Enhanced Activity of Meprin-α, a Pro-Migratory and Pro-Angiogenic Protease, in Colorectal Cancer

Meprin-α is a metalloprotease overexpressed in cancer cells, leading to the accumulation of this protease in a subset of colorectal tumors. The impact of increased meprin-α levels on tumor progression is not known. We investigated the effect of this protease on cell migration and angiogenesis in vitro and studied the expression of meprin-α mRNA, protein and proteolytic activity in primary tumors at progressive stages and in liver metastases of patients with colorectal cancer, as well as inhibitory activity towards meprin-α in sera of cancer patient as compared to healthy controls. We found that the hepatocyte growth factor (HGF)- induced migratory response of meprin-transfected epithelial cells was increased compared to wild-type cells in the presence of plasminogen, and that the angiogenic response in organ-cultured rat aortic explants was enhanced in the presence of exogenous human meprin-α. In patients, meprin-α mRNA was expressed in colonic adenomas, primary tumors UICC (International Union Against Cancer) stage I, II, III and IV, as well as in liver metastases. In contrast, the corresponding protein accumulated only in primary tumors and liver metastases, but not in adenomas. However, liver metastases lacked meprin-α activity despite increased expression of the corresponding protein, which correlated with inefficient zymogen activation. Sera from cancer patients exhibited reduced meprin-α inhibition compared to healthy controls. In conclusion, meprin-α activity is regulated differently in primary tumors and metastases, leading to high proteolytic activity in primary tumors and low activity in liver metastases. By virtue of its pro-migratory and pro-angiogenic activity, meprin-α may promote tumor progression in colorectal cancer

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

FMR1, circadian genes and depression: suggestive associations or false discovery?

BACKGROUND: There are several indications that malfunctions of the circadian clock contribute to depression. To search for particular circadian gene polymorphisms associated with depression, diverse polymorphisms were genotyped in two samples covering a range of depressed volunteers and participants with normal mood. METHODS: Depression mood self-ratings and DNA were collected independently from a sample of patients presenting to a sleep disorders center (1086 of European origin) and from a separate sample consisting of 399 participants claiming delayed sleep phase symptoms and 406 partly-matched controls. A custom Illumina Golden Gate array of 768 selected single nucleotide polymorphisms (SNPs) was assayed in both samples, supplemented by additional SNPlex and Taqman assays, including assay of 41 ancestry-associated markers (AIMs) to control stratification. RESULTS: In the Sleep Clinic sample, these assays yielded Bonferroni-significant association with depressed mood in three linked SNPs of the gene FMR1: rs25702 (nominal P=1.77E-05), rs25714 (P=1.83E-05), and rs28900 (P=5.24E-05). This FMR1 association was supported by 8 SNPs with nominal significance and a nominally-significant gene-wise set test. There was no association of depressed mood with FMR1 in the delayed sleep phase case–control sample or in downloaded GWAS data from the GenRED 2 sample contrasting an early-onset recurrent depression sample with controls. No replication was located in other GWAS studies of depression. Our data did weakly replicate a previously-reported association of depression with PPARGC1B rs7732671 (P=0.0235). Suggestive associations not meeting strict criteria for multiple testing and replication were found with GSK3B, NPAS2, RORA, PER3, CRY1, MTNR1A and NR1D1. Notably, 16 SNPs nominally associated with depressed mood (14 in GSK3B) were also nominally associated with delayed sleep phase syndrome (P=3E10(-6)). CONCLUSIONS: Considering the inconsistencies between samples and the likelihood that the significant three FMR1 SNPs might be linked to complex polymorphisms more functionally related to depression, large gene resequencing studies may be needed to clarify the import for depression of these circadian genes

FMR1, circadian genes and depression: suggestive associations or false discovery?

Abstract Background There are several indications that malfunctions of the circadian clock contribute to depression. To search for particular circadian gene polymorphisms associated with depression, diverse polymorphisms were genotyped in two samples covering a range of depressed volunteers and participants with normal mood. Methods Depression mood self-ratings and DNA were collected independently from a sample of patients presenting to a sleep disorders center (1086 of European origin) and from a separate sample consisting of 399 participants claiming delayed sleep phase symptoms and 406 partly-matched controls. A custom Illumina Golden Gate array of 768 selected single nucleotide polymorphisms (SNPs) was assayed in both samples, supplemented by additional SNPlex and Taqman assays, including assay of 41 ancestry-associated markers (AIMs) to control stratification. Results In the Sleep Clinic sample, these assays yielded Bonferroni-significant association with depressed mood in three linked SNPs of the gene FMR1: rs25702 (nominal P=1.77E-05), rs25714 (P=1.83E-05), and rs28900 (P=5.24E-05). This FMR1 association was supported by 8 SNPs with nominal significance and a nominally-significant gene-wise set test. There was no association of depressed mood with FMR1 in the delayed sleep phase case–control sample or in downloaded GWAS data from the GenRED 2 sample contrasting an early-onset recurrent depression sample with controls. No replication was located in other GWAS studies of depression. Our data did weakly replicate a previously-reported association of depression with PPARGC1B rs7732671 (P=0.0235). Suggestive associations not meeting strict criteria for multiple testing and replication were found with GSK3B, NPAS2, RORA, PER3, CRY1, MTNR1A and NR1D1. Notably, 16 SNPs nominally associated with depressed mood (14 in GSK3B) were also nominally associated with delayed sleep phase syndrome (P=3E10-6). Conclusions Considering the inconsistencies between samples and the likelihood that the significant three FMR1 SNPs might be linked to complex polymorphisms more functionally related to depression, large gene resequencing studies may be needed to clarify the import for depression of these circadian genes

Genetic variants associated with sleep disorders.

ObjectiveThe diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders.MethodsPatients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance.ResultsIn peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep.ConclusionsSNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations