Signatures of a jet cocoon in early spectra of a supernova associated with a γ-ray burst.

Long γ-ray bursts are associated with energetic, broad-lined, stripped-envelope supernovae1,2 and as such mark the death of massive stars. The scarcity of such events nearby and the brightness of the γ-ray burst afterglow, which dominates the emission in the first few days after the burst, have so far prevented the study of the very early evolution of supernovae associated with γ-ray bursts3. In hydrogen-stripped supernovae that are not associated with γ-ray bursts, an excess of high-velocity (roughly 30,000 kilometres per second) material has been interpreted as a signature of a choked jet, which did not emerge from the progenitor star and instead deposited all of its energy in a thermal cocoon4. Here we report multi-epoch spectroscopic observations of the supernova SN 2017iuk, which is associated with the γ-ray burst GRB 171205A. Our spectra display features at extremely high expansion velocities (around 115,000 kilometres per second) within the first day after the burst5,6. Using spectral synthesis models developed for SN 2017iuk, we show that these features are characterized by chemical abundances that differ from those observed in the ejecta of SN 2017iuk at later times. We further show that the high-velocity features originate from the mildly relativistic hot cocoon that is generated by an ultra-relativistic jet within the γ-ray burst expanding and decelerating into the medium that surrounds the progenitor star7,8. This cocoon rapidly becomes transparent9 and is outshone by the supernova emission, which starts to dominate the emission three days after the burst.

Population structure and relatedness estimates in a Mexican sample.

Population stratification (PS) is a confounding factor in genome-wide association studies (GWASs) and also an interesting process itself. Latin American populations have mixed genetic ancestry, which may account for PS. We have analyzed the relatedness, by means of the identity-by-descent (IBD) estimations, in a sample of 1805 individuals and 1.006.703 autosomal mutations from a case-control study of colorectal cancer in Mexico. When using the recommended protocol for quality control assessment, 402 should have been removed due to relatedness. Our purpose was to analyze this value in the context of an admixed population. For that aim, we reanalyzed the sample using two software designed for admixed populations, obtaining estimates of 110 and 70 related individuals to remove. The results showed that the first estimation of relatedness was an effect of the higher Native American contribution in part of the data samples, being a confounding factor for IBD estimations. We conclude in the importance of considering PS and genetic ancestry in order to avoid spurious results, not only in GWAS but also in relatedness analysis.

Cerebellar Cognitive Affective Syndrome in Costa da Morte Ataxia (SCA36).

SCA36 is an autosomal dominant spinocerebellar ataxia (SCA) affecting many families from Costa da Morte, a northwestern region of Spain. It is caused by an intronic GGCCTG repeat expansion in NOP56. In order to characterize the cognitive and affective manifestations of this cerebellar disease, a group of 30 SCA36 mutation carriers (11 preataxic and 19 ataxic patients) were assessed with a comprehensive battery of standardized tests. Phonological verbal fluency - but not semantic fluency - was already mildly impaired in preataxic subjects. In ataxic patients, both phonological and semantic fluencies were significantly below normal. Depression, while more frequent and prominent in ataxic patients, was also often present in the preataxic stage. This is the first systematic study supporting the presence of a mild cerebellar cognitive and affective syndrome in SCA36. Routine evaluation of cognitive and emotional spheres in SCA36 patients as well as asymptomatic mutation carriers should allow early detection and timely therapeutic intervention.

Obesity-Related Genetic Determinants of Heart Failure Prognosis.

PURPOSE: Recent advances in genomics offer a smart option for predicting future risk of disease and prognosis. The objective of this study was to examine the prognostic value in heart failure (HF) patients, of a series of single nucleotide polymorphisms (SNPs). METHODS: A selection of 192 SNPs found to be related with obesity, body mass index, circulating lipids or cardiovascular diseases were genotyped in 191 patients with HF. Anthropometrical and clinical variables were collected for each patient, and death and readmission by HF were registered as the primary endpoint. RESULTS: A total of 53 events were registered during a follow-up period of 438 (263-1077) days (median (IQR)). Eight SNPs strongly related to obesity and HF prognosis were selected as possible prognostic variables. From these, rs10189761 and rs737337 variants were independently associated with HF prognosis (HR 2.295 (1.287-4.089, 95% CI); p = 0.005), whereas rs10423928, rs1800437, rs737337 and rs9351814 were related with bad prognosis only in obese patients (HR 2.142 (1.438-3.192, 95% CI); p = 0.00018). Combined scores of the genomic variants were highly predictive of poor prognosis. CONCLUSIONS: SNPs rs10189761 and rs737337 were identified, for the first time, as independent predictors of major clinical outcomes in patients with HF. The data suggests an additive predictive value of these SNPs for a HF prognosis. In particular for obese patients, SNPs rs10423928, rs1800437, rs737337 and rs9351814 were related with a bad prognosis. Combined scores weighting the risk of each genomic variant could effect interesting new tools to stratify the prognostic risk of HF patients.

