American psychiatry in the new millennium: a critical appraisal

2021 ◽  
pp. 1-9
Author(s):  
Andrew Scull
Keyword(s):  
Mental Illness ◽  
Association Studies ◽  
Scientific Progress ◽  
Mental Illnesses ◽  
Future Research ◽  
Rapid Decline ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
American Psychiatry ◽  
The Status

Abstract This article casts a critical eye over the development of American psychiatry from 1980 to the present. It notes the rapid decline of psychoanalysis that followed the publication of DSM III; the rising influence of genetics and neuroscience; the re-emphasis on the biology of mental illness; and the collapse of public psychiatry that accompanied deinstitutionalization. It argues that while genetics and neuroscience have made scientific progress, the clinical utility of their findings to date has been very limited. The fifth edition of the DSM was supposed to base itself on this new science but that proved impossible. Diagnosis remains purely phenomenological and controversial. One of the ironies of research on psychiatric genetics is that has failed to find either a Mendelian origin of schizophrenia and depression or to validate the importance of hypothesized candidate genes. Genome-wide association studies have instead uncovered risk factors for major mental illnesses, but these overlap considerably, and the genetic associations are not dispositive. Most of those who carry these genetic variants do not develop mental illness. The status of psychopharmacology since the mid-1950s is scrutinized, as is the influence of the pharmaceutical industry on contemporary psychiatry, and the implications of its recent decision to abandon work in this arena. The paper concludes with an assessment of the crisis that it contends confronts contemporary American psychiatry: its overemphasis on biology; the urgent questions that persist about diagnosis and therapeutics; concerns about the directions of future research; and its inability to reduce the excess mortality that plagues the mentally ill.

scholarly journals Penalized partial least squares for pleiotropy

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Camilo Broc ◽  
Therese Truong ◽  
Benoit Liquet
Keyword(s):  
Least Squares ◽  
Partial Least Squares ◽  
Association Studies ◽  
A Priori ◽  
Simulated Data ◽  
Real Data ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Multiple Traits ◽  
Application Fields

Abstract Background The increasing number of genome-wide association studies (GWAS) has revealed several loci that are associated to multiple distinct phenotypes, suggesting the existence of pleiotropic effects. Highlighting these cross-phenotype genetic associations could help to identify and understand common biological mechanisms underlying some diseases. Common approaches test the association between genetic variants and multiple traits at the SNP level. In this paper, we propose a novel gene- and a pathway-level approach in the case where several independent GWAS on independent traits are available. The method is based on a generalization of the sparse group Partial Least Squares (sgPLS) to take into account groups of variables, and a Lasso penalization that links all independent data sets. This method, called joint-sgPLS, is able to convincingly detect signal at the variable level and at the group level. Results Our method has the advantage to propose a global readable model while coping with the architecture of data. It can outperform traditional methods and provides a wider insight in terms of a priori information. We compared the performance of the proposed method to other benchmark methods on simulated data and gave an example of application on real data with the aim to highlight common susceptibility variants to breast and thyroid cancers. Conclusion The joint-sgPLS shows interesting properties for detecting a signal. As an extension of the PLS, the method is suited for data with a large number of variables. The choice of Lasso penalization copes with architectures of groups of variables and observations sets. Furthermore, although the method has been applied to a genetic study, its formulation is adapted to any data with high number of variables and an exposed a priori architecture in other application fields.

scholarly journals Genetic association studies of alterations in protein function expose recessive effects on cancer predisposition

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadav Brandes ◽  
Nathan Linial ◽  
Michal Linial
Keyword(s):  
Cancer Risk ◽  
Protein Function ◽  
Association Studies ◽  
Genetic Effects ◽  
Cancer Predisposition ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Functional Interpretation ◽  
Gene Damage ◽  
Genomic Regions

