Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling

5-HT2 and corticotrophin releasing factor (CRF) receptors both regulate stress responses and anxiety behavior; however, potential cross-talk between the two pathways is poorly understood. Magalhaes et al. find that CRF receptor activation causes cell-surface recruitment of constitutively internalized 5-HT2 receptor and that this mechanism is relevant to anxiety-related behaviors

Foot pain in rheumatoid arthritis prevalence, risk factors and management: an epidemiological study

Foot involvement is a major feature of rheumatoid arthritis (RA). Most epidemiological studies of the RA foot report radiological changes and results of clinical examination. This study aimed to determine the prevalence of foot symptoms, frequency of foot assessment and access to foot care from the perspective of people with RA. A questionnaire was sent to 1,040 people with RA throughout the UK enquiring about foot symptoms, their anatomical distribution (via validated mannequins) availability of podiatry services and perceived usefulness of interventions for alleviating foot symptoms. Altogether 585 useable replies were received; 93.5% of respondents reported having experienced foot pain, and 35.4% reported current foot pain as the presenting symptom. Most (68.2%) reported moderate or severe foot pain daily. Pain was most prevalent in the forefoot and/or ankle. The main predictive factors for reporting current foot pain were longer disease duration (mean 13 vs 10.3 years, p = 0.009), higher BMI (25.6 vs 24.1 p = 0.001) and the prevalent foot symptoms foot stiffness and numbness (both p < 0.0001). Age, gender and current treatment were not significantly associated. Most (82%) had discussed foot symptoms with their rheumatologist, and only 64% had seen a podiatrist. Reported current adherence to prescribed orthoses was 55.8% and to prescribed shoes was 29.5%. Foot symptoms are ubiquitous in RA and frequently severe. Most patients had discussed their symptoms with their rheumatologist, and only 64% had specifically seen a podiatrist. Despite the remarkable progress in development of new treatment modalities for RA, foot pain remains a common and disabling symptom. Our findings support the need for wider access to specific foot care services and evidence-based, patient-centred interventions

Proxy-reported health-related quality of life of patients with juvenile idiopathic arthritis: the Pediatric Rheumatology International Trials Organization multinational quality of life cohort study

To investigate the proxy-reported health-related quality of life (HRQOL) and its determinants in patients with juvenile idiopathic arthritis (JIA)

CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling

Stress and anxiety disorders are risk factors for depression and these behaviours are modulated by corticotropin releasing factor (CRFR1) and serotonin (5-HT2R) receptors. However, the potential behavioral and cellular interaction between these two receptors is unclear. Here, we showed that pre-administration of CRF into the prefrontal cortex of mice sensitized 5-HT2R-mediated anxiety behaviours in response to 2,5-dimethoxy-4-iodoamphetamine. In both heterologous cell cultures and mouse cortical neurons, the activation of CRFR1 also sensitized 5-HT2 receptor-mediated inositol phosphate formation. CRFR1-mediated increases in 5-HT2R signaling were dependent upon receptor internalization and receptor recycling via rapid recycling endosomes resulting in increased cell surface 5-HT2R expression. The sensitization of 5-HT2R signaling by CRFR1 required intact PDZ domain binding motifs at the end of the C-terminal tails of both receptor types. These data reveal a novel mechanism by which CRF, a peptide known to be released by stress, sensitized anxiety-related behaviour via sensitization of 5-HT2R signaling