Differential effects of FXR or TGR5 activation in cholangiocarcinoma progression.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is an aggressive tumor type affecting cholangiocytes. CCAs frequently arise under certain cholestatic liver conditions. Intrahepatic accumulation of bile acids may facilitate cocarcinogenic effects by triggering an inflammatory response and cholangiocyte proliferation. Here, the role of bile acid receptors FXR and TGR5 in CCA progression was evaluated. METHODS: FXR and TGR5 expression was determined in human CCA tissues and cell lines. An orthotopic model of CCA was established in immunodeficient mice and tumor volume was monitored by magnetic resonance imaging under chronic administration of the specific FXR or TGR5 agonists, obeticholic acid (OCA) or INT-777 (0,03% in chow; Intercept Pharmaceuticals), respectively. Functional effects of FXR or TGR5 activation were evaluated on CCA cells in vitro. RESULTS: FXR was downregulated whereas TGR5 was upregulated in human CCA tissues compared to surrounding normal liver tissue. FXR expression correlated with tumor differentiation and TGR5 correlated with perineural invasion. TGR5 expression was higher in perihilar than in intrahepatic CCAs. In vitro, FXR was downregulated and TGR5 was upregulated in human CCA cells compared to normal human cholangiocytes. OCA halted CCA growth in vivo, whereas INT-777 showed no effect. In vitro, OCA inhibited CCA cell proliferation and migration which was associated with decreased mitochondrial energy metabolism. INT-777, by contrast, stimulated CCA cell proliferation and migration, linked to increased mitochondrial energy metabolism. CONCLUSION: Activation of FXR inhibits, whereas TGR5 activation may promote, CCA progression by regulating proliferation, migration and mitochondrial energy metabolism. Modulation of FXR or TGR5 activities may represent potential therapeutic strategies for CCA.

A pathway-based association study reveals variants from Wnt signalling genes contributing to asthma susceptibility.

BACKGROUND: Genetic susceptibility to asthma is currently linked to a handful of genes which have a limited ability to predict the overall disease risk, suggesting the existence of many other genes involved in disease development. Accumulated evidence from association studies in genes related by biological pathways could reveal novel asthma genes. OBJECTIVE: To reveal novel asthma susceptibility genes by means of a pathway-based association study. METHODS: Based on summary data from a previous a genomewide association study (GWAS) of asthma, we first identified significant biological pathways using a gene-set enrichment analysis. We then mapped all tested single nucleotide polymorphisms (SNPs) on the genes contributing to significant pathways and prioritized those with a disproportionate number of nominal significant associations for further studies. For those prioritized genes, association studies were performed for selected SNPs in independent case-control samples (n = 1765) using logistic regression models, and results were meta-analysed with those from the GWAS. RESULTS: Two biological processes were significantly enriched: the cytokine-cytokine receptor interaction (P = 0.002) and the Wnt signalling (P = 0.012). From the 417 genes interacting in these two pathways, 10 showed an excess of nominal associations, including a known asthma susceptibility locus (encoding SMAD family member 3) and other novel candidate genes. From the latter, association studies of 14 selected SNPs evidenced replication in a locus near the frizzled class receptor 6 (FZD6) gene (P = 9.90 × 10-4 ), which had a consistent direction of effects with the GWAS findings (meta-analysed odds ratio = 1.49; P = 5.87 × 10-6 ) and was in high linkage disequilibrium with expression quantitative trait loci in lung tissues. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the importance of two biological pathways in asthma pathogenesis and identified a novel susceptibility locus near Wnt signalling genes.

Inference of biogeographical ancestry across central regions of Eurasia.

