Search

Highlights • First study of both serum and DNAm CRP associations with depression/neuroimaging. • Serum CRP is associated with somatic symptoms and reduced entorhinal cortex thickness. • DNAm CRP is associated with widespread reductions in white matter integrity. • Evidence for central effects of peripheral inflammation from serum and DNAm markers., Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases = 271, Ncontrols = 609). Serum CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β = 0.145, PFDR = 6 × 10−4) and energy levels (β = 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (β = −0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, βFA= −0.12 to −0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = −0.15 versus βaverage = 0.01 respectively). These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.

There have been several recent studies addressing the genetic architecture of depression. This review serves to take stock of what is known now about the genetics of depression, how it has increased our knowledge and understanding of its mechanisms, and how the information and knowledge can be leveraged to improve the care of people affected. We identify four priorities for how the field of MD genetics research may move forward in future years, namely by increasing the sample sizes available for genome-wide association studies (GWASs), greater inclusion of diverse ancestries and low-income countries, the closer integration of psychiatric genetics with electronic medical records, and the development of the neuroscience toolkit for polygenic disorders.

Background: DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions. Methods: Here, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPACadults, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432). Findings: Each trait MS was significantly associated with its corresponding phenotype in GS (βrange=0.089–1.457) and in ALSPAC (βrange=0.078–2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (βrange=0.053–0.145). After accounting for relevant lifestyle factors, MS for educational attainment (β=0.094) and alcohol consumption (MSp-valuerange=-0.069–0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes. Interpretation: We showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (pnominalALSPAC=565; NGS=9,502), potentially due to demographic differences or low statistical power, but effect sizes were consistent with the direction reported in GS. DNAm scores for modifiable MDD risk factors may contribute to disease vulnerability and, in some cases, explain additional variance to their observed phenotypes. Funding: Wellcome Trust.

Background: Depression is the leading cause of disability worldwide with >50% of cases emerging before the age of 25yrs. Large-scale neuroimaging studies in depression implicate robust structural brain differences in the disorder. However most studies have been conducted in adults and therefore, the temporal origins of depression-related imaging features remain unknown. This has important implications for understanding aetiology and informing timings of potential intervention. Methods: Here, we examine associations between brain structure (cortical metrics and white matter microstructural integrity) and depression ratings (from caregiver and child), in a large sample of early adolescents from the Adolescent Brain and Cognitive Development (ABCD) Study (N=9981, 9-11-year olds). Findings: We report significantly decreased global cortical and white matter metrics, and regionally in frontal, limbic and temporal areas in adolescent depression (Cohen’s d = -0.018 to -0.041, β = -0.019 to -0.057). Further, we report consistently stronger imaging associations for caregiver-reported compared to child-reported depression ratings. Divergences between reports (caregiver vs child) were found to significantly relate to negative socio-environmental factors (e.g., family conflict, absolute β=0.048 to 0.169). Interpretation: Depression ratings in early adolescence were associated with similar imaging findings to those seen in adult depression samples, suggesting neuroanatomical abnormalities may be present early in the disease course, arguing for the importance of early intervention. Associations between socio-environmental factors and reporter discrepancy warrant further consideration, both in the wider context of the assessment of adolescent psychopathology, and in relation to their role in aetiology. Funding: The study is funded by Wellcome Trust Strategic Award “Stratifying Resilience and Depression Longitudinally” (STRADL) (Reference 104036/Z/14/Z) and MRC Mental Health Data Pathfinder Award (Reference MC_PC_17209). HCW is supported by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh and by an ESAT College Fellowship from the University of Edinburgh. AMM receives the Wellcome Trust Strategic Award (Reference 104036/Z/14/Z). Declaration of Interests: AMM has received research funding from The Sackler Trust, Eli Lilly and Janssen. No other conflicts of interest declared by other authors. Ethics Approval Statement: The study was approved by the National Institute of Mental Health Data Archive, United States (NIMH). Data was accessed through the NDA data base (http://nda.nih.gov/abcd, Federal-Wide Assurance: FWA00018101).

