Cochlear implantation in advanced otosclerosis: utility of pre-operative radiological assessment in predicting intra-operative difficulty and final electrode position.

OBJECTIVE: This study aimed to determine if pre-operative radiological scoring can reliably predict intra-operative difficulty and final cochlear electrode position in patients with advanced otosclerosis. METHOD: A retrospective cohort study of advanced otosclerosis patients who underwent cochlear implantation (n = 48, 52 ears) was compared with a larger cohort of post-lingually deaf adult patients (n = 1414) with bilateral hearing loss and normal cochlear anatomy. Pre-operative imaging for advanced otosclerosis patients and final electrode position were scored and correlated with intra-operative difficulty and speech outcomes. RESULTS: Advanced otosclerosis patients benefit significantly from cochlear implantation. Mean duration of deafness was longer in the advanced otosclerosis group (19.5 vs 14.3 years; p < 0.05). CONCLUSION: Anatomical changes in advanced otosclerosis can result in increased difficulty of surgery. Evidence of pre-operative cochlear luminal changes was associated with intra-operative difficult insertion and final non-scala tympani position. Nearly all electrodes implanted in the advanced otosclerosis cohort were peri-modiolar. No reports of facial nerve stimulation were observed.

High frequency of cholecystitis in dogs with gallbladder mucocoele in Hong Kong.

The aims of this retrospective study were to characterise the epidemiological, clinical, histopathological, and microbiological findings as well as surgical outcomes in dogs admitted to a specialist veterinary hospital in Hong Kong for surgical management of gallbladder mucocoele (GBM). Inclusion criteria were cases with histopathological diagnosis of GBM and accompanying abdominal imaging, serum biochemistry, bile culture, and liver biopsy histology results. Fifty-six cases met the inclusion criteria. The median age at diagnosis was 12 years (range, 5-16 years). Miniature or toy pure-breed dogs were most commonly affected, including Poodles, Pomeranians, Schnauzers, Bichon frises and Chihuahuas. However, no breed was over-represented compared with their expected proportions among annual hospital admissions. Histological evidence of cholecystitis was present in 84% of cases, including acute cholecystitis in 18%, chronic cholecystitis in 37.5%, acute on chronic cholecystitis in 28% and acute with necrosis in 6%. The most common liver lesions were cholestasis in 64%, along with portal fibrosis in 55%, oedema in 50% and bile duct hyperplasia in 50%. Bile culture was positive in 29.6% of cases. Escherichia coli and Enterobacter species were most commonly isolated. Stentrophomonas maltophili was cultured from one case. Of the 16 cases where bacteria were isolated from bile culture, 94% had evidence of chronic cholecystitis and 81% had evidence of cholangiohepatitis. Fifty dogs (89.3%) survived to discharge including 5/5 dogs with ruptured gallbladders. Of 34 dogs with follow-up data, 21/34 (61.8%) were still alive 12 months later. Gallbladder mucocoeles were frequently associated with both acute and chronic inflammation. High survival rates to discharge were achieved.

Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis.

We interrogate the joint genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis. We identify four broad factors (neurodevelopmental, compulsive, psychotic and internalizing) that underlie genetic correlations among the disorders and test whether these factors adequately explain their genetic correlations with biobehavioral traits. We introduce stratified genomic structural equation modeling, which we use to identify gene sets that disproportionately contribute to genetic risk sharing. This includes protein-truncating variant-intolerant genes expressed in excitatory and GABAergic brain cells that are enriched for genetic overlap across disorders with psychotic features. Multivariate association analyses detect 152 (20 new) independent loci that act on the individual factors and identify nine loci that act heterogeneously across disorders within a factor. Despite moderate-to-high genetic correlations across all 11 disorders, we find little utility of a single dimension of genetic risk across psychiatric disorders either at the level of biobehavioral correlates or at the level of individual variants.

Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms.

OBJECTIVE: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. METHOD: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. RESULTS: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, neffective = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (|rg| > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range |rg| = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. CONCLUSION: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

Scedosporium apiospermum infections in the middle ear and mastoid: case series and review of the literature.