AbstractThe characterization of germline genetic variation affecting cancer risk, known as cancer predisposition, is fundamental to preventive and personalized medicine. Studies of genetic cancer predisposition typically identify significant genomic regions based on family-based cohorts or genome-wide association studies (GWAS). However, the results of such studies rarely provide biological insight or functional interpretation. In this study, we conducted a comprehensive analysis of cancer predisposition in the UK Biobank cohort using a new gene-based method for detecting protein-coding genes that are functionally interpretable. Specifically, we conducted proteome-wide association studies (PWAS) to identify genetic associations mediated by alterations to protein function. With PWAS, we identified 110 significant gene-cancer associations in 70 unique genomic regions across nine cancer types and pan-cancer. In 48 of the 110 PWAS associations (44%), estimated gene damage is associated with reduced rather than elevated cancer risk, suggesting a protective effect. Together with standard GWAS, we implicated 145 unique genomic loci with cancer risk. While most of these genomic regions are supported by external evidence, our results also highlight many novel loci. Based on the capacity of PWAS to detect non-additive genetic effects, we found that 46% of the PWAS-significant cancer regions exhibited exclusive recessive inheritance. These results highlight the importance of recessive genetic effects, without relying on familial studies. Finally, we show that many of the detected genes exert substantial cancer risk in the studied cohort determined by a quantitative functional description, suggesting their relevance for diagnosis and genetic consulting.

scholarly journals Genetic Basis of Mastitis Resistance in Dairy Cattle – A Review / Podstawy Genetyczne Odporności Krów Mlecznych Na Zapalenie Wymienia – Artykuł Przeglądowy

2013 ◽  
Vol 13 (4) ◽  
pp. 663-673 ◽  
Author(s):  
Grażyna Sender ◽  
Agnieszka Korwin-Kossakowska ◽  
Adrianna Pawlik ◽  
Karima Galal Abdel Hameed ◽  
Jolanta Oprządek
Keyword(s):  
Dairy Cattle ◽  
Association Studies ◽  
Genetic Resistance ◽  
Clinical Mastitis ◽  
Future Research ◽  
Complex Nature ◽  
Candidate Gene Approach ◽  
Genome Wide Association Studies ◽  
Polygenic Control ◽  
Breeding Programmes

Abstract Mastitis is one of the most important mammary gland diseases impacting lactating animals. Resistance to this disease could be improved by breeding. There are several selection methods for mastitis resistance. To improve the natural genetic resistance of cows in succeeding generations, current breeding programmes use somatic cell count and clinical mastitis cases as resistance traits. However, these methods of selection have met with limited success. This is partly due to the complex nature of the disease. The limited progress in improving udder health by conventional selection procedures requires applying information on molecular markers of mastitis susceptibility in marker-assisted selection schemes. Mastitis is under polygenic control, so there are many genes that control this trait in many loci. This review briefly describes genome-wide association studies which have been carried out to identify quantitative trait loci associated with mastitis resistance in dairy cattle worldwide. It also characterizes the candidate gene approach focus on identifying genes that are strong candidates for the mastitis resistance trait. In the conclusion of the paper we focus our attention on future research which should be conducted in the field of the resistance to mastitis.

scholarly journals Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1181
Author(s):  
Alessandro Maglione ◽  
Miriam Zuccalà ◽  
Martina Tosi ◽  
Marinella Clerico ◽  
Simona Rolla
Keyword(s):  
Multiple Sclerosis ◽  
Environmental Factors ◽  
Lupus Erythematosus ◽  
Gut Microbiome ◽  
Complex Disease ◽  
Current Knowledge ◽  
Association Studies ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Host Genetics

As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we focus on these dual aspects of MS pathogenesis: we describe the current knowledge on genetic factors related to MS, based on genome-wide association studies, and then illustrate the interactions between the immune system, gut microbiome and central nervous system in MS, summarizing the evidence available from Experimental Autoimmune Encephalomyelitis mouse models and studies in patients. Finally, as the understanding of influence of host genetics on the gut microbiome composition in MS is in its infancy, we explore this issue based on the evidence currently available from other autoimmune diseases that share with MS the interplay of genetic with environmental factors (Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus), and discuss avenues for future research.