The inference of biogeographical ancestry (BGA) can provide useful information for forensic investigators when there are no suspects to be compared with DNA collected at the crime scene or when no DNA database matches exist. Although public databases are increasing in size and population scope, there is a lack of information regarding genetic variation in Eurasian populations, especially in central regions such as the Middle East. Inhabitants of these regions show a high degree of genetic admixture, characterized by an allele frequency cline running from NW Europe to East Asia. Although a proper differentiation has been established between the cline extremes of western Europe and South Asia, populations geographically located in between, i.e, Middle East and Mediterranean populations, require more detailed study in order to characterize their genetic background as well as to further understand their demographic histories. To initiate these studies, three ancestry informative SNP (AI-SNP) multiplex panels: the SNPforID 34-plex, Eurasiaplex and a novel 33-plex assay were used to describe the ancestry patterns of a total of 24 populations ranging across the longitudinal axis from NW Europe to East Asia. Different ancestry inference approaches, including STRUCTURE, PCA, DAPC and Snipper Bayes analysis, were applied to determine relationships among populations. The structure results show differentiation between continental groups and a NW to SE allele frequency cline running across Eurasian populations. This study adds useful population data that could be used as reference genotypes for future ancestry investigations in forensic cases. The 33-plex assay also includes pigmentation predictive SNPs, but this study primarily focused on Eurasian population differentiation using 33-plex and its combination with the other two AI-SNP sets.

High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.

Sequenom MassARRAY approach in the arrhythmogenic right ventricular cardiomyopathy post-mortem setting: clinical and forensic implications.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease characterized by myocardial fibrofatty replacement, which can lead to sudden death. Previous studies have described a reduction of plakoglobin (PKG) protein at the level of intercalated disks as the hallmark of ARVC. The main objective of this study was to investigate the involvement of desmosome mutations in the histological phenotype of ARVC. We performed a genetic analysis of ARVC cases, and histological characterization of ARVC heart tissue samples. We genetically analyzed 48 ARVC cases distributed into two groups: 42 human tissue heart samples with conclusive diagnoses of ARVC after post-mortem examination; and six DNA samples from peripheral blood of living patients who were clinically diagnosed. Sequenom MassARRAY analysis revealed three ARVC-associated variants in three patients in 42 tissue samples (7.14 %). Three individuals carried one single pathogenic mutation, p.R811S _PKP2, p.S824L_DSC2, and p.T526M_PKP2 in postmortem samples. In the living patients group, Sequenom MassARRAY revealed no mutation, however, later Sanger sequencing analysis identified three ARVC mutations in 2/6 patients not included in the Sequenom design. In post-mortem tissue samples we performed immunohistochemical labeling for desmosomal proteins and Connexin 43. This study revealed that PKP2 carriers present either absent or clearly reduced PKG immunolabeling, while the DSC2 carrier showed PKG immunolabeling similar to control samples. Immunolabeling for Cx43 did not show any differences compared to controls. The present Sequenom MassARRAY design is a useful tool for post-mortem genetic diagnosis of ARVC. Plakoglobin reduction occurs at intercalated disks, while other desmosome proteins and Cx43 remain unaltered.

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.

High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.

Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2.

High-throughput genotyping assay for the large-scale genetic characterization of Cryptosporidium parasites from human and bovine samples.

The epidemiological study of human cryptosporidiosis requires the characterization of species and subtypes involved in human disease in large sample collections. Molecular genotyping is costly and time-consuming, making the implementation of low-cost, highly efficient technologies increasingly necessary. Here, we designed a protocol based on MALDI-TOF mass spectrometry for the high-throughput genotyping of a panel of 55 single nucleotide variants (SNVs) selected as markers for the identification of common gp60 subtypes of four Cryptosporidium species that infect humans. The method was applied to a panel of 608 human and 63 bovine isolates and the results were compared with control samples typed by Sanger sequencing. The method allowed the identification of species in 610 specimens (90·9%) and gp60 subtype in 605 (90·2%). It displayed excellent performance, with sensitivity and specificity values of 87·3 and 98·0%, respectively. Up to nine genotypes from four different Cryptosporidium species (C. hominis, C. parvum, C. meleagridis and C. felis) were detected in humans; the most common ones were C. hominis subtype Ib, and C. parvum IIa (61·3 and 28·3%, respectively). 96·5% of the bovine samples were typed as IIa. The method performs as well as the widely used Sanger sequencing and is more cost-effective and less time consuming.

Cognitive and clinical predictors of a long-term course in obsessive compulsive disorder: A machine learning approach in a prospective cohort study.

