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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.
Many studies have identified changes in the brain associated with obsessive–compulsive disorder (OCD), but few have examined the relationship between genetic determinants of OCD and brain variation.
We present the first genome-wide investigation of overlapping genetic risk for OCD and genetic influences on subcortical brain structures.
Using single nucleotide polymorphism effect concordance analysis, we measured genetic overlap between the first genome-wide association study (GWAS) of OCD (1465 participants with OCD, 5557 controls) and recent GWASs of eight subcortical brain volumes (13 171 participants).
We found evidence of significant positive concordance between OCD risk variants and variants associated with greater nucleus accumbens and putamen volumes. When conditioning OCD risk variants on brain volume, variants influencing putamen, amygdala and thalamus volumes were associated with risk for OCD.
These results are consistent with current OCD neurocircuitry models. Further evidence will clarify the relationship between putamen volume and OCD risk, and the roles of the detected variants in this disorder.
Declaration of interest
The authors have declared that no competing interests exist.
Fourteenth Century England aims to publish high-quality refereed academic research on topics relating to England, its dominions and neighbours. This volume follows in the footsteps of the previous eight volumes in the series by showcasing a wide-ranging selection of studies reflecting the concerns and trends of current scholarship in the field. We make no attempt to ‘theme’ the volumes, preferring to present whatever is good and innovative in current research in the period, thereby acting as a channel for the dissemination of new ideas, trends and debates. In this volume there are two essays on politics, two on religion, two on chronicle writing and two on aspects of the law. We are also delighted to introduce a new ‘Notes and Documents’ format for shorter, source-focused discussion. Although we do not rely on the proceedings of a specific conference, the continuing vitality of fourteenth-century studies owes much to the sessions organised under the auspices of the Society for Fourteenth-Century Studies at the annual International Medieval Congress (IMC), Leeds, and the Society of the White Hart at the annual International Congress on Medieval Studies, Kalamazoo, Michigan. A number of essays in this volume received their first ‘public airing’ in one of these contexts, and the cosmopolitan nature of these conferences allows us constant access to a vibrant source of medieval research from around the globe.
This volume marks a change in both the team responsible for organising the sessions at IMC Leeds and in preparing the Fourteenth Century England (FCE) volumes for publication. We are delighted and honoured to have been asked to join the FCE team by its existing members – Chris Given-Wilson, Jeff Hamilton, Mark Ormrod and Nigel Saul. We would like to thank them for their assistance in the organisation of the sessions at Leeds as well as the assiduousness with which they, along with various external referees, read and commented on submissions to this volume. Additionally, Alison McHardy in particular should be thanked for her willingness to look over submissions in this regard. We would also like to extend our collective thanks to Caroline Palmer and the staff at Boydell & Brewer for their continuing support of the series, and for the expertise and patience they have shown in seeing this volume through to publication.
The wide-ranging studies collected here reflect the latest concerns of and trends in fourteenth-century research, including work on politics, the law, religion, and chronicle writing. The lively (andcontroversial) debate around the death of Edward II, and the brief but eventful career of John of Eltham, earl of Cornwall, receive detailed treatment, as does the theory and implementation of both the law of treason in England and high status execution in Ireland. There is an investigation of the often overlooked, yet ever present, lesser parish clergy of pre-Black Death England, along with the notable connections between Roman remains and craft guild piety in fourteenth-century York. There are also chapters shedding new light on fourteenth-century chronicles: one examines the St Albans chronicle through the prism of chivalric culture, another analyses the importance of the Chester Annals of 1385-8 in the writing culture of the Midlands. Introduced with this volume is a new section on "Notes and Documents"; re-examined here is an often-cited letter from the reign of Richard II and the problematic, yet crucial, issue of its authorship and dating.
James Bothwell is Lecturer in Later Medieval History at the University of Leicester; Gwilym Dodd is Associate Professor of Medieval History at the University of Nottingham
Contributors: Paul Dryburgh, ine Foley, Christopher Guyol, Andy King, Jessica Knowles, E. Amanda McVitty, D.A.L. Morgan, Philip Morgan, David Robinson.
