Utility of the pooling approach as applied to whole genome association scans with high-density Affymetrix microarrays

Background: We report an attempt to extend the previously successful approach of combining SNP (single nucleotide polymorphism) microarrays and DNA pooling (SNP-MaP) employing high-density microarrays. Whereas earlier studies employed a range of Affymetrix SNP microarrays comprising from 10 K to 500 K SNPs, this most recent investigation used the 6.0 chip which displays 906,600 SNP probes and 946,000 probes for the interrogation of CNVs (copy number variations). The genotyping assay using the Affymetrix SNP 6.0 array is highly demanding on sample quality due to the small feature size, low redundancy, and lack of mismatch probes. Findings: In the first study published so far using this microarray on pooled DNA, we found that pooled cheek swab DNA could not accurately predict real allele frequencies of the samples that comprised the pools. In contrast, the allele frequency estimates using blood DNA pools were reasonable, although inferior compared to those obtained with previously employed Affymetrix microarrays. However, it might be possible to improve performance by developing improved analysis methods. Conclusions: Despite the decreasing costs of genome-wide individual genotyping, the pooling approach may have applications in very large-scale case-control association studies. In such cases, our study suggests that high-quality DNA preparations and lower density platforms should be preferred

Genomewide Association Scan of Suicidal Thoughts and Behaviour in Major Depression

Background Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT. Methodology/Principal Findings A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality. Conclusions/Significance This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling

J. Kaprio, A. Palotie, A. Raevuori-Helkamaa ja S. Ripatti ovat työryhmän Eating Disorders Working Group of the Psychiatric Genomics Consortium jäseniä. Erratum in: Sci Rep. 2017 Aug 21;7(1):8379, doi: 10.1038/s41598-017-06409-3We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 x 10(-7); OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

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

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Associations between Attention-Deficit/Hyperactivity Disorder and various eating disorders: A Swedish nationwide population study using multiple genetically informative approaches

Background Although attention-deficit hyperactivity/impulsivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs (OED, including bulimia nervosa [BN]). Methods We applied different genetically informative designs to register-based information of a Swedish nationwide population (N=3,550,118). We first examined the familial co-aggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores (PRS) and ED symptoms, and between AN PRS and ADHD symptoms, in a genotyped population-based sample (N=13,472). Results Increased risk of all types of EDs was found in individuals with ADHD (any ED: OR [95% CI]=3.97 [3.81-4.14], AN: 2.68 [2.15-2.86], OED: 4.66 [4.47-4.87], BN: 5.01 [4.63-5.41]) and their relatives compared to individuals without ADHD and their relatives. The magnitude of the associations reduced as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with OED (0.37 [0.31-0.42]) than with AN (0.14 [0.05-0.22]). ADHD PRS correlated positively with ED symptom measures overall and sub-scales “drive for thinness” and “body dissatisfaction”, despite small effect sizes. Conclusions We observed stronger genetic association with ADHD for non-AN EDs than AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders

Cost-effectiveness analysis of an ambulant psychiatric rehabilitation programme in Austria

