Adolescent Verbal Memory as a Psychosis Endophenotype: A Genome-Wide Association Study in an Ancestrally Diverse Sample

Verbal memory impairment is one of the most prominent cognitive deficits in psychosis. However, few studies have investigated the genetic basis of verbal memory in a neurodevelopmental context, and most genome-wide association studies (GWASs) have been conducted in European-ancestry populations. We conducted a GWAS on verbal memory in a maximum of 11,017 participants aged 8.9 to 11.1 years in the Adolescent Brain Cognitive Development Study®, recruited from a diverse population in the United States. Verbal memory was assessed by the Rey Auditory Verbal Learning Test, which included three measures of verbal memory: immediate recall, short-delay recall, and long-delay recall. We adopted a mixed-model approach to perform a joint GWAS of all participants, adjusting for ancestral background and familial relatedness. The inclusion of participants from all ancestries increased the power of the GWAS. Two novel genome-wide significant associations were found for short-delay and long-delay recall verbal memory. In particular, one locus (rs9896243) associated with long-delay recall was mapped to the NSF (N-Ethylmaleimide Sensitive Factor, Vesicle Fusing ATPase) gene, indicating the role of membrane fusion in adolescent verbal memory. Based on the GWAS in the European subset, we estimated the SNP-heritability to be 15% to 29% for the three verbal memory traits. We found that verbal memory was genetically correlated with schizophrenia, providing further evidence supporting verbal memory as an endophenotype for psychosis

Ground State Properties and Optical Conductivity of the Transition Metal Oxide Sr2VO4{\rm Sr_{2}VO_{4}}

Combining first-principles calculations with a technique for many-body problems, we investigate properties of the transition metal oxide ${\rm Sr_{2}VO_{4}}$ from the microscopic point of view. By using the local density approximation (LDA), the high-energy band structure is obtained, while screened Coulomb interactions are derived from the constrained LDA and the GW method. The renormalization of the kinetic energy is determined from the GW method. By these downfolding procedures, an effective Hamiltonian at low energies is derived. Applying the path integral renormalization group method to this Hamiltonian, we obtain ground state properties such as the magnetic and orbital orders. Obtained results are consistent with experiments within available data. We find that ${\rm Sr_{2}VO_{4}}$ is close to the metal-insulator transition. Furthermore, because of the coexistence and competition of ferromagnetic and antiferromgnetic exchange interactions in this system, an antiferromagnetic and orbital-ordered state with a nontrivial and large unit cell structure is predicted in the ground state. The calculated optical conductivity shows characteristic shoulder structure in agreement with the experimental results. This suggests an orbital selective reduction of the Mott gap.Comment: 38pages, 22figure

Genetics of Myasthenia Gravis: A Case-Control Association Study in the Hellenic Population

Myasthenia gravis (MG) is an heterogeneous autoimmune disease characterized by the production of autoantibodies against proteins of the postsynaptic membrane, in the neuromuscular junction. The contribution of genetic factors to MG susceptibility has been evaluated through family and twin studies however, the precise genetic background of the disease remains elusive. We conducted a case-control association study in 101 unrelated MG patients of Hellenic origin and 101 healthy volunteers in order to assess the involvement of common genetic variants in susceptibility to MG. We focused on three candidate genes which have been clearly associated with several autoimmune diseases, aiming to investigate their potential implication in MG pathogenesis. These are interferon regulatory factor 5 (IRF-5), TNFα-induced protein 3 (TNFAIP3), also known as A20, and interleukin-10 (IL-10), key molecules in the regulation of immune function. A statistical trend of association (P=0.068) between IL-10 promoter single nucleotide polymorphisms (SNPs) and the subgroups of early and late-onset MG patients was revealed. No statistically significant differences were observed in the rest of the variants examined. As far as we are aware, this is the first worldwide attempt to address the possible association between IRF-5 and TNFAIP3 common genetic variants and the genetic basis of MG