Certain crystalline materials can exist in more than one solid phase, where a phase is identified by a distinct crystal structure. Typically, one phase is preferred under certain conditions of stress and temperature, while another is favored under different conditions. As the stress or temperature varies, the material may therefore transform abruptly, from one phase to another, leading to a discontinuous change in the properties of the body. Examples of such materials include the shape-memory alloy NiTi, the ferroelectric alloy BaTiO3, the ferromagnetic alloy FeNi and the high-temperature superconducting ceramic alloy ErRh4B4. In each of these examples the transition occurs without diffusion and one speaks of the transformation as being martensitic (or displacive).
Alloys such as Au–47.5%Cd and Cu–15.3%Sn are known to have a cubic lattice at high temperatures and an orthorhombic lattice at low temperatures. Therefore, if such a material is subjected to thermal cycling, it will transform between these two phases. Similarly, alloys such as Ni–36%Al and Fe–7%Al–2%C transform between a high-temperature cubic phase and a low-temperature tetragonal phase, whereas near-equiatomic NiTi has a high-temperature cubic phase and low-temperature monoclinic phase.
If a stress-free single crystal of such a two-phase material is slowly cooled from a sufficiently high temperature, it starts out in the high-temperature phase and at first, merely undergoes a thermal contraction.
We next turn to the dynamics of the two-phase nonlinearly elastic materials introduced in Chapter 2. As in the theory of mixed-phase equilibria and quasistatic processes for such materials set out in Chapter 3, the notion of driving force plays a central role in the analysis when inertial effects are taken into account. The indeterminacy exhibited in Chapter 3 by even the simplest static or quasistatic problems for two-phase materials manifests itself again in the present much richer dynamical context. Moreover, the continuum-mechanical interpretations of nucleation and kinetics again serve to restore the uniqueness of solutions to the dynamic problems to be considered here. As in the preceding chapters, thermal effects are omitted; they will be included in the more general settings of later chapters.
The main vehicle for our study of one-dimensional dynamics of two-phase materials is the impact problem. There is an enormous body of experimental literature pertaining to the response of solids to shock or impact loading, much of it motivated by questions concerning the behavior of materials at extremely high pressures, as occurs, for example, deep in the earth. The reader will find some guidance to the experimental literature in this field of the dynamic behavior of materials in the books by Graham  and Meyers .
In the preceding chapter we determined the kinetics of a certain phase transformation using experiments that involved fast loading in which inertia was important. In the present chapter we determine the kinetics of a different transformation using data from quasistatic experiments. The transformation studied here is a twinning deformation, not a phase transformation, a twin boundary being an interface that separates two variants of martensite; see Example 1 in Section 12.2. The change in lattice orientation across a twin boundary makes it analogous, in certain ways, to a phase boundary, and in particular, the motion of a twin boundary is governed by a kinetic relation.
As we have seen, the simplest form of kinetic relation governing the isothermal motion of an interface relates the driving force on it to its normal velocity of propagation: Vn = Φ(f). Since the kinetic response function Φ here is a function of a single scalar independent variable, one set of experiments, say uniaxial tension tests, completely determines Φ; and the function Φ thus determined characterizes all motions of this interface such as, say, in biaxial conditions. If the deformation field is inhomogeneous, and the phase or twin boundary is curved, one would use this same kinetic relation locally, at each point along the interface, relating the driving force at that point to the normal velocity of propagation of that point.
In this chapter, we assemble the basic field equations and jump conditions for a one-dimensional, purely mechanical theory of nonlinear elasticity; although thermal effects will be omitted, inertia will be taken into account. The theory presented here is general enough to describe nonlinearly elastic materials that, under suitable conditions of stress, are capable of existing in either of two phases. As we shall see, a key feature of this theory is that the potential energy of the material, as a function of strain at a fixed stress, has two local minima. The associated constitutive relation between stress and strain will then necessarily be nonmonotonic, possessing a maximum and a minimum connected by an unstable regime in which stress declines with increasing strain.
Experiments that provide the motivation for the theory about to be developed fall into two categories. The first of these involves slow tensile loading and unloading of slender bars or wires composed of materials such as shape-memory alloys. The model to be constructed to describe experiments of this kind is one of uniaxial stress in a one-dimensional nonlinearly elastic continuum, and the processes to be studied for this model are quasistatic. The stress-induced phase transitions in such experiments occur in tension, so the two minima in the potential energy density occur at positive – or extensional – values of strain, as do the extrema in the stress– strain relation.