overexpressed (PLEKHA9, MAP6D1, SMPD4, C11orf73) genes in the late stage of ccRCC. Second, models were developed using state-of-art techniques and achieved maximum accuracy of 72.64% and 0.81 ROC using 64 genes on validation dataset. Similar accuracy was obtained on 38 genes selected from subset of genes, involved in cancer hallmark biological processes. Our analysis further implied a need to develop gender-specific models for stage classification. A web server, CancerCSP, has been developed to predict stage of ccRCC using gene expression data derived from RNAseq experiments.