Prenylated flavonoids as evolutionary indicators in the genus Dahlstedtia.

Abstract: Three chalcones, two beta-hydroxychalcones, four flavanones, six flavones, four flavonols, one rotenoid and one pterocarpan were isolated from the roots of Dahlstedtia pinnata and D. pentaphylla. With the exception of the pterocarpan, all the compounds exhibit prenylation in the A ring, a characteristic of flavonoids produced by species of the Tephrosieae. Of the 21 flavonoids identified, five (2 flavanones and 3 flavones) are new as naturally occurring compounds. A neat distinction in the biosynthetic capability of the two species, leading to the production of flavanones and flavonols in D. pentaphylla, but not in D. pinnata, is observed. In this latter species, biosynthesis is totally oriented toward dehydrogenation, producing flavones. By both criteria-higher oxidation state and suppression of enzyme systems-D. pinnata is the more advanced species

Polygenic risk score, parental socioeconomic status, family history of psychiatric disorders, and the risk for schizophrenia: a Danish population-based study and meta-analysis

IMPORTANCE Schizophrenia has a complex etiology influenced both by genetic and nongenetic factors but disentangling these factors is difficult. OBJECTIVE To estimate (1) how strongly the risk for schizophrenia relates to the mutual effect of the polygenic risk score, parental socioeconomic status, and family history of psychiatric disorders; (2) the fraction of cases that could be prevented if no one was exposed to these factors; (3) whether family background interacts with an individual's genetic liability so that specific subgroups are particularly risk prone; and (4) to what extent a proband's genetic makeup mediates the risk associated with familial background. DESIGN, SETTINGS, AND PARTICIPANTS We conducted a nested case-control study based onDanish population-based registers. The study consisted of 866 patients diagnosed as having schizophrenia between January 1, 1994, and December 31, 2006, and 871 matched control individuals. Genome-wide data and family psychiatric and socioeconomic background information were obtained from neonatal biobanks and national registers. Results from a separate meta-analysis (34 600 cases and 45 968 control individuals) were applied to calculate polygenic risk scores. EXPOSURES Polygenic risk scores, parental socioeconomic status, and family psychiatric history. MAIN OUTCOMES AND MEASURES Odds ratios (ORs), attributable risks, liability R2 values, and proportions mediated. RESULTS Schizophrenia was associated with the polygenic risk score (OR, 8.01; 95%CI, 4.53-14.16 for highest vs lowest decile), socioeconomic status (OR, 8.10; 95%CI, 3.24-20.3 for 6 vs no exposures), and a history of schizophrenia/psychoses (OR, 4.18; 95%CI, 2.57-6.79). The R2 values were 3.4%(95%CI, 2.1-4.6) for the polygenic risk score, 3.1%(95%CI, 1.9-4.3) for parental socioeconomic status, and 3.4%(95%CI, 2.1-4.6) for family history. Socioeconomic status and psychiatric history accounted for 45.8% (95%CI, 36.1-55.5) and 25.8% (95%CI, 21.2-30.5) of cases, respectively. There was an interaction between the polygenic risk score and family history (P = .03). A total of 17.4%(95%CI, 9.1-26.6) of the effect associated with family history of schizophrenia/psychoses was mediated through the polygenic risk score. CONCLUSIONS AND RELEVANCE Schizophrenia was associated with the polygenic risk score, family psychiatric history, and socioeconomic status. Our study demonstrated that family history of schizophrenia/psychoses is partly mediated through the individual's genetic liability

Whole-exome sequencing of individuals from an isolated population implicates rare risk variants in bipolar disorder

