Major depressive disorder (MDD), one of the most frequently encountered forms of mental illness and a leading cause of disability worldwide1, poses a major challenge to genetic analysis. To date no robustly replicated genetic loci have been identified 2, despite analysis of more than 9,000 cases3. Using low coverage genome sequence of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, we identified and replicated two genome-wide significant loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene (P-value = 2.53×10−10) the other in an intron of the LHPP gene (P = 6.45×10−12). Analysis of 4,509 cases with a severe subtype of MDD, melancholia, yielded an increased genetic signal at the SIRT1 locus. We attribute our success to the recruitment of relatively homogeneous cases with severe illness.
Comparative population genomics offers an opportunity to discover the signatures of artificial selection during animal domestication, however, their function cannot be directly revealed. We discover the selection signatures using genome-wide comparisons among 40 mallards, 36 indigenous-breed ducks, and 30 Pekin ducks. Then, the phenotypes are fine-mapped based on resequencing of 1026 ducks from an F2 segregating population generated by wild × domestic crosses. Interestingly, the two key economic traits of Pekin duck are associated with two selective sweeps with fixed mutations. A novel intronic insertion most possibly leads to a splicing change in MITF accounted for white duck down feathers. And a putative long-distance regulatory mutation causes continuous expression of the IGF2BP1 gene after birth which increases body size by 15% and feed efficiency by 6%. This study provides new insights into genotype–phenotype associations in animal research and constitutes a promising resource on economically important genes in fowl.
SummaryAdversity, particularly in early life, can cause illness. Clues to the responsible mechanisms may lie with the discovery of molecular signatures of stress, some of which include alterations to an individual’s somatic genome. Here, using genome sequences from 11,670 women, we observed a highly significant association between a stress-related disease, major depression, and the amount of mtDNA (p = 9.00 × 10−42, odds ratio 1.33 [95% confidence interval [CI] = 1.29–1.37]) and telomere length (p = 2.84 × 10−14, odds ratio 0.85 [95% CI = 0.81–0.89]). While both telomere length and mtDNA amount were associated with adverse life events, conditional regression analyses showed the molecular changes were contingent on the depressed state. We tested this hypothesis with experiments in mice, demonstrating that stress causes both molecular changes, which are partly reversible and can be elicited by the administration of corticosterone. Together, these results demonstrate that changes in the amount of mtDNA and telomere length are consequences of stress and entering a depressed state. These findings identify increased amounts of mtDNA as a molecular marker of MD and have important implications for understanding how stress causes the disease.
We have demonstrated that the angiotensin-converting enzyme (ACE) genotype is associated with Alzheimer's disease (AD) in the Japanese population (1). To determine why ACE affects susceptibility to AD, we examined the effect of purified ACE on aggregation of the amyloid -peptide (A) in vitro. Surprisingly, ACE was found to significantly inhibit A aggregation in a dose response manner. The inhibition of aggregation was specifically blocked by preincubation of ACE with an ACE inhibitor, lisinopril. ACE was confirmed to retard A fibril formation with electron microscopy. ACE inhibited A deposits on a synthaloid plate, which was used to monitor A deposition on autopsied brain tissue. ACE also significantly inhibited A cytotoxicity on PC12 h. The most striking fact was that ACE degraded A by cleaving A-(1-40) at the site Asp 7 -Ser 8 . This was proven with reverse-phase HPLC, amino acid sequence analysis, and MALDI-TOF/MS. Compared with A-(1-40), aggregation and cytotoxic effects of the degradation products A-(1-7) and A-(8 -40) peptides were reduced or virtually absent. These findings led to the hypothesis that ACE may affect susceptibility to AD by degrading A and preventing the accumulation of amyloid plaques in vivo.Progressive cerebral dysfunction in Alzheimer's disease (AD) 1 is accompanied by innumerable extracellular amyloid deposits in the form of senile plaque and microvascular amyloid. Amyloid protein is derived from the integral membrane polypeptide, -amyloid precursor protein (APP). The released 39 -43 residue amyloid -peptide (A) may subsequently undergo aggregation to form amyloid fibrils under the influence of various amyloid-associated factors (2). The aggregation and deposition of A has been linked to the toxic effects causing cell damage in AD. Because A is present in both normal and AD subjects, an answer to the question of why A accumulates in AD but not in the normal brain may lead to a possible cure for AD.Angiotensin-converting enzyme (ACE; dipeptidyl carboxypeptidase, EC 3.4.15.1) is a membrane-bound ectoenzyme. It catalyzes the conversion of angiotensin I (AngI) to angiotensin II (AngII), which plays an important role in blood pressure and body fluid and sodium homeostasis (3). The cloning of the ACE gene revealed a 287-bp insertion (I)/deletion (D) polymorphism in intron 16. The serum ACE activity of the ACE DD genotype was twice as high as that of the ACE II genotype (4). The ACE genotype is considered to be associated with hypertension, coronary artery disease, left ventricular hypertrophy, myocardial infarction, and diabetic nephropathy (5-7). In particular, the ACE DD genotype is considered to be a risk factor for vascular diseases.We have compared the distribution of an I/D polymorphism of the gene coding for ACE in 133 Japanese sporadic AD patients and 257 control subjects (1). The association between AD and ACE genotypes or alleles was found to be significant. The frequency of the ACE II genotype was 1.4ϫ higher in AD than in controls, whereas that of ACE DD gen...
Background ALKBH5 regulated the malignant behavior of breast cancer and glioblastoma. However, the expression and function of ALKBH5 in epithelial ovarian cancer have not yet been determined. In the present study, we investigated the expression and function of ALKBH5 in epithelial ovarian cancer with respect to its potential role in the tumorigenesis of the disease as well as an early diagnostic marker. Methods Immunohistochemistry and western blot were used to detect protein expression. Gene silencing and over-expression experiment were used to study gene function. Cell proliferation assay and Matrigel invasion assays were used to detect cell proliferation and invasion, respectively. The nude mouse tumor formation experiment was used to evaluate the growth of cells in vivo. Results The expression of ALKBH5 was found to be increased in epithelial ovarian cancer tissue as compared to the normal ovarian tissues. The silencing of ALKBH5 in SKOV3 cells enhanced the autophagy and inhibited the proliferation and invasion in vitro and in vivo, whereas the ectopic expression of ALKBH5 in A2780 cells exerted an opposite effect. Mechanical study revealed that ALKBH5 physically interacted with HuR. ALKBH5 activated EGFR-PIK3CA-AKT-mTOR signaling pathway. Also, ALKBH5 enhanced the stability of BCL-2 mRNA and promoted the interaction between Bcl-2 and Beclin1. Conclusion Overall, the present study identified ALKBH5 as a candidate oncogene in epithelial ovarian cancer and a potential target for ovarian cancer therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1159-2) contains supplementary material, which is available to authorized users.
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