OBJECTIVES: To present our case series and management of Scedosporium apiospermum infections of the middle ear and mastoid, and review the current literature on this rare yet potentially life-threatening condition. METHODS: Medical records of patients treated at the Royal Victorian Eye and Ear Hospital for S apiospermum middle ear and mastoid infections between 2009 and 2019 were reviewed. A literature search was conducted using PubMed, Medline and Cochrane Library databases. RESULTS: Two patients were identified in our institution: a 62-year-old diabetic woman with otogenic skull base osteomyelitis, and a 12-year-old boy with unilateral chronic suppurative otitis media which developed after tympanostomy tube insertion. The persistence of otalgia and otorrhoea despite prolonged antibiotic treatment characterised these cases. Both patients received voriconazole, and achieved disease resolution without complications. Ten relevant cases were identified after review of the literature. Despite treatment, there were three patient deaths, and four patients with otological or neurological complications. CONCLUSION: The presence of a middle ear or mastoid infection refractory to appropriate topical and systemic antibiotics should prompt clinicians to consider a fungal infection. The role of surgical debridement in the treatment of S apiospermum infection of the middle ear and mastoid is equivocal.

Longevity of an immunocontraceptive vaccine effect on fecundity in rats.

•Increases in human-wildlife conflicts alongside cultural shifts against lethal control methods are driving the need for alternative wildlife management tools such as fertility control. Contraceptive formulations suitable for oral delivery would permit broader remote application in wildlife species.•This study evaluated the contraceptive effect and immune response to two novel injectable immunocontraceptive formulations targeting the Gonadotropin Releasing Hormone (GnRH): MAF-IMX294 and MAF-IMX294P conjugates, both identified as having potential as oral contraceptives. The study also explored whether in multiparous species immunocontraceptives may either totally prevent reproduction or also affect litter size.•Female rats, chosen as a model species, were given three doses of either MAF-IMX294 or MAF-IMX294P to compare anti-GnRH immune response and reproductive output up to 310 days post-treatment.•Both formulations induced anti-GnRH antibody titres in 100% of rats and significantly impaired fertility compared to control animals. Following treatment with MAF-IMX294 and MAF-IMX294P 0 of 9 and 1 of 10 females respectively produced litters following the first mating challenge 45 days post-treatment, compared to 9 of 9 control animals.•Across the whole 310 day study period 7 of 9 females from the MAF-IMX294 group and 10 of 10 females in the MAF-IMX294P group became fertile, producing at least one litter throughout six mating challenges.•No significant differences were found between the two formulations in antibody titre response or duration of contraceptive effect, with an average time to first pregnancy of 166 days for MAF-IMX294 and 177 days for MAF-IMX294P for all females that became fertile.•Following treatment with MAF-IMX294 and MAF-IMX294P the first litter produced post-infertility in treated females was significantly smaller than in control animals. This indicates treatment with immunocontraceptives may induce an overall suppression of fecundity extending past an initial infertility effect. This increases the potential long-term impact of these immunocontraceptives in multiparous species such as commensal rodents.

Genetic association study of childhood aggression across raters, instruments, and age.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction.

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Effect of vaccination with a novel GnRH-based immunocontraceptive on immune responses and fertility in rats.

1. As human-wildlife conflicts increase worldwide, novel methods are required for mitigating these conflicts. Fertility control, based on immunocontraceptives, has emerged as an alternative option to lethal methods for managing wildlife. 2. Immunocontraceptives are vaccines that generate an immune response to key components of an animal's reproductive system. Some of these vaccines target the gonadotropin-releasing hormone (GnRH) and have been used successfully as contraceptives for many wildlife species. However, the need to capture animals for treatment limits the field applications of injectable vaccines. The availability of orally delivered immunocontraceptives would increase the breadth of applications of fertility control for wildlife management. 3. This study explored a new approach to developing an oral immunocontraceptive, exploiting the bioadhesive and immunologically active properties of killed Mycobacterium avium cell wall fragments (MAF). The MAF was conjugated to a GnRH recombinant protein called IMX294, used as a GnRH-specific immunogen. 4. An initial trial using the MAF-IMX294 conjugate provided the first evidence that an orally delivered immunocontraceptive vaccine could generate anti-GnRH antibody titres in laboratory rats. 5. Increasing the dose and frequency of vaccine administered to rats, in a second trial, enhanced the immune response, eliciting titres that reduced the proportion of females giving birth. This provided the first evidence of the contraceptive effect of an oral anti-GnRH vaccine. 6. Future work is required to further increase the immunogenic effect of the oral vaccine and to establish a dosing schedule that is effective for practical field applications.