Bipolar disorder affects about 1% of the world's population, and its estimated heritability is about 75%. Only few whole genome or whole-exome sequencing studies in bipolar disorder have been reported, and no rare coding variants have yet been robustly identified. The use of isolated populations might help finding variants with a recent origin, more likely to have drifted to higher frequency by chance. Following this approach, we investigated 28 bipolar cases and 214 controls from the Faroe Islands by whole exome sequencing, and the results were followed-up in a British sample of 2025 cases and 1358 controls. Seventeen variants in 16 genes in the single-variant analysis, and 3 genes in the gene-based statistics surpassed exome-wide significance in the discovery phase. The discovery findings were supported by enrichment analysis of common variants from genome-wide association studies (GWAS) data and interrogation of protein-protein interaction networks. The replication in the British sample confirmed the association with NOS1 (missense variant rs79487279) and NCL (gene-based test). A number of variants from the discovery set were not present in the replication sample, including a novel PITPNM2 missense variant, which is located in a highly significant schizophrenia GWAS locus. Likewise, PIK3C2A identified in the gene-based analysis is located in a combined bipolar and schizophrenia GWAS locus. Our results show support both for existing findings in the literature, as well as for new risk genes, and identify rare variants that might provide additional information on the underlying biology of bipolar disorder

Sensitivity to Gravitational Waves from Compact Binary Coalescences Achieved during LIGO's Fifth and Virgo's First Science Run

We summarize the sensitivity achieved by the LIGO and Virgo gravitational wave detectors for compact binary coalescence (CBC) searches during LIGO's fifth science run and Virgo's first science run. We present noise spectral density curves for each of the four detectors that operated during these science runs which are representative of the typical performance achieved by the detectors for CBC searches. These spectra are intended for release to the public as a summary of detector performance for CBC searches during these science runs.Comment: 12 pages, 5 figure

Directional limits on persistent gravitational waves using LIGO S5 science data

The gravitational-wave (GW) sky may include nearby pointlike sources as well as astrophysical and cosmological stochastic backgrounds. Since the relative strength and angular distribution of the many possible sources of GWs are not well constrained, searches for GW signals must be performed in a model-independent way. To that end we perform two directional searches for persistent GWs using data from the LIGO S5 science run: one optimized for pointlike sources and one for arbitrary extended sources. The latter result is the first of its kind. Finding no evidence to support the detection of GWs, we present 90% confidence level (CL) upper-limit maps of GW strain power with typical values between 2-20x10^-50 strain^2 Hz^-1 and 5-35x10^-49 strain^2 Hz^-1 sr^-1 for pointlike and extended sources respectively. The limits on pointlike sources constitute a factor of 30 improvement over the previous best limits. We also set 90% CL limits on the narrow-band root-mean-square GW strain from interesting targets including Sco X-1, SN1987A and the Galactic Center as low as ~7x10^-25 in the most sensitive frequency range near 160 Hz. These limits are the most constraining to date and constitute a factor of 5 improvement over the previous best limits.Comment: 10 pages, 4 figure

Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source

<p>Abstract</p> <p>Background</p> <p>The search to identify disease-susceptible genes requires access to biological material from numerous well-characterized subjects. Archived residual dried blood spot (DBS) samples, also known as Guthrie cards, from national newborn screening programs may provide a DNA source for entire populations. Combined with clinical information from medical registries, DBS samples could provide a rich source for productive research. However, the amounts of DNA which can be extracted from these precious samples are minute and may be prohibitive for numerous genotypings. Previously, we demonstrated that DBS DNA can be whole-genome amplified and used for reliable genetic analysis on different platforms, including genome-wide scanning arrays. However, it remains unclear whether this approach is workable on a large sample scale. We examined the robustness of using DBS samples for whole-genome amplification following genome-wide scanning, using arrays from Illumina and Affymetrix.</p> <p>Results</p> <p>This study is based on 4,641 DBS samples from the Danish Newborn Screening Biobank, extracted for three separate genome-wide association studies. The amount of amplified DNA was significantly (P < 0.05) affected by the year of storage and storage conditions. Nine (0.2%) DBS samples failed whole-genome amplification. A total of 4,586 (98.8%) samples met our criterion of success of a genetic call-rate above 97%. The three studies used different arrays, with mean genotyping call-rates of 99.385% (Illumina Infinium Human610-Quad), 99.722% (Illumina Infinium HD HumanOmni1-Quad), and 99.206% (Affymetrix Axiom Genome-Wide CEU). We observed a concordance rate of 99.997% in the 38 methodological replications, and 99.999% in the 27 technical replications. Handling variables such as time of storage, storage conditions and type of filter paper were shown too significantly (P < 0.05) affect the genotype call-rates in some of the arrays, although the effect was minimal.</p> <p>Conclusion</p> <p>Our study indicates that archived DBS samples from the Danish Newborn Screening Biobank represent a reliable resource of DNA for whole-genome amplification and subsequent genome-wide association studies. With call-rates equivalent to high quality DNA samples, our results point to new opportunities for using the neonatal biobanks available worldwide in the hunt for genetic components of disease.</p

Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder

Analyses of the polygenic architecture of childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder (ADHD) in a Danish population-based case-cohort sample identify differences among ADHD subgroups with respect to common and rare variants. Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset in childhood (childhood ADHD); two-thirds of affected individuals continue to have ADHD in adulthood (persistent ADHD), and sometimes ADHD is diagnosed in adulthood (late-diagnosed ADHD). We evaluated genetic differences among childhood (n = 14,878), persistent (n = 1,473) and late-diagnosed (n = 6,961) ADHD cases alongside 38,303 controls, and rare variant differences in 7,650 ADHD cases and 8,649 controls. We identified four genome-wide significant loci for childhood ADHD and one for late-diagnosed ADHD. We found increased polygenic scores for ADHD in persistent ADHD compared with the other two groups. Childhood ADHD had higher genetic overlap with hyperactivity and autism compared with late-diagnosed ADHD and the highest burden of rare protein-truncating variants in evolutionarily constrained genes. Late-diagnosed ADHD had a larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants. Overall, these results suggest a genetic influence on age at first ADHD diagnosis, persistence of ADHD and the different comorbidity patterns among the groups.Peer reviewe

First LIGO search for gravitational wave bursts from cosmic (super)strings

We report on a matched-filter search for gravitational wave bursts from cosmic string cusps using LIGO data from the fourth science run (S4) which took place in February and March 2005. No gravitational waves were detected in 14.9 days of data from times when all three LIGO detectors were operating. We interpret the result in terms of a frequentist upper limit on the rate of gravitational wave bursts and use the limits on the rate to constrain the parameter space (string tension, reconnection probability, and loop sizes) of cosmic string models.Comment: 11 pages, 3 figures. Replaced with version submitted to PR

Patterns of alcohol drinking and its association with obesity: data from the third national health and nutrition examination survey, 1988–1994

BACKGROUND: Recent reports suggest that alcohol use may have a protective effect on obesity. This study explores association between obesity and alcohol consumption in the non-smoking U.S. adult population. METHODS: We analyzed data on a total of 8,236 respondents who participated in the Third National Health and Nutrition Examination Survey. Body mass index (weight-kg/height-m(2)) was derived from measured height and weight data and categorized into: normal weight, overweight, and obese. Alcohol consumption was measured using following measures: history of drinking, binge drinking, quantity of drinks/day, frequency of drinking, and average volume of drinks/week. RESULTS: Mean body mass index in this sample of non-smokers was 26.4 (95% CI: 26.1, 26.7). Approximately 46% of respondents were classified as current drinkers. Current drinkers had lower odds of obesity (Adjusted odds ratio = 0.73, 95% CI: 0.55, 0.97) as compared to non-drinkers. The odds of overweight and obesity were significantly greater among binge drinkers and those consuming four or more drinks/day. However, those who reported drinking one or two drinks per day had 0.46 (95% CI: 0.34, 0.62) and 0.59 (95% CI: 0.41, 0.86) times the odds of obesity, respectively. Similarly, the odds of obesity were significantly lower among those who reported drinking frequently and consuming less than five drinks per week. The association between overweight and other alcohol measures was less pronounced. CONCLUSION: The results suggest further exploring the possible role of moderate alcohol drinking in controlling body weight in adults