BACKGROUND: Obsessive compulsive disorder (OCD) is a disabling illness with a chronic course, yet data on long-term outcomes are scarce. This study aimed to examine the long-term course of OCD in patients treated with different approaches (drugs, psychotherapy, and psychosurgery) and to identify predictors of clinical outcome by machine learning. METHOD: We included outpatients with OCD treated at our referral unit. Demographic and neuropsychological data were collected at baseline using standardized instruments. Clinical data were collected at baseline, 12 weeks after starting pharmacological treatment prescribed at study inclusion, and after follow-up. RESULTS: Of the 60 outpatients included, with follow-up data available for 5-17 years (mean = 10.6 years), 40 (67.7 %) were considered non-responders to adequate treatment at the end of the study. The best machine learning model achieved a correlation of 0.63 for predicting the long-term Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score by adding clinical response (to the first pharmacological treatment) to the baseline clinical and neuropsychological characteristics. LIMITATIONS: Our main limitations were the sample size, modest in the context of traditional ML studies, and the sample composition, more representative of rather severe OCD cases than of patients from the general community. CONCLUSIONS: Many patients with OCD showed persistent and disabling symptoms at the end of follow-up despite comprehensive treatment that could include medication, psychotherapy, and psychosurgery. Machine learning algorithms can predict the long-term course of OCD using clinical and cognitive information to optimize treatment options.

Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.

Global population variability in Promega PowerPlex CS7, D6S1043, and Penta B STRs.

Supplementary short tandem repeats (STRs) can be added to forensic DNA analyses when core markers fail to provide sufficient discrimination power in identity and relationship testing. We combined D6S1043 and Penta B with Promega's PowerPlex CS7 supplementary STR kit, comprising Pentas D and E plus LPL, F13A01, FES/FPS, F13B, and Penta C. The nine STRs were typed in 941 individuals from 51 diverse populations of the CEPH Human Genome Diversity Panel (HGDP-CEPH), and we report allele frequency estimates plus rare alleles identified. Both Penta B and D6S1043 show highly informative variation in all populations, exceeding most CS7 STRs and raising cumulative random match probabilities by at least two orders of magnitude. However, Penta B genotype distributions show an excess of homozygotes across all HGDP-CEPH population groups indicating likely allele dropout from uncharted SNP or Indel variation at the primer sites chosen to type this STR. The first sequence analysis of common regular and rare intermediate D6S1043 alleles is reported. D6S1043 .3 intermediate alleles were found to occur at a high frequency in Native Americans, providing scope for differentiation of this group.

The non-coding genome in Autism Spectrum Disorders.

Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders (NDDs) characterized by difficulties in social interaction and communication, repetitive behavior, and restricted interests. While ASD have been proven to have a strong genetic component, current research largely focuses on coding regions of the genome. However, non-coding DNA, which makes up for ∼99% of the human genome, has recently been recognized as an important contributor to the high heritability of ASD, and novel sequencing technologies have been a milestone in opening up new directions for the study of the gene regulatory networks embedded within the non-coding regions. Here, we summarize current progress on the contribution of non-coding alterations to the pathogenesis of ASD and provide an overview of existing methods allowing for the study of their functional relevance, discussing potential ways of unraveling ASD's "missing heritability".

eQTL colocalization analysis highlights novel susceptibility genes in Autism Spectrum Disorders (ASD).

Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders (NDDs) characterized by difficulties in social interaction and communication, repetitive behavior, and restricted interests. ASD has proven to have a strong genetic component. However, defining causal genes is still one of the main challenges in GWAS, since the vast majority (>90%) of detected signals lie within the non-coding genome. Expression quantitative trait locus (eQTL) colocalization analysis determines whether a specific variant is responsible for both a local eQTL and GWAS association and has helped leverage data and rendering gene discovery for a wide array of diseases. Here we further mine the largest ASD GWAS performed to date (18,381 cases and 27,969 controls) altogether with GWAS summary statistics from the main PGC studies (Schizophrenia, MD (Major Depression) and ADHD (Attention Deficit/Hyperactivity Disorder)), by using eQTpLot, a newly developed tool that illustrates the colocalization of GWAS and eQTL signals in a locus, and the enrichment of and correlation between the candidate gene eQTLs and trait-significant variants. This analysis points up 8 genes with a significant eQTL colocalization signal in ASD (CRHR1, KANSL1, MANBA, MAPT, MMP12, NKX2-2, PTPRE and WNT3) and one gene (SRPK2) with a marginally significant colocalization signal (r = 0.69, p < 1 × 10-6), and specifically highlights the potentially causal role of MAPT (r = 0.76, p < 1 × 10-6), NKX2-2 (r = 0.71, p-value = 2.26-02) and PTPRE (r = 0.97, p-value = 2.63-04) when restricting the analysis to brain tissue.

