Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples

Mitigation and screening for environmental assessment

This article considers how, as a matter of law and policy, mitigation measures should be taken into account in determining whether a project will have significant environmental effects and therefore be subject to assessment under the EU Environmental Impact Assessment (EIA) Directive. This is not straightforward: it is problematic to distinguish clearly between an activity and the measures proposed to minimise or mitigate for the adverse consequences of the activity. The issue is a salient one in impact assessment law, but under-explored in the literature and handled with some difficulty by the courts. I argue that there is an unnecessarily and undesirably narrow approach currently taken under the EIA Directive, which could be improved upon by taking a more adaptive approach; alternatively a heightened standard of review of ‘significance’, and within this of the scope for mitigation measures to bring projects beneath the significance threshold, may also be desirable

The Bimodal Galaxy Stellar Mass Function in the COSMOS Survey to z~1: A Steep Faint End and a New Galaxy Dichotomy

We present a new analysis of stellar mass functions (MF) in the COSMOS field to fainter limits than has been previously probed to z~1. Neither the total nor the passive or star-forming MF can be well fit with a single Schechter function once one probes below 3e9 Msun. We observe a dip or plateau at masses ~1e10 Msun, and an upturn towards a steep faint-end slope of -1.7 at lower mass at any z<1. This bimodal nature of the MF is not solely a result of the blue/red dichotomy. The blue MF is by itself bimodal at z~1. This suggests a new dichotomy in galaxy formation that predates the appearance of the red sequence. We propose two interpretations for this bimodality. If the gas fraction increases towards lower mass, galaxies with M_baryon~1e10 Msun would shift to lower stellar masses, creating the observed dip. This would indicate a change in star formation efficiency, perhaps linked to supernovae feedback becoming much more efficient. Therefore, we investigate whether the dip is present in the baryonic (stars+gas) MF. Alternatively, the dip could be created by an enhancement of the galaxy assembly rate at ~1e11 Msun, a phenomenon that naturally arises if the baryon fraction peaks at M_halo ~1e12 Msun. In this scenario, galaxies occupying the bump around M* would be identified with central galaxies and the second fainter component having a steep faint-end slope with satellites. While the dip is apparent in the total MF at any z, it appears to shift from the blue to red population, likely as a result of transforming high-mass blue galaxies into red ones. At the same time, we detect a drastic upturn in the number of low-mass red galaxies. Their increase with time reflects a decrease in the number of blue systems and so we tentatively associate them with satellite dwarf galaxies that have undergone quenching.Comment: 16 pages, 10 figures, accepted for publication in Ap

The Impact of Adolescent Chronic Pain on Functioning: Disentangling the Complex Role of Anxiety

A number of adolescents with chronic pain have clinically significant disability across physical, social, and academic activities, and pain severity only explains a portion of the variance in functioning. Thus, it is important to identify therapeutic options to improve adolescents’ functioning. In contrast to studies with adults with chronic pain, research in pediatric pain has not consistently found anxiety to be a good predictor of pain-related disability. The present study evaluated pain, anxiety, and functioning in 222 adolescents with chronic pain. Results indicated that pain was consistently and linearly related to disability across measures of physical and social functioning, school attendance, and physician visits. The relation between anxiety and functioning was complex; increased anxiety was related to poorer physical and social functioning and was related to fewer physician visits, although it was not associated with school attendance. Additional analyses revealed that anxiety serves to moderate the relation between pain and functioning. Specifically, at high anxiety, pain was not related to functioning, but at low anxiety pain consistently predicted disability. In other words, highly anxious adolescents were functioning poorly regardless of the level of pain. The moderating role of anxiety highlights a number of research and clinical possibilities to explore with adolescents with chronic pain-related disability. Data suggest that high anxiety is associated with poor functioning irrespective of pain intensity. At low anxiety, higher pain predicted greater disability. Anxiety is important to assess when investigating potential reasons for pain-related disability

The VIMOS-VLT Deep Survey: Evolution in the Halo Occupation Number since z ∼\sim 1

We model the evolution of the mean galaxy occupation of dark-matter halos over the range $0.1<z<1.3$, using the data from the VIMOS-VLT Deep Survey (VVDS). The galaxy projected correlation function $w_p(r_p)$ was computed for a set of luminosity-limited subsamples and fits to its shape were obtained using two variants of Halo Occupation Distribution models. These provide us with a set of best-fitting parameters, from which we obtain the average mass of a halo and average number of galaxies per halo. We find that after accounting for the evolution in luminosity and assuming that we are largely following the same population, the underlying dark matter halo shows a growth in mass with decreasing redshift as expected in a hierarchical structure formation scenario. Using two different HOD models, we see that the halo mass grows by 90% over the redshift interval z=[0.5,1.0]. This is the first time the evolution in halo mass at high redshifts has been obtained from a single data survey and it follows the simple form seen in N-body simulations with $M(z) = M_0 e^{-\beta z}$, and $\beta = 1.3 \pm 0.30$. This provides evidence for a rapid accretion phase of massive halos having a present-day mass $M_0 \sim 10^{13.5} h^{-1} M_\odot$, with a $m > 0.1 M_0$ merger event occuring between redshifts of 0.5 and 1.0. Futhermore, we find that more luminous galaxies are found to occupy more massive halos irrespectively of the redshift. Finally, the average number of galaxies per halo shows little increase from redshift z$\sim$ 1.0 to z$\sim$ 0.5, with a sharp increase by a factor $\sim$3 from z$\sim$ 0.5 to z$\sim$ 0.1, likely due to the dynamical friction of subhalos within their host halos.Comment: 14 pages, 6 figures, 5 tables. MNRAS accepted