Content, diagnostic, correlational, and genetic similarities between common measures of childhood aggressive behaviors and related psychiatric traits.

BACKGROUND: Given the role of childhood aggressive behavior (AGG) in everyday child development, precise and accurate measurement is critical in clinical practice and research. This study aims to quantify agreement among widely used measures of childhood AGG regarding item content, clinical concordance, correlation, and underlying genetic construct. METHODS: We analyzed data from 1254 Dutch twin pairs (age 8-10 years, 51.1% boys) from a general population sample for whom both parents completed the A-TAC, CBCL, and SDQ at the same occasion. RESULTS: There was substantial variation in item content among AGG measures, ranging from .00 (i.e., mutually exclusive) to .50 (moderate agreement). Clinical concordance (i.e., do the same children score above a clinical threshold among AGG measures) was very weak to moderate with estimates ranging between .01 and .43 for mother-reports and between .12 and .42 for father-reports. Correlations among scales were weak to strong, ranging from .32 to .70 for mother-reports and from .32 to .64 for father-reports. We found weak to very strong genetic correlations among the measures, with estimates between .65 and .84 for mother-reports and between .30 and .87 for father-reports. CONCLUSIONS: Our results demonstrated that degree of agreement between measures of AGG depends on the type (i.e., item content, clinical concordance, correlation, genetic correlation) of agreement considered. Because agreement was higher for correlations compared to clinical concordance (i.e., above or below a clinical cutoff), we propose the use of continuous scores to assess AGG, especially for combining data with different measures. Although item content can be different and agreement among observed measures may not be high, the genetic correlations indicate that the underlying genetic liability for childhood AGG is consistent across measures.

Genetic meta-analysis of obsessive-compulsive disorder and self-report compulsive symptoms.

We investigated whether obsessive-compulsive (OC) symptoms from a population-based sample could be analyzed to detect genetic variants influencing obsessive-compulsive disorder (OCD). We performed a genome-wide association studies (GWAS) on the obsession (rumination and impulsions) and compulsion (checking, washing, and ordering/precision) subscales of an abbreviated version of the Padua Inventory (N = 8,267 with genome-wide genotyping and phenotyping). The compulsion subscale showed a substantial and significant positive genetic correlation with an OCD case-control GWAS (r G = 0.61, p = .017) previously published by the Psychiatric Genomics Consortium (PGC-OCD). The obsession subscale and the total Padua score showed no significant genetic correlations (r G = -0.02 and r G = 0.42, respectively). A meta-analysis of the compulsive symptoms GWAS with the PGC-OCD revealed no genome-wide significant Single-Nucleotide Polymorphisms (SNPs combined N = 17,992, indicating that the power is still low for individual SNP effects). A gene-based association analysis, however, yielded two novel genes (WDR7 and ADCK1). The top 250 genes in the gene-based test also showed a significant increase in enrichment for psychiatric and brain-expressed genes. S-Predixcan testing showed that for genes expressed in hippocampus, amygdala, and caudate nucleus significance increased in the meta-analysis with compulsive symptoms compared to the original PGC-OCD GWAS. Thus, the inclusion of dimensional symptom data in genome-wide association on clinical case-control GWAS of OCD may be useful to find genes for OCD if the data are based on quantitative indices of compulsive behavior. SNP-level power increases were limited, but aggregate, gene-level analyses showed increased enrichment for brain-expressed genes related to psychiatric disorders, and increased association with gene expression in brain tissues with known emotional, reward processing, memory, and fear-formation functions.

Genomics of human aggression: current state of genome-wide studies and an automated systematic review tool.

There are substantial differences, or variation, between humans in aggression, with its molecular genetic basis mostly unknown. This review summarizes knowledge on the genetic contribution to variation in aggression with the following three foci: (1) a comprehensive overview of reviews on the genetics of human aggression, (2) a systematic review of genome-wide association studies (GWASs), and (3) an automated tool for the selection of literature based on supervised machine learning. The phenotype definition 'aggression' (or 'aggressive behaviour', or 'aggression-related traits') included anger, antisocial behaviour, conduct disorder, and oppositional defiant disorder. The literature search was performed in multiple databases, manually and using a novel automated selection tool, resulting in 18 reviews and 17 GWASs of aggression. Heritability estimates of aggression in children and adults are around 50%, with relatively small fluctuations around this estimate. In 17 GWASs, 817 variants were reported as suggestive (P ≤ 1.0E), including 10 significant associations (P ≤ 5.0E). Nominal associations (P ≤ 1E) were found in gene-based tests for genes involved in immune, endocrine, and nervous systems. Associations were not replicated across GWASs. A complete list of variants and their position in genes and chromosomes are available online. The automated literature search tool produced literature not found by regular search strategies. Aggression in humans is heritable, but its genetic basis remains to be uncovered. No sufficiently large GWASs have been carried out yet. With increases in sample size, we expect aggression to behave like other complex human traits for which GWAS has been successful.

Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability.

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits.

Genetic correlations estimated from genome-wide association studies (GWASs) reveal pervasive pleiotropy across a wide variety of phenotypes. We introduce genomic structural equation modelling (genomic SEM): a multivariate method for analysing the joint genetic architecture of complex traits. Genomic SEM synthesizes genetic correlations and single-nucleotide polymorphism heritabilities inferred from GWAS summary statistics of individual traits from samples with varying and unknown degrees of overlap. Genomic SEM can be used to model multivariate genetic associations among phenotypes, identify variants with effects on general dimensions of cross-trait liability, calculate more predictive polygenic scores and identify loci that cause divergence between traits. We demonstrate several applications of genomic SEM, including a joint analysis of summary statistics from five psychiatric traits. We identify 27 independent single-nucleotide polymorphisms not previously identified in the contributing univariate GWASs. Polygenic scores from genomic SEM consistently outperform those from univariate GWASs. Genomic SEM is flexible and open ended, and allows for continuous innovation in multivariate genetic analysis.

Biological insights into multiple birth: genetic findings from UK Biobank.

The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10-8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.

Multivariate genome-wide analyses of the well-being spectrum.

We introduce two novel methods for multivariate genome-wide-association meta-analysis (GWAMA) of related traits that correct for sample overlap. A broad range of simulation scenarios supports the added value of our multivariate methods relative to univariate GWAMA. We applied the novel methods to life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum (Nobs = 2,370,390), and found 304 significant independent signals. Our multivariate approaches resulted in a 26% increase in the number of independent signals relative to the four univariate GWAMAs and in an ~57% increase in the predictive power of polygenic risk scores. Supporting transcriptome- and methylome-wide analyses (TWAS and MWAS, respectively) uncovered an additional 17 and 75 independent loci, respectively. Bioinformatic analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABAergic interneurons are enriched in their effect on the well-being spectrum.

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Characterizing the Relation Between Expression QTLs and Complex Traits: Exploring the Role of Tissue Specificity.

Measurement of gene expression levels and detection of eQTLs (expression quantitative trait loci) are difficult in tissues with limited sample availability, such as the brain. However, eQTL overlap between tissues might be high, which would allow for inference of eQTL functioning in the brain via eQTLs detected in readily accessible tissues, e.g. whole blood. Applying Stratified Linkage Disequilibrium Score Regression (SLDSR), we quantified the enrichment in polygenic signal of blood and brain eQTLs in genome-wide association studies (GWAS) of 11 complex traits. We looked at eQTLs discovered in 44 tissues by the Genotype-Tissue Expression (GTEx) consortium and two other large representative studies, and found no tissue-specific eQTL effects. Next, we integrated the GTEx eQTLs with regions associated with tissue-specific histone modifiers, and interrogated their effect on rheumatoid arthritis and schizophrenia. We observed substantially enriched effects of eQTLs located inside regions bearing modification H3K4me1 on schizophrenia, but not rheumatoid arthritis, and not tissue-specific. Finally, we extracted eQTLs associated with tissue-specific differentially expressed genes and determined their effects on rheumatoid arthritis and schizophrenia, these analysis revealed limited enrichment of eQTLs associated with gene specifically expressed in specific tissues. Our results pointed to strong enrichment of eQTLs in their effect on complex traits, without evidence for tissue-specific effects. Lack of tissue-specificity can be either due to a lack of statistical power or due to the true absence of tissue-specific effects. We conclude that eQTLs are strongly enriched in GWAS signal and that the enrichment is not specific to the eQTL discovery tissue. Until sample sizes for eQTL discovery grow sufficiently large, working with relatively accessible tissues as proxy for eQTL discovery is sensible and restricting lookups for GWAS hits to a specific tissue for which limited samples are available might not be advisable.