Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

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

A genetic investigation of sex bias in the prevalence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish populationregister data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence

Experience with incontinent urinary diversion--review of 31 ureterocutaneostomies, 101 ileal conduits and 107 colonic conduits

1)尿管皮膚瘻(31例)は主に高齢者, high risk症例, 根治性のない浸潤癌症例に施行された.術後のストーマ狭窄の頻度は高く, 63.5%にカテーテル留置を要した.又, 急性腎盂腎炎の発症頻度も高かった. 2)回腸導管(101例)と結腸導管(107例)の比較では, 前者に急性腎盂腎炎や尿路結石の発生頻度が高かった.しかし, イレウスや腸管吻合不全には差はなかった. 3)導管造影を施行したところ, 回腸導管では66.7%に導管尿管逆流を認めたが, 結腸導管では1.3%に逆流を認めたに過ぎなかった. 4)術後の腎機能は, 結腸導管で最も良好に保たれ, 尿管皮膚瘻では低下する傾向がみられたDuring the past 20 years, 31 ureterocutaneostomies (UC), 101 ileal conduits (IC) and 107 colonic conduits (CC) were performed. In the UC group, most of the patients were aged or had unresectable invasive pelvic malignancies. The operative mortality was 6.5% and acute pyelonephritis was noted frequently (48.3%). Stomal stenosis also developed significantly (63.5%). The operative mortalities in the IC group and CC group were 6.9% and 9.3%, respectively. Although the incidences of bowel obstruction, bowel fistula and renal calculi were higher in the IC group (18.8% vs 7.5% and 6.9% vs 0%, respectively). The serum creatinine level was lowest in the CC group (0.90 +/- 0.46 mg/dl) and highest in the UC group (1.36 +/- 0.75 mg/dl). Conduit ureteral reflux was frequent in the UC group (66.7%) but rare in the CC group (1.3%). We conclude that UC should be indicated in the selected patients with high risk, and IC and CC are indicated in patients who may have good prognosis but not indicated for continent reservoir or neobladder. We prefer CC in the younger group

Obstructive sleep apnea syndrome with bilateral papilledema and vision loss in a 3-year-old child.

We describe bilateral papilledema and vision loss in a 3-year-old child with obstructive sleep apnea. Although lumbar puncture initially disclosed a normal opening pressure, cerebrospinal fluid (CSF) pressure monitoring during sleep confirmed intermittent episodes of elevated intracranial pressure corresponding to increased airway resistance. The association of obstructive sleep apnea and raised intracranial pressure is recognized in children with craniosynostosis but has not been reported in its absence.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text from the publisher's site