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Background: Depression and anxiety are the most common mental health problems in young people. Currently, clinicians are advised to wait before initiating treatment for young people with these disorders as many spontaneously remit. However, others develop recurrent disorder but this subgroup cannot be identified at the outset. We examined whether psychiatric polygenic scores (PGS) could help inform stratification efforts to predict those at higher risk of recurrence. Methods: Probable emotional disorder was examined in two UK population cohorts using the emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ). Those with emotional disorder at two or more time points between ages 5 and 25 years were classed as 'recurrent emotional disorder' (n = 1,643) and those with emotional disorder at one time point as having 'single episode emotional disorder' (n = 1,435, controls n = 8,715). We first examined the relationship between psychiatric PGS and emotional disorders in childhood and adolescence. Second, we tested whether psychiatric PGS added to predictor variables of known association with emotional disorder (neurodevelopmental comorbidity, special educational needs, family history of depression and socioeconomic status) when discriminating between single‐episode and recurrent emotional disorder. Analyses were conducted separately in individuals of European and South Asian ancestry. Results: Probable emotional disorder was associated with higher PGS for major depressive disorder (MDD), anxiety, broad depression, ADHD and autism spectrum disorder (ASD) in those of European ancestry. Higher MDD and broad depression PGS were associated with emotional disorder in people of South Asian ancestry. Recurrent, compared to single‐episode, emotional disorder was associated with ASD and parental psychiatric history. PGS were not associated with episode recurrence, and PGS did not improve discrimination of recurrence when combined with clinical predictors. Conclusions: Our findings do not support the use of PGS as a tool to assess the likelihood of recurrence in young people experiencing their first episode of emotional disorder. [ABSTRACT FROM AUTHOR]

Kaposi sarcoma‐associated herpesvirus (KSHV) causes Kaposi sarcoma (KS). The risk of KS is amplified in HIV‐immunosuppressed individuals and antiretroviral therapy (ART) reduces KS incidence. Reliable data on the relationship between these factors are lacking in Africa. We used questionnaires and serum from 7886 black South Africans (18‐74 years) with incident cancer, recruited between 1995 and 2016. ART rollout started in 2004. We measured associations between KS, HIV‐1 and KSHV before and after ART rollout. We measured seropositivity to HIV‐1, KSHV latency‐associated nuclear antigen (LANA) and glycoprotein (K8.1) and calculated case‐control‐adjusted odds ratios (ORadj) and 95% confidence intervals (CI) in relation to KS and KSHV infection, before (1995‐2004), early (2005‐2009) and late (2010‐2016) ART rollout periods. KSHV seropositivity among 1237 KS cases was 98%. Among 6649 controls, KSHV seropositivity was higher in males (ORadj = 1.4 [95%CI 1.23‐1.52]), in persons with HIV, (ORadj = 4.2 [95%CI 3.74‐4.73]) and lower in high school leavers (ORadj = 0.7 [95%CI 0.59‐0.83]). KSHV seropositivity declined over the three ART rollout periods (37%, 28% and 28%, Ptrend <.001) coinciding with increases in high school leavers over the same periods (46%, 58% and 67%, Ptrend <.001). HIV‐1 seroprevalence increased from 10% in the pre‐ART period to 22% in the late ART period (Ptrend <.001). Compared to HIV‐1 and KSHV seronegatives, KSHV seropositives yielded an OR for KS of 26 (95%CI 11‐62) in HIV‐1 seronegative participants and an OR of 2501 (95%CI 1083‐5776) in HIV‐1 seropositive participants. HIV‐1 increases the risk of KS in those infected with KSHV by 100‐fold. Declines in KSHV seroprevalence coincide with ART rollout and with improvements in educational standards and general hygiene. [ABSTRACT FROM AUTHOR]