Type 2 diabetes risks and determinants in second-generation migrants and mixed ethnicity people of South Asian and African Caribbean descent in the UK

AIMS/HYPOTHESIS: Excess risks of type 2 diabetes in UK South Asians (SA) and African Caribbeans (AC) compared with Europeans remain unexplained. We studied risks and determinants of type 2 diabetes in first- and second-generation (born in the UK) migrants, and in those of mixed ethnicity. METHODS: Data from the UK Biobank, a population-based cohort of ~500,000 participants aged 40-69 at recruitment, were used. Type 2 diabetes was assigned using self-report and HbA1c. Ethnicity was both self-reported and genetically assigned using admixture level scores. European, mixed European/South Asian (MixESA), mixed European/African Caribbean (MixEAC), SA and AC groups were analysed, matched for age and sex to enable comparison. In the frames of this cross-sectional study, we compared type 2 diabetes in second- vs first-generation migrants, and mixed ethnicity vs non-mixed groups. Risks and explanations were analysed using logistic regression and mediation analysis, respectively. RESULTS: Type 2 diabetes prevalence was markedly elevated in SA (599/3317 = 18%) and AC (534/4180 = 13%) compared with Europeans (140/3324 = 4%). Prevalence was lower in second- vs first-generation SA (124/1115 = 11% vs 155/1115 = 14%) and AC (163/2200 = 7% vs 227/2200 = 10%). Favourable adiposity (i.e. lower waist/hip ratio or BMI) contributed to lower risk in second-generation migrants. Type 2 diabetes in mixed populations (MixESA: 52/831 = 6%, MixEAC: 70/1045 = 7%) was lower than in comparator ethnic groups (SA: 18%, AC: 13%) and higher than in Europeans (4%). Greater socioeconomic deprivation accounted for 17% and 42% of the excess type 2 diabetes risk in MixESA and MixEAC compared with Europeans, respectively. Replacing self-reported with genetically assigned ethnicity corroborated the mixed ethnicity analysis. CONCLUSIONS/INTERPRETATION: Type 2 diabetes risks in second-generation SA and AC migrants are a fifth lower than in first-generation migrants. Mixed ethnicity risks were markedly lower than SA and AC groups, though remaining higher than in Europeans. Distribution of environmental risk factors, largely obesity and socioeconomic status, appears to play a key role in accounting for ethnic differences in type 2 diabetes risk

The influence of CYP2D6 and CYP2C19 genetic variation on diabetes mellitus risk in people taking antidepressants and antipsychotics

CYP2D6 and CYP2C19 enzymes are essential in the metabolism of antidepressants and antipsychotics. Genetic variation in these genes may increase risk of adverse drug reactions. Antidepressants and antipsychotics have previously been associated with risk of diabetes. We examined whether individual genetic differences in CYP2D6 and CYP2C19 contribute to these effects. We identified 31,579 individuals taking antidepressants and 2699 taking antipsychotics within UK Biobank. Participants were classified as poor, intermediate, or normal metabolizers of CYP2D6, and as poor, intermediate, normal, rapid, or ultra-rapid metabolizers of CYP2C19. Risk of diabetes mellitus represented by HbA1c level was examined in relation to the metabolic phenotypes. CYP2D6 poor metabolizers taking paroxetine had higher Hb1Ac than normal metabolizers (mean difference: 2.29 mmol/mol; p < 0.001). Among participants with diabetes who were taking venlafaxine, CYP2D6 poor metabolizers had higher HbA1c levels compared to normal metabolizers (mean differences: 10.15 mmol/mol; p < 0.001. Among participants with diabetes who were taking fluoxetine, CYP2D6 intermediate metabolizers and decreased HbA1c, compared to normal metabolizers (mean difference −7.74 mmol/mol; p = 0.017). We did not observe any relationship between CYP2D6 or CYP2C19 metabolic status and HbA1c levels in participants taking antipsychotic medication. Our results indicate that the impact of genetic variation in CYP2D6 differs depending on diabetes status. Although our findings support existing clinical guidelines, further research is essential to inform pharmacogenetic testing for people taking antidepressants and antipsychotics