Introduction: Psychiatric rehabilitation promotes recovery, full community integration, and improved quality of life for individuals who have experienced severe psychiatric disabilities that limit their capacity to perform certain tasks and functions and their ability to perform in certain roles. The current study focuses on an ambulant psychiatric rehabilitation programme in Vienna, Austria. In Austria, psychiatric rehabilitation has been established since 2002, initially as inpatient treatment programmes, and, later on, in 2010 the “Zentrum für seelische Gesundheit BBRZ-Med, Wien-Leopoldau,” initiated ambulant psychiatric rehabilitation in Vienna. Aim: The aim of the study was to perform a cost-effectiveness study of this ambulant psychiatric rehabilitation programme. Methods: From January 2014 to December 2016, a total of 2,486 patients were admitted to the “Zentrum für seelische Gesundheit Wien-Leopoldau” and filled out questionnaire-based surveys at time of pre-contact before starting rehabilitation (screening interview), at time of admission, at time of discharge, 6 months after discharge (6-months catamnesis), and 12 months after discharge (12-months catamnesis). Clinical effectiveness was assessed using 1) the BSI-18 (Brief Symptom Inventory) to measure symptom burden, 2) the BDI (Beck Depression Inventory) to measure depressive symptoms, and 3-5) the GAF (Global Assessment of Functioning), the WHODAS 2.0 (World Health Organisation Disability Assessment Schedule 2.0) and the ICF-AT-3F (International Classification of Functioning, Disability and Health) to measure different aspects of functioning. For the cost calculation, both direct costs and indirect costs were considered. The direct costs included the treatment by specialist in psychiatry and/or general practitioner and/or psychotherapist and/or psychological treatment, as well as costs of psycho-pharmacological treatment, inpatient treatment costs, and costs of rehabilitation. Indirect costs were calculated as productivity loss measured in non-working days depending on the average income of each rehabilitand. The average income was calculated based on the Austrian classification of economic occupation groups called OENACE depending on gender, age, and scope of employment (full-time or part-time). To overcome the problem that the period of 6 weeks rehabilitation and 12 months after rehabilitation as assessed at the 12-months catamnesis (in sum 13.5 months), and the period of 12 months before admission are not directly comparable, we designed a pseudo control group to calculate the total costs of the 13.5 months period before admission. Results: Of the 2,482 patients admitted to the ambulant rehabilitation programme from 2014 to 2016, complete data on occupational information based on OENACE 2008 (including brutto income) was available for 1,781 rehabilitands after thorough data cleaning. With regard to the clinical effectiveness measures, significant improvements were found in BSI, BDI, GAF, WHODAS 2.0 and ICF-AT-3F, especially regarding rehabilitands that were employed at time of admission. Unemployed rehabilitands showed improvement to a less successful extent, and the worst outcome was found for patients receiving rehabilitation allowance. We further found a significant reduction in treatment days within the period of 12 months after rehabilitation as compared to the period of 12 months before admission, with the only exception of patients receiving rehabilitation allowance. Again, with exception of patients receiving rehabilitation allowance, treatment costs significantly decreased within the period of 12 months after end of rehabilitation when excluding the costs of 6 weeks rehabilitation in order to compare the period of 12 months before admission and the 12 months after the end of rehabilitation. However, when adding the costs of 6 weeks rehabilitation to the treatment costs, and comparing to the 13.5 months period before admission, slightly increased treatment costs were measured at 12-months catamnesis. In contrast to the treatment costs, a reduction of productivity loss was found in all subgroups. When adding up treatment costs and costs of productivity loss, we again found a significant reduction in total costs when excluding the costs of 6 weeks rehabilitation, both in the whole sample (total annual costs during the period of 12 months before admission: on average 27,325.19 EUR per rehabilitand; total annual costs during the 12 months period after rehabilitation: on average 18,588.82 EUR per rehabilitand) and in all occupational subgroups. When adding the costs of 6 weeks rehabilitation to the total costs of the period of 12 months after the end of rehabilitation, we still found a reduction of total costs within the 12 period of months after rehabilitation both in the whole sample (total annual costs during the 12 months period after rehabilitation: 22,868.74 EUR) and in all occupational subgroups, although this reduction of total costs did not remain significant in any of these groups. Subsequently, to overcome the problem that the period of 6 weeks rehabilitation and 12 months after rehabilitation as assessed at 12-months catamnesis (in sum 13.5 months), and the period of 12 months before admission are not directly comparable, we designed a pseudo control group to calculate the total costs of the 13.5 months period before admission. Using this pseudo control group, the total costs of the 13.5 months before admission were calculated to be 30,740.84 Euros, as compared to the above mentioned 22,868.74 Euros total costs within the 13.5 months after admission. This corresponds to a cost saving of 7,872.10 Euros per rehabilitand in the whole sample. Dividing the rehabilitands according to occupational status, the cost savings were 6,996.58 Euros in employed, 6,191.74 Euros in unemployed, and 12,063.62 Euros in rehabilitands receiving rehabilitation allowance. Conclusion: With regard to clinical effectiveness measures, significant improvements were found for depressive symptoms, symptom burden, and different aspects of functioning. Thus, the ambulant rehabilitation programme is without doubt highly effective in terms of clinical improvement. Nevertheless, the results of cost-effectiveness analyses were clearly promising as well, with cost savings of on average -7,872.10 Euros per rehabilitand. For the cost measures, we designed a pseudo control group to compare the period of 13.5 months before admission and the period of 13.5 months after admission, finding incremental cost savings in all occupational subgroups, whereas the incremental effectiveness was higher in employed and unemployed rehabilitands, however ambiguous in rehabilitands receiving rehabilitation allowance. Interestingly, dividing the incremental costs according to occupational subgroups, the highest cost savings were found for the patients receiving rehabilitation allowance. Investigating the latter more in detail, we found that 15.79% were employed at 12-months catamnesis. It has to be pointed out that, although only a few of those receiving rehabilitation allowance at admission were employed 12 months after rehabilitation, the latter seem to have high financial impact on the whole group of patients receiving rehabilitation allowance. In short, the results of the current study clearly show that ambulant psychiatric rehabilitation is highly effective, and it is of high importance that patients suffering from a psychiatric disease should be referred to a rehabilitation programme at an early state of disease to show the highest benefit in sense of clinical effectiveness and cost savings. Nevertheless, the rehabilitation of those chronically ill showed cost effectiveness as well, and we should put further effort in the rehabilitation of this group not only for clinical and ethic reasons but also from an economic perspective.eingereicht von Alexandra SchosserMedizinische Universität Wien, Masterarb., 2018(VLID)256885