Psychiatric polygenic risk as a predictor of COVID-19 risk and severity: insight into the genetic overlap between schizophrenia and COVID-19.

Despite the high contagion and mortality rates that have accompanied the coronavirus disease-19 (COVID-19) pandemic, the clinical presentation of the syndrome varies greatly from one individual to another. Potential host factors that accompany greater risk from COVID-19 have been sought and schizophrenia (SCZ) patients seem to present more severe COVID-19 than control counterparts, with certain gene expression similarities between psychiatric and COVID-19 patients reported. We used summary statistics from the last SCZ, bipolar disorder (BD), and depression (DEP) meta-analyses available on the Psychiatric Genomics Consortium webpage to calculate polygenic risk scores (PRSs) for a target sample of 11,977 COVID-19 cases and 5943 subjects with unknown COVID-19 status. Linkage disequilibrium score (LDSC) regression analysis was performed when positive associations were obtained from the PRS analysis. The SCZ PRS was a significant predictor in the case/control, symptomatic/asymptomatic, and hospitalization/no hospitalization analyses in the total and female samples; and of symptomatic/asymptomatic status in men. No significant associations were found for the BD or DEP PRS or in the LDSC regression analysis. SNP-based genetic risk for SCZ, but not for BD or DEP, may be associated with higher risk of SARS-CoV-2 infection and COVID-19 severity, especially among women; however, predictive accuracy barely exceeded chance level. We believe that the inclusion of sexual loci and rare variations in the analysis of genomic overlap between SCZ and COVID-19 will help to elucidate the genetic commonalities between these conditions.

The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS.

BACKGROUND: The study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. METHODS: We analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. RESULTS: No SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. LIMITATIONS: Our main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. CONCLUSIONS: Our results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response.

Development and evaluations of the ancestry informative markers of the VISAGE Enhanced Tool for Appearance and Ancestry.

The VISAGE Enhanced Tool for Appearance and Ancestry (ET) has been designed to combine markers for the prediction of bio-geographical ancestry plus a range of externally visible characteristics into a single massively parallel sequencing (MPS) assay. We describe the development of the ancestry panel markers used in ET, and the enhanced analyses they provide compared to previous MPS-based forensic ancestry assays. As well as established autosomal single nucleotide polymorphisms (SNPs) that differentiate sub-Saharan African, European, East Asian, South Asian, Native American, and Oceanian populations, ET includes autosomal SNPs able to efficiently differentiate populations from Middle East regions. The ability of the ET autosomal ancestry SNPs to distinguish Middle East populations from other continentally defined population groups is such that characteristic patterns for this region can be discerned in genetic cluster analysis using STRUCTURE. Joint cluster membership estimates showing individual co-ancestry that signals North African or East African origins were detected, or cluster patterns were seen that indicate origins from central and Eastern regions of the Middle East. In addition to an augmented panel of autosomal SNPs, ET includes panels of 85 Y-SNPs, 16 X-SNPs and 21 autosomal Microhaplotypes. The Y- and X-SNPs provide a distinct method for obtaining extra detail about co-ancestry patterns identified in males with admixed backgrounds. This study used the 1000 Genomes admixed African and admixed American sample sets to fully explore these enhancements to the analysis of individual co-ancestry. Samples from urban and rural Brazil with contrasting distributions of African, European, and Native American co-ancestry were also studied to gauge the efficiency of combining Y- and X-SNP data for this purpose. The small panel of Microhaplotypes incorporated in ET were selected because they showed the highest levels of haplotype diversity amongst the seven population groups we sought to differentiate. Microhaplotype data was not formally combined with single-site SNP genotypes to analyse ancestry. However, the haplotype sequence reads obtained with ET from these loci creates an effective system for de-convoluting two-contributor mixed DNA. We made simple mixture experiments to demonstrate that when the contributors have different ancestries and the mixture ratios are imbalanced (i.e., not 1:1 mixtures) the ET Microhaplotype panel is an informative system to infer ancestry when this differs between the contributors.