Herschel / HIFI observations of CO, H2O and NH3 in Mon R2

Context. Mon R2 is the only ultracompact HII region (UCHII) where the associated photon-dominated region (PDR) can be resolved with Herschel. Due to its brightness and proximity, it is the best source to investigate the chemistry and physics of highly UV-irradiated PDRs. Aims. Our goal is to estimate the abundance of H2O and NH3 in this region and investigate their origin. Methods. We present new observations obtained with HIFI and the IRAM-30m telescope. Using a large velocity gradient approach, we model the line intensities and derive an average abundance of H2O and NH3 across the region. Finally, we model the line profiles with a non-local radiative transfer model and compare these results with the abundance predicted by the Meudon PDR code. Results. The variations of the line profiles and intensities indicate complex geometrical and kinematical patterns. The H2O lines present a strong absorption at the ambient velocity and emission in high velocity wings towards the HII region. The spatial distribution of the o-H2^18O line shows that the its emission arises in the PDR surrounding the HII region. By modeling the o-H2^18O emission we derive a mean abundance of o-H2O of ~10^-8 relative to H2. The ortho-H2O abundance is however larger, ~1x10^-7, in the high velocity wings. Possible explanations for this larger abundance include an expanding hot PDR and/or an outflow. Ammonia seems to be present only in the envelope with an average abundance of ~2x10^-9 relative to H2. Conclusions. The Meudon PDR code can account for the measured water abundance in the high velocity gas as long as we assume that it originates from a <1 mag hot expanding layer of the PDR, i.e. that the outflow has only a minor contribution to this emission. To explain the abundances in the rest of the cloud the molecular freeze out and grain surface chemistry would need to be included.Comment: 12 pages, 7 figures, 3 tables. Accepted for publication in A&A. Abstract shortened. Updated references, language editing applied in v

Spectral line survey of the ultracompact HII region Mon R2

Ultracompact (UC) HII regions constitute one of the earliest phases in the formation of a massive star and are characterized by extreme physical conditions (Go>10^5 Habing field and n>10^6 cm^-3). The UC HII Mon R2 is the closest one and therefore an excellent target to study the chemistry in these complex regions. We carried out a 3mm and 1mm spectral survey using the IRAM 30-m telescope towards three positions that represent different physical environments in Mon R2: (i) the ionization front (IF) at (0",0"); two peaks in the molecular cloud (ii) MP1 at the offset (+15",-15") and (iii) MP2 at the farther offset (0",40"). In addition, we carried out extensive modeling to explain the chemical differences between the three observed regions. We detected more than thirty different species. We detected SO+ and C4H suggesting that UV radiation plays an important role in the molecular chemistry of this region. We detected the typical PDR molecules CN, HCN, HCO, C2H, and c-C3H2. While the IF and the MP1 have a chemistry similar to that found in high UV field and dense PDRs like the Orion Bar, the MP2 is more similar to lower UV/density PDRs like the Horsehead nebula. We also detected complex molecules that are not usually found in PDRs (CH3CN, H2CO, HC3N, CH3OH and CH3C2H). Sulfur compounds CS, HCS+, C2S, H2CS, SO and SO2 and the deuterated species DCN and C2D were also identified. [DCN]/[HCN]=0.03 and [C2D]/[C2H]=0.05, are among the highest in warm regions. Our results show that the high UV/dense PDRs present a different chemistry from that of the low UV case. Abundance ratios like [CO+]/[HCO+] or [HCO]/[HCO+] are good diagnostics to differentiate between them. In Mon R2 we have the two classes of PDRs, a high UV PDR towards the IF and the adjacent molecular bar and a low-UV PDR which extends towards the north-west following the border of the cloud.Comment: 31 page