Are Keratoacanthomas Variants of Squamous Cell Carcinomas? A Comparison of Chromosomal Aberrations by Comparative Genomic Hybridization

Keratoacanthoma (KA) is a benign keratinocytic neoplasm that usually presents as a solitary nodule on sun-exposed areas, develops within 6–8 weeks and spontaneously regresses after 3–6 months. KAs share features such as infiltration and cytological atypia with squamous cell carcinomas (SCCs). Furthermore, there are reports of KAs that have metastasized, invoking the question of whether or not KA is a variant of SCC. To date no reported criteria are sensitive enough to discriminate reliably between KA and SCC, and consequently there is a clinical need for discriminating markers. We screened fresh frozen material from 132 KAs and 37 SCCs for gross chromosomal aberrations by using comparative genomic hybridization (CGH). Forty-nine KAs (37.1%) and 31 SCCs (83.7%) showed genomic aberrations, indicating a higher degree of chromosomal instability in SCCs. Gains of chromosomal material from 1p, 14q, 16q, 20q, and losses from 4p were seen significantly more frequently in SCCs compared with KAs (P-values 0.0033, 0.0198, 0.0301, 0.0017, and 0.0070), whereas loss from 9p was seen significantly more frequently in KAs (P-value 0.0434). The patterns of recurrent aberrations were also different in the two types of neoplasms, pointing to different genetic mechanisms involved in their developments

Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate

Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the “missing heritability” of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q–Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versawith a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders

Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci

Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21 856) and multiple sclerosis (MS) (n=43 879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16 731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Implications of transient methane flux on associated biological communities in high-arctic seep habitats, Storbanken, Norwegian Barents sea

The continental margins of the Arctic Ocean basin contain methane seeps, where transient fluxes of seafloor methane are released due to the thermal dissociation of gas hydrates. An increase in shallow methane seeps identified over the past decade, potentially due to enhanced warming of the Arctic Ocean bottom water and associated destabilization of hydrate structure. Biological communities associated with methane release east of Svalbard in the Barents Sea (Storbanken Crater site, 76° 46.7′N, 35° 43.5′E, depths between 120 m–300 m depths) were investigated using towed camera imagery and ship-based platforms during a 2017 CAGE17-2 cruise on the RV Helmer Hanssen. We analyzed relationships among methane flux data, seafloor habitat characteristics, and biological community structure (i.e., presence and distribution of megafauna and expression of microbial mats) from a total of 14 surveys (6827 images and 40 multicore sediment cores) within the Storbanken Crater area and compared it to 2015 data. Unlike seep expressions at deeper sites (∼1200 m) in the Norwegian margin region, no seep-endemic, chemosynthetic-associated megafaunal species were observed at the shallow surveyed sites and all sites hosted similarly diverse communities of non-seep species, including commercially important fish and crustaceans. Methane concentrations did not markedly differ between the crater and non-crater sites. Rates of methane gas advection through sediments (in the form of flares) were relatively low and concentration of methane was even lower in porewater samples at the crater site. We present the first evidence of methane flare flux and intermittent microbial mat distribution with associated folliculinid ciliates, which suggests a long history of methane emissions and a transient seep environment in spatial and temporal flux. Together, this study presents a critical baseline on the temporal release of arctic methane and benthic biological communities to initiate temporal studies that identify future changes and predict the impact of climate chang

Massive blow-out craters formed by hydrate-controlled methane expulsion from the Arctic seafloor

Widespread methane release from thawing Arctic gas hydrates is a major concern, yet the processes, sources, and fluxes involved remain unconstrained. We present geophysical data documenting a cluster of kilometer-wide craters and mounds from the Barents Sea floor associated with large-scale methane expulsion. Combined with ice sheet/gas hydrate modeling, our results indicate that during glaciation, natural gas migrated from underlying hydrocarbon reservoirs and was sequestered extensively as subglacial gas hydrates. Upon ice sheet retreat, methane from this hydrate reservoir concentrated in massive mounds before being abruptly released to form craters. We propose that these processes were likely widespread across past glaciated petroleum provinces and that they also provide an analog for the potential future destabilization of subglacial gas hydrate reservoirs beneath contemporary ice sheets.authorsversionPeer reviewe

Demographic history has shaped the strongly differentiated corkwing wrasse populations in Northern Europe.

Understanding the biological processes involved in genetic differentiation and divergence between populations within species is a pivotal aim in evolutionary biology. One particular phenomenon that requires clarification is the maintenance of genetic barriers despite the high potential for gene flow in the marine environment. Such patterns have been attributed to limited dispersal or local adaptation, and to a lesser extent to the demographic history of the species. The corkwing wrasse (Symphodus melops) is an example of a marine fish species where regions of particular strong divergence are observed. One such genetic break occurred at a surprisingly small spatial scale (FST ~0.1), over a short coastline (<60 km) in the North Sea‐Skagerrak transition area in southwestern Norway. Here, we investigate the observed divergence and purported reproductive isolation using genome resequencing. Our results suggest that historical events during the post‐glacial recolonization route can explain the present population structure of the corkwing wrasse in the northeast Atlantic. While the divergence across the break is strong, we detected ongoing gene flow between populations over the break suggesting recent contact or negative selection against hybrids. Moreover, we found few outlier loci and no clear genomic regions potentially being under selection. We concluded that neutral processes and random genetic drift e.g., due to founder events during colonization have shaped the population structure in this species in Northern Europe. Our findings underline the need to take into account the demographic process in studies of divergence processes.acceptedVersio

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Not that clean: Aquaculture-mediated translocation of cleaner fish has led to hybridization on the northern edge of the species' range

publishedVersionPaid Open AccessUNIT agreemen

Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder : differential involvement of immune-related gene loci

J. Saarela työryhmäjäsen.Peer reviewe