scholarly journals Four Loci Are Associated with Cardiorespiratory Fitness and Endurance Performance in Young Chinese Females

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ying Zhao ◽  
Guoyuan Huang ◽  
Zuosong Chen ◽  
Xiang Fan ◽  
Tao Huang ◽  
...  
Keyword(s):  
Cardiorespiratory Fitness ◽  
Association Studies ◽  
Endurance Performance ◽  
Young Female ◽  
Future Research ◽  
Genome Wide Association Studies ◽  
Genetic Trait ◽  
Young Females ◽  
Genome Wide ◽  
Fixed Model

AbstractCardiorespiratory fitness (CRF) and endurance performance are characterized by a complex genetic trait with high heritability. Although research has identified many physiological and environmental correlates with CRF, the genetic architecture contributing to CRF remains unclear, especially in non-athlete population. A total of 762 Chinese young female participants were recruited and an endurance run test was used to determine CRF. We used a fixed model of genome-wide association studies (GWAS) for CRF. Genotyping was performed using the Affymetrix Axiom and illumina 1 M arrays. After quality control and imputation, a linear regression-based association analysis was conducted using a total of 5,149,327 variants. Four loci associated with CRF were identified to reach genome-wide significance (P < 5.0 × 10-8), which located in 15q21.3 (rs17240160, P = 1.73 × 10-9, GCOM1), 3q25.31 (rs819865, P = 8.56 × 10-9, GMPS), 21q22.3 (rs117828698, P = 9.59 × 10-9, COL18A1), and 17q24.2 (rs79806428, P = 3.85 × 10-8, PRKCA). These loci (GCOM1, GMPS, COL18A1 and PRKCA) associated with cardiorespiratory fitness and endurance performance in Chinese non-athlete young females. Our results suggest that these gene polymorphisms provide further genetic evidence for the polygenetic nature of cardiorespiratory endurance and be used as genetic biomarkers for future research.

scholarly journals Heterogeneous Network Edge Prediction: A Data Integration Approach to Prioritize Disease-Associated Genes

2014 ◽  
Author(s):  
Daniel S Himmelstein ◽  
Sergio E Baranzini
Keyword(s):  
Data Integration ◽  
Protein Interactions ◽  
Heterogeneous Network ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Protein Coding ◽  
Multiple Node ◽  
Pathogenic Variants ◽  
Disease Associated Genes

The first decade of Genome Wide Association Studies (GWAS) has uncovered a wealth of disease-associated variants. Two important derivations will be the translation of this information into a multiscale understanding of pathogenic variants, and leveraging existing data to increase the power of existing and future studies through prioritization. We explore edge prediction on heterogeneous networks—graphs with multiple node and edge types—for accomplishing both tasks. First we constructed a network with 18 node types—genes, diseases, tissues, pathophysiologies, and 14 MSigDB (molecular signatures database)collections—and 19 edge types from high-throughput publicly-available resources. From this network composed of 40,343 nodes and 1,608,168 edges, we extracted features that describe the topology between specific genes and diseases. Next, we trained a model from GWAS associations and predicted the probability of association between each protein-coding gene and each of 29 well-studied complex diseases. The model, which achieved 132-fold enrichment in precision at 10% recall, outperformed any individual domain, highlighting the benefit of integrative approaches. We identified pleiotropy, transcriptional signatures of perturbations, pathways, and protein interactions as fundamental mechanisms explaining pathogenesis. Our method successfully predicted the results (with AUROC = 0.79) from a withheld multiple sclerosis (MS) GWAS despite starting with only 13 previously associated genes. Finally, we combined our network predictions with statistical evidence of association to propose four novel MS genes, three of which (JAK2, REL, RUNX3) validated on the masked GWAS. Furthermore, our predictions provide biological support highlighting REL as the causal gene within its gene-rich locus. Users can browse all predictions online (http://het.io). Heterogeneous network edge prediction effectively prioritized genetic associations and provides a powerful new approach for data integration across multiple domains.

