Publications

In a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease.

Coffee’s long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = −0.0007, 95% C.I. −0.009 to 0.008, P = 0.87; β = −0.001, 95% C.I. −0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (Pheterogeneity > 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.

Although the introduction of genome-wide association studies (GWAS) have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD), rheumatoid arthritis (RA) and type 1 diabetes (T1D) with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC). The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10(-3)-10(-20)) with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes) for T1D, 350 SNPs (189 genes) for RA and 493 SNPs (277 genes) for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC) and RA (85% AUC), and weakly predictive of CD (60% AUC). The predictive ability of the T1D model (without any parameter refitting) had good predictive ability (79% AUC) in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.

We studied the polarization dependence of the resonance Raman spectra for several different isolated single-wall carbon nanotubes (SWNTs). One isolated SWNT acts as a dipolar antenna, polarized along the tube axis. For light polarized parallel to the tube axis, the strong resonance-effect breaks the symmetry-selection rules, and symmetry-forbidden modes appear in the Raman spectrum. When the light is not polarized parallel to the tube axis, G-band mode symmetries can be identified. Unusual G-mode intensity behavior is observed when the Raman signal is obtained from more than one SWNT, suggesting a complex multipolar antenna pattern.

Pulsed laser deposition combined with atomic beam techniques have been exploited to grow carbon nitride thin films with controlled nitrogen composition. The nitrogen composition in the thin films was found to increase as the laser fluence was decreased for laser ablation at both 532 and 248 nm wavelengths. Analysis of these carbon nitride materials shows that over a wide range of conditions the film growth rate determines the overall nitrogen composition, although at the lowest growth rates the composition saturates at a value close to 50% nitrogen. Infrared spectroscopy indicates that a cyanogen-like impurity is present in all of the films with nitrogen composition greater than 30%, and that the amount of this impurity increases with increasing nitrogen content. However, the cyanogen-like impurity phase was eliminated by a thermal annealing process to yield a single phase material. Systematic studies of the carbon nitride film electrical resistivity and thermal conductivity as a function of nitrogen composition will be discussed.

The etiology of facial pain is multifactorial. Based on the results of a questionnaire included in the study of the 1966 Northern Finland Birth Cohort, performed in 1997-98, we found an association of facial pain with subjective symptoms of temporomandibular disorders (TMD), neck pain and with occlusal factors reported by 5,696 subjects. The aim of the present study was to examine these associations clinically. In the year 2000, a new inquiry was sent to the following subjects living in Oulu: 1. all subjects who had reported facial pain in the former questionnaire (n=162) (case group); and 2. to a randomly selected group of nonpain controls (n=200), group matched for gender. Those who reported willingness to participate were invited to a clinical examination. Finally, the total number of subjects was 104, including 52 (10 men, 42 women) cases and 52 (10 men, 42 women) controls. Anamnestic data were collected, and clinical stomatognathic and musculoskeletal examinations were performed, both the clinicians and the subjects being unaware of the case-control status. Anamnestically, stress was the most often reported provoking factor for facial pain. Facial pain associated significantly with reported TMD symptoms and allergies. Based on clinical findings, most of the cases were classified in the myogenous subgroup of TMD. The risk for facial pain was six-fold in subjects with clinically assessed TMD, defined as moderate (DiII) or severe (DiIII) by Helkimo's clinical dysfunction index, almost six-fold in subjects with protrusion interferences and approximately three-fold in subjects with clinically assessed tenderness of distinct fibromyalgia (FM) points in the neck. According to the adjusted logistic regression analyses, TMD had the strongest influence on facial pain, followed by protrusion interferences, anamnestically reported allergies and "other headaches". The present study shows that as well as being connected with TMD, facial pain is associated with pain and muscle tenderness in the neck area.

Abstract BACKGROUND The role of branched-chain amino acids (BCAAs) in cardiovascular disease (CVD) remains poorly understood. We hypothesized that baseline BCAA concentrations predict future risk of CVD and that a Mediterranean diet (MedDiet) intervention may counteract this effect. METHODS We developed a case-cohort study within the Prevención con Dieta Mediterránea (PREDIMED), with 226 incident CVD cases and 744 noncases. We used LC-MS/MS to measure plasma BCAAs (leucine, isoleucine, and valine), both at baseline and after 1 year of follow-up. The primary outcome was a composite of incident stroke, myocardial infarction, or cardiovascular death. RESULTS After adjustment for potential confounders, baseline leucine and isoleucine concentrations were associated with higher CVD risk: the hazard ratios (HRs) for the highest vs lowest quartile were 1.70 (95% CI, 1.05–2.76) and 2.09 (1.27–3.44), respectively. Stronger associations were found for stroke. For both CVD and stroke, we found higher HRs across successive quartiles of BCAAs in the control group than in the MedDiet groups. With stroke as the outcome, a significant interaction (P = 0.009) between baseline BCAA score and intervention with MedDiet was observed. No significant effect of the intervention on 1-year changes in BCAAs or any association between 1-year changes in BCAAs and CVD were observed. CONCLUSIONS Higher concentrations of baseline BCAAs were associated with increased risk of CVD, especially stroke, in a high cardiovascular risk population. A Mediterranean-style diet had a negligible effect on 1-year changes in BCAAs, but it may counteract the harmful effects of BCAAs on stroke.