Background and Aims: The use of cannabis has previously been linked to both depression and self‐harm; however, the role of genetics in this relationship is unclear. This study aimed to estimate the phenotypic and genetic associations between cannabis use and depression and self‐harm. Design Cross‐sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self‐harm. UK Biobank genetic data were then combined with consortia genome‐wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods. Setting: United Kingdom, with additional international consortia data. Participants: A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank. Measurements Phenotypic outcomes were life‐time history of cannabis use (including initial and continued cannabis use), depression (including single‐episode and recurrent depression) and self‐harm. Genome‐wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data. Findings In UK Biobank, cannabis use is associated with an increased likelihood of depression [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59–1.70] and self‐harm (OR = 2.85, 95% CI = 2.69–3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome‐wide summary statistics, significant genetic correlations are seen between cannabis use and depression [rg = 0.289, standard error (SE) = 0.036]. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self‐harm within a UK Biobank target sample. However, two‐sample Mendelian randomization analyses were not significant. Conclusions: Cannabis use appeared to be both phenotypically and genetically associated with depression and self‐harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies.Methods: We genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data.Results: We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 × 10-13 ) and rs1411478 in STX6 (P = 3.45 × 10-10 ). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP.Conclusions: Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face‐related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing. [ABSTRACT FROM AUTHOR]

Background Within a therapeutic gene by environment (G × E) framework, we recently demonstrated that variation in the Serotonin Transporter Promoter Polymorphism; 5 HTTLPR and marker rs6330 in Nerve Growth Factor gene; NGF is associated with poorer outcomes following cognitive behaviour therapy ( CBT) for child anxiety disorders. The aim of this study was to explore one potential means of extending the translational reach of G × E data in a way that may be clinically informative. We describe a 'risk-index' approach combining genetic, demographic and clinical data and test its ability to predict diagnostic outcome following CBT in anxious children. Method DNA and clinical data were collected from 384 children with a primary anxiety disorder undergoing CBT. We tested our risk model in five cross-validation training sets. Results In predicting treatment outcome, six variables had a minimum mean beta value of 0.5:5 HTTLPR, NGF rs6330, gender, primary anxiety severity, comorbid mood disorder and comorbid externalising disorder. A risk index (range 0-8) constructed from these variables had moderate a predictive ability ( AUC = .62-.69) in this study. Children scoring high on this index (5-8) were approximately three times as likely to retain their primary anxiety disorder at follow-up as compared with those children scoring 2 or less. Conclusion Significant genetic, demographic and clinical predictors of outcome following CBT for anxiety-disordered children were identified. Combining these predictors within a risk index could be used to identify which children are less likely to be diagnosis-free following CBT alone and require longer or enhanced treatment. The 'risk-index' approach represents one means of harnessing the translational potential of G × E data. [ABSTRACT FROM AUTHOR]

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis.Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry.Results: Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01).Conclusion: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further. [ABSTRACT FROM AUTHOR]

Objectives To analyse genotype information from cleavage-stage human embryos and assess the chromosomal status and feasibility of performing aneuploidy screening by microsatellite analysis. Methods DNA from 49 blastomeres from eight cleavage-stage human embryos was amplified using multiple displacement amplification, then tested for panels of 64 polymorphic microsatellite markers on seven different chromosomes, and for two non-polymorphic sequences on the X and Y chromosomes. Results There was an overall allele drop out (ADO) rate of 28%. Novel alleles in single cells were seen in 0.3% of amplifications, interpreted as either somatic microsatellite mutation events or 'slippage' of the MDA ϕ 29 polymerase. Three-allele results for a single marker in a single cell were found in 0.07% of amplifications, interpreted as 'slippage' of the MDA ϕ 29 polymerase. One apparent segmental duplication was found. Only one embryo with no normal cells was found, probably arising from the chaotic cleavage division following a triploid conception. Six embryos were mosaic, of which four had only one abnormal cell. Conclusions Abnormalities in human embryos may be present in only a single cell, leading to potentially false abnormal results at pre-implantation genetic diagnosis. ADO associated with MDA reduces the efficacy of this approach for detection of aneuploidy. Statistical analysis showed that, for ADO of 28%, seven informative markers would be required to give 95% confidence of detecting trisomic embryos. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Examines the methods for the identification of linkage or association using genetic markers. Identification of population outliers; Determination of marker allele frequency distributions; Calculation of individual genotypes across all markers.

Examines the power of transmission disequilibrium test to detect association between the loci. Effect of linkage disequilibrium between genetic markers and an unobserved disease mutation; Frequency between mutations and tested allele; Reduction in linkage equilibrium.

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents., (© 2020 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis., (© 2014 Wiley Periodicals, Inc.)

