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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
The G72/G30 gene is one of the common loci shared both by schizophrenia and bipolar disorder. Studies accumulating since the discovery of this gene complex in 2002 produced controversial results in both disorders in different populations.
We investigated the association between G72/G30 gene and bipolar I disorder (BPI) in the Romanian population paying special attention to the association of G72/G30 locus with lifetime psychosis in BPI patients.
Fourteen G72-SNPs were genotyped in a Romanian sample of 198 BPI patients and 180 controls screened for psychiatric disorders in the Institute of Human Genetics, Life & Brain Center of the University of Bonn, Germany. Statistical analysis was performed with FAMHAP and Haploview-v3.32. The significance level of the results was corrected for multiple testing through permutations in 100,000 Monte Carlo simulations.
None of the fourteen SNPs was associated with the global diagnosis of BPI in our total patient sample or with the psychotic BPI subtype. But four SNPs reached nominal significance in the non-psychotic BPI subgroup [rs3916965 (M12) (P=0.044), rs1935057 (P=0.037), rs3916967 (M14) (P=0.043), rs2391191 (M15, non-synonymous) (P=0.043)]. In the non-psychotic subgroup, the haploblock including M14 and M15 (GA) remained significantly associated with BPI after correction through permutations (P=0.0524; OR=1.82).
Our results are the first replication of the study by Williams et al. (2006) reporting the same G72-SNPs [M12(A) and the functional SNP M15(A)], with the same alleles, to be associated with non-psychotic BPI disorder.
Since the discovery of the tryptophan hydroxylase 2 gene (TPH2) several studies reported association of TPH2 genetic variation with bipolar I disorder (BPI). Our objectives were to replicate in the Romanian population the recently described association of a rare functional SNP (rs17110563) and of a haplotype covering the 5′ region of TPH2 with BPI (Cichon et al., 2008) and to investigate the influence of the phenotypic traits age-of-onset, family history and parent-of-origin”, defined according to clinical criteria, on the degree of association between TPH2 and BPI.
Sixteen TPH2 SNPs were genotyped in a Romanian sample of 198 BPI patients and 180 controls screened for psychiatric disorders. Statistical analysis of the data was performed with Haploview3.32 and FAMHAP.
The functional SNP rs17110563 (encoding a Pro206Ser substitution) was present in Romanian BPI patients and absent in controls. SNPs located in the 5′-region (rs11178997, rs11178998, rs7954758), significantly associated with BPI in German patients were not associated with BPI in Romanian patients at single-marker level, but gave evidence for association at haplotypic level in a subgroup of patients with paternal transmission of BPI. Evidence for association was identified between haplotypes located in the 3′-region of TPH2 and BPI in the overall sample as well as in the subgroups of familial cases, the subgroup with paternal transmission, and the subgroup with AO≤25 years.
Our data provide support for the involvement of TPH2 in the etiology of BPI.
In this work, a laser-produced plasma extreme ultraviolet source and a free electron laser were used to create Ne photo-ionized plasmas. In both cases, a radiation beam was focused onto a gas stream injected into a vacuum chamber synchronously with the radiation pulse. Extreme ultraviolet radiation from the plasma spanned a wide spectral range with pronounced maximum centered at λ = 11 ± 1 nm while the free electron laser pulses were emitted at a wavelength of 32 nm. The power density of the focused plasma radiation was approximately 2 × 107 W/cm2 and was seven orders of magnitude lower compared with the focused free electron laser beam. Radiation fluences in both experimental conditions were comparable. Despite quite different spectral characteristics and extremely different power densities, emission spectra of both photo-ionized plasmas consist of the same spectral lines within a wavelength range of 20 to 50 nm, however, with different relative intensities of the corresponding lines. The dominating spectral lines originated from singly charged ions (Ne II); however, Ne III lines were also detected. Additionally, computer simulations of the emission spectra, obtained for photo-ionized plasmas, driven by the plasma extreme ultraviolet source, were performed. The corresponding measured and calculated spectra are presented. An electron temperature and ionic composition were estimated. Differences between the experimental spectra, obtained for both irradiation conditions, were analyzed. The differences were attributed mainly to different energies of driving photons.
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