Abstract 49: Adipose-Specific Knockout of Trib1 Reduces Plasma Lipids and Diet-Induced Insulin Resistance, and Increases Circulating Adiponectin

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Mikhaila A Smith ◽  
Jian Cui ◽  
Sumeet A Kheterpal ◽  
Daniel J Rader ◽  
Robert C Bauer
Keyword(s):  
Body Mass ◽  
Plasma Lipids ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Tissue Mass ◽  
Fed State ◽  
Plasma Adiponectin ◽  
Metabolic Role

Tribbles-1 (TRIB1) was recently identified through genome-wide association studies as a novel mediator of plasma lipids and coronary artery disease in humans. While subsequent in vivo mouse work confirmed a role for hepatic TRIB1 in these associations, little is known about metabolic roles for extra-hepatic Trib1. Interestingly, SNPs near the TRIB1 gene are significantly associated with circulating adiponectin levels in humans, suggesting a metabolic role for adipose TRIB1 . To further investigate this, we generated adipose-specific Trib1 KO mice (Trib1_ASKO) by crossing Trib1 cKO mice to transgenic Adiponectin-Cre mice. Chow-fed Trib1_ASKO mice exhibited no differences in adipose tissue mass and overall body mass as compared to control littermates (N=8/group). However, Trib1_ASKO mice had reduced total (-16.9%, p <0.01), HDL (-16.7%, p <0.01), and non-HDL cholesterol (-17.3%, p =0.068), as well as plasma triglycerides (-28.6%, p <0.001) as compared to WT mice. Trib1_ASKO mice also had increased plasma adiponectin levels, a finding more pronounced in female mice (+33.3%, p <0.001) than in males (+16.4%, p =0.072). Despite this increase, transcript levels of adipoQ were moderately decreased in Trib1_ASKO mice, suggesting a post-transcriptional mode of regulation. Transcript and protein levels of C/EBPα, the best described target of Trib1 and a key regulator of adipogenesis, remained unchanged. To further investigate the metabolic consequences of adipose-specific KO of Trib1 , WT and Trib1_ASKO mice were fed high-fat diet (HFD, 45% kCal fat) for 12 weeks to induce obesity. HFD-fed Trib1_ASKO mice had reduced fasting plasma glucose (-22.3%, p <0.05), insulin (-38.2%, p <0.05), and glucose tolerance (-19.8% AUC, p <0.05) compared to control mice. Body mass and fat mass of HFD-fed Trib1_ASKO mice remained unchanged from WT, and the reductions in plasma lipids and increase in plasma adiponectin persisted in the HFD-fed state. In summary, we present here the first in vivo validation of the human genetic association between TRIB1 and plasma adiponectin, and provide evidence suggesting that adipose TRIB1 contributes to the genetic associations observed in humans between TRIB1 and multiple metabolic parameters.

Timing of pubertal development and midlife blood pressure in men and women: A Mendelian randomization study

2021 ◽  
Author(s):  
Io Ieong Chan ◽  
Man Ki Kwok ◽  
C Mary Schooling
Keyword(s):  
Blood Pressure ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Pubertal Development ◽  
Sensitivity Analyses ◽  
Age At Menarche ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Pubertal Maturation ◽  
Pubertal Growth