Stressful life events are an established trigger for depression and may contribute to the heterogeneity within genome-wide association analyses. With depression cases showing an excess of exposure to stressful events compared to controls, there is difficulty in distinguishing between "true" cases and a "normal" response to a stressful environment. This potential contamination of cases, and that from genetically at risk controls that have not yet experienced environmental triggers for onset, may reduce the power of studies to detect causal variants. In the RADIANT sample of 3,690 European individuals, we used propensity score matching to pair cases and controls on exposure to stressful life events. In 805 case-control pairs matched on stressful life event, we tested the influence of 457,670 common genetic variants on the propensity to depression under comparable level of adversity with a sign test. While this analysis produced no significant findings after genome-wide correction for multiple testing, we outline a novel methodology and perspective for providing environmental context in genetic studies. We recommend contextualizing depression by incorporating environmental exposure into genome-wide analyses as a complementary approach to testing gene-environment interactions. Possible explanations for negative findings include a lack of statistical power due to small sample size and conditional effects, resulting from the low rate of adequate matching. Our findings underscore the importance of collecting information on environmental risk factors in studies of depression and other complex phenotypes, so that sufficient sample sizes are available to investigate their effect in genome-wide association analysis., (Copyright © 2013 Wiley Periodicals, Inc.)

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder., (2012 Wiley Periodicals, Inc)

Suicidal behavior is commonly associated with depression. Twin studies indicate that both suicidality and major depressive disorder (MDD) are heritable. However, epidemiological evidence suggests that the inheritance of suicidality is likely to be independent of the underlying psychiatric disorder, implying a distinct genetic contribution to suicidality. We conducted a genomewide linkage search aiming to detect genomic loci that may harbor susceptibility genes contributing to risk for suicidality in recurrent MDD. Affected sibling pair (ASP) variance components analysis was performed using the Depression Network cohort of 971 ASPs. The quantitative trait measuring suicidality as a broad phenotype, encompassing ideation and suicide attempts, was established from Schedules for Clinical Assessment in Neuropsychiatry interview items. We examined 1,060 genotyped microsatellite markers with an average spacing of 3.3 cM. Empirical thresholds for linkage evidence were set by whole-genome simulations (LOD = 2.71 for genomewide significance, 1.71 for suggestive linkage). No genomewide significant findings were found. Marker D3S1234 on 3p14 achieved suggestive linkage and yielded a maximum LOD of 1.853 (P = 0.0017), loci 9p24.3 and 18q22-q23 achieved LOD scores >1.5. We found some support for linkage to 2p12 (LOD = 1.2, P = 0.0087) which was previously implicated in linkage studies of suicidality. Our follow-up meta-analysis of five studies showed strong linkage to this region (P = 2 × 10(-6) ). In conclusion, this study analyzed suicidality as a continuous trait in MDD. We found modest evidence for linkage on 3p14. Our meta-analysis supports previous evidence of linkage to suicidality on 2p12. Some candidate genes in these regions may plausibly be implicated in suicidality. © 2010 Wiley-Liss, Inc., (Copyright © 2010 Wiley-Liss, Inc.)

Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P(SR) = 0.00034, P(OR) = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes., (Copyright 2008 Wiley-Liss, Inc.)

Objective: Levels of interleukin-6 (IL-6) have been shown to correlate with the fever and disease activity of systemic juvenile idiopathic arthritis (JIA). In a previous case-control study, a significant association between the IL-6 -174 nucleotide variant and systemic JIA was noted, and HeLa cell transfection assays show functional differences in levels of transcription of the IL-6 -174 alleles. The present study was undertaken to confirm the previous findings and to assess possible association with variations of the A(n)T(n) tract in the promoter., Methods: We studied a cohort of JIA families from 3 countries, using transmission disequilibrium testing. Genotyping of the -174 nucleotide variant was done by restriction fragment length polymorphism, heteroduplex analysis, or allelic discrimination. The A(n)T(n) tract at -392 to -373 was typed using DNA sequencing. Statistical analysis was performed using the programs Transmit and EHplus., Results: There was a significant excess transmission of the -174G allele in the systemic JIA families (P = 0.041). The excess transmission was only to systemic JIA patients with age at onset >5 years (P = 0.007). No significant association with the other subtypes was found. No A(n)T(n) alleles or -174/A(n)T(n) haplotypes were significantly associated with systemic JIA., Conclusion: This study confirms that the IL-6 -174 nucleotide variant is significantly associated with systemic JIA. The significant excess transmission to patients with age at onset >5 years but not to those with age at onset < or =5 years suggests that there may be genetic heterogeneity between the 2 groups.