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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.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
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.
Results
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.
Conclusions
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.
Flat plate turbulent boundary layers under zero pressure gradient are simulated using synthetic turbulence generated by the fast random particle–mesh method. The stochastic realisation is based on time-averaged turbulence statistics derived from Reynolds-averaged Navier–Stokes simulation of flat plate turbulent boundary layers at Reynolds numbers $\mathit{Re}_{\unicode[STIX]{x1D70F}}=2513$ and $\mathit{Re}_{\unicode[STIX]{x1D70F}}=4357$. To determine fluctuating pressure, a Poisson equation is solved with an unsteady right-hand side source term derived from the synthetic turbulence realisation. The Poisson equation is solved via fast Fourier transform using Hockney’s method. Due to its efficiency, the applied procedure enables us to study, for high Reynolds number flow, the effect of variations of the modelled turbulence characteristics on the resulting wall pressure spectrum. The contributions to wall pressure fluctuations from the mean-shear turbulence interaction term and the turbulence–turbulence interaction term are studied separately. The results show that both contributions have the same order of magnitude. Simulated one-point spectra and two-point cross-correlations of wall pressure fluctuations are analysed in detail. Convective features of the fluctuating pressure field are well determined. Good agreement for the characteristics of the wall pressure fluctuations is found between the present results and databases from other investigators.
For a class of anisotropic integrodifferential operators ${\cal B}$ arising as semigroup generators of Markov processes, we present a sparse tensor product wavelet compression scheme for the Galerkin finite element discretization of the corresponding integrodifferential equations ${\cal B}$ u = f on [0,1]n with possibly large n. Under certain conditions on ${\cal B}$, the scheme is of essentially optimal and dimension independent complexity $\mathcal{O}$(h-1| log h |2(n-1)) without corrupting the convergence or smoothness requirements of the original sparse tensor finite element scheme. If the conditions on ${\cal B}$ are not satisfied, thecomplexity can be bounded by $\mathcal{O}$(h-(1+ε)), whereε$\ll 1$ tends to zero with increasing number of the wavelets' vanishing moments. Here h denotes the width of the corresponding finite element mesh. The operators under consideration are assumed to be of non-negative (anisotropic) order and admit a non-standard kernel κ$(\cdot,\cdot)$ that can be singular on all secondary diagonals. Practical examples of such operators from Mathematical Finance are given and some numerical results are presented.
This is a study of relations between pure cubic fields and their normal closures. Explicit formula shows how the discriminant, regulator and class number of the normal closure can be expressed in terms of the cubic field.
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