Abstract Introduction Observational studies suggest earlier puberty is associated with higher adulthood blood pressure (BP), but these findings have not been replicated using Mendelian randomization (MR). We examined this question sex-specifically using larger genome-wide association studies (GWAS) with more extensive measures of pubertal timing. Methods We obtained genetic instruments proxying pubertal maturation (age at menarche (AAM) or voice breaking (AVB)) from the largest published GWAS. We applied them to summary sex-specific genetic associations with systolic and diastolic BP z-scores, and self-reported hypertension in women (n=194174) and men (n=167020) from the UK Biobank, using inverse-variance weighting meta-analysis. We conducted sensitivity analyses using other MR methods, including multivariable MR adjusted for childhood obesity proxied by body mass index (BMI). We used late pubertal growth as a validation outcome. Results AAM (beta per one-year later = -0.030 [95% confidence interval (CI) -0.055, -0.005] and AVB (beta -0.058 [95% CI -0.100, -0.015]) were inversely associated with systolic BP independent of childhood BMI, as were diastolic BP (-0.035 [95% CI -0.060, -0.009] for AAM and -0.046 [95% CI -0.089, -0.004] for AVB) and self-reported hypertension (odds ratios 0.89 [95% CI 0.84, 0.95] for AAM and 0.87 [95% CI 0.79, 0.96] for AVB). AAM and AVB were positively associated with late pubertal growth, as expected. The results were robust to sensitivity analysis using other MR methods. Conclusion Timing of pubertal maturation was associated with adulthood BP independent of childhood BMI, highlighting the role of pubertal maturation timing in midlife BP.

scholarly journals Insights into the genetic basis of retinal detachment

2019 ◽  
Vol 29 (4) ◽  
pp. 689-702 ◽  
Author(s):  
Thibaud S Boutin ◽  
David G Charteris ◽  
Aman Chandra ◽  
Susan Campbell ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Retinal Detachment ◽  
Association Studies ◽  
Genetic Correlations ◽  
Self Report ◽  
Cataract Operation ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Data Set ◽  
Genome Wide

Abstract Retinal detachment (RD) is a serious and common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. In the UK Biobank data set, where RD was ascertained by self-report or hospital records, genetic correlations between RD and high myopia or cataract operation were, respectively, 0.46 (SE = 0.08) and 0.44 (SE = 0.07). These correlations are consistent with known epidemiological associations. Through meta-analysis of genome-wide association studies using UK Biobank RD cases (N = 3 977) and two cohorts, each comprising ~1 000 clinically ascertained rhegmatogenous RD patients, we uncovered 11 genome-wide significant association signals. These are near or within ZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1 and LOXL1. Replication in the 23andMe data set, where RD is self-reported by participants, firmly establishes six RD risk loci: FAT3, COL22A1, TYR, BMP3, ZC3H11B and PLCE1. Based on the genetic associations with eye traits described to date, the first two specifically impact risk of a RD, whereas the last four point to shared aetiologies with macular condition, myopia and glaucoma. Fine-mapping prioritized the lead common missense variant (TYR S192Y) as causal variant at the TYR locus and a small set of credible causal variants at the FAT3 locus. The larger study size presented here, enabled by resources linked to health records or self-report, provides novel insights into RD aetiology and underlying pathological pathways.

Offenders with Mental Illness in Prison

2016 ◽  
Author(s):  
Sarah M. Manchak ◽  
Robert D. Morgan
Keyword(s):  
Mental Illness ◽  
Mentally Ill ◽  
Justice System ◽  
Mental Illnesses ◽  
Future Research ◽  
Mentally Disordered Offenders ◽  
Prison Management ◽  
Mentally Disordered ◽  
Prison Environment ◽  
Offenders With Mental Illness

This essay describes trends in the number of mentally disordered offenders in prison and the unique challenges posed by them in terms of prison management and service delivery. The essay first explores why persons with mental illnesses are overrepresented in the criminal justice system, then discusses efforts to rehabilitate this population should not take place within the prison environment (and, if they do, what changes in current practices are necessary to adapt to the prison setting). How the challenges posed by mentally ill inmates are managed is also covered, with critical discussions of these strategies. Finally, an analysis of the changes that are needed to improve conditions for inmates with mental illness in prisons is presented, with a description of one promising program for treating these offenders. Suggestions for future research with this population that will help inform and improve prison conditions for offenders with mental illness are also provided.

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