BackgroundUnderstanding and improving outcomes for people with anxiety or depression often requires large sample sizes. To increase participation and reduce costs, such research is typically unable to utilise “gold-standard” methods to ascertain diagnoses, instead relying on remote, self-report measures.AimsAssess the comparability of remote diagnostic methods for anxiety and depression disorders commonly used in research.MethodParticipants from the UK-based GLAD and COPING NBR cohorts (N = 58,400) completed an online questionnaire between 2018 and 2020. Responses to detailed symptom reports were compared to DSM-5 criteria to generate symptom-based diagnoses of major depressive disorder (MDD), generalised anxiety disorder (GAD), specific phobia, social anxiety disorder, panic disorder, and agoraphobia. Participants also self-reported any prior diagnoses from health professionals, termed self-reported diagnoses. “Any anxiety” included participants with at least one anxiety disorder. Agreement was assessed by calculating accuracy, Cohen’s kappa, McNemar’s chi-squared, sensitivity, and specificity.ResultsAgreement between diagnoses was moderate for MDD, any anxiety, and GAD, but varied by cohort. Agreement was slight to fair for the phobic disorders. Many participants with self-reported GAD did not receive a symptom-based diagnosis. In contrast, symptom-based diagnoses of the phobic disorders were more common than self-reported diagnoses.ConclusionsAgreement for MDD, any anxiety, and GAD was higher for cases in the case-enriched GLAD cohort and for controls in the general population COPING NBR cohort. For anxiety disorders, self-reported diagnoses classified most participants as having GAD, whereas symptom-based diagnoses distributed participants more evenly across the anxiety disorders. Further validation against gold standard measures is required.

Background Depression is the leading cause of disability worldwide with > 50% of cases emerging before the age of 25 years. Large-scale neuroimaging studies in depression implicate robust structural brain differences in the disorder. However, most studies have been conducted in adults and therefore, the temporal origins of depression-related imaging features remain largely unknown. This has important implications for understanding aetiology and informing timings of potential intervention. Methods Here, we examine associations between brain structure (cortical metrics and white matter microstructural integrity) and depression ratings (from caregiver and child), in a large sample (N = 8634) of early adolescents (9 to 11 years old) from the US-based, Adolescent Brain and Cognitive Development (ABCD) Study®. Data was collected from 2016 to 2018. Findings We report significantly decreased global cortical and white matter metrics, and regionally in frontal, limbic and temporal areas in adolescent depression (Cohen's d = -0⋅018 to -0⋅041, β = -0·019 to -0⋅057). Further, we report consistently stronger imaging associations for caregiver-reported compared to child-reported depression ratings. Divergences between reports (caregiver vs child) were found to significantly relate to negative socio-environmental factors (e.g., family conflict, absolute β = 0⋅048 to 0⋅169). Interpretation Depression ratings in early adolescence were associated with similar imaging findings to those seen in adult depression samples, suggesting neuroanatomical abnormalities may be present early in the disease course, arguing for the importance of early intervention. Associations between socio-environmental factors and reporter discrepancy warrant further consideration, both in the wider context of the assessment of adolescent psychopathology, and in relation to their role in aetiology. Funding Wellcome Trust (References: 104036/Z/14/Z and 220857/Z/20/Z) and the Medical Research Council (MRC, Reference: MC_PC_17209).

There are established differences in cortical thickness (CT) in schizophrenia (SCZ) and bipolar (BD) patients when compared to healthy controls (HC). However, it is unknown to what extent environmental or genetic risk factors impact on CT in these populations. We have investigated the effect of Environmental Risk Scores (ERS) and Polygenic Risk Scores for SCZ (PGRS-SCZ) on CT.\ud \ud Structural MRI scans were acquired at 3T for patients with SCZ or BD (n = 57) and controls (n = 41). Cortical reconstructions were generated in FreeSurfer (v5.3). The ERS was created by determining exposure to cannabis use, childhood adverse events, migration, urbanicity and obstetric complications. The PGRS-SCZ were generated, for a subset of the sample (Patients = 43, HC = 32), based on the latest PGC GWAS findings. ANCOVAs were used to test the hypotheses that ERS and PGRS-SCZ relate to CT globally, and in frontal and temporal lobes.\ud \ud An increase in ERS was negatively associated with CT within temporal lobe for patients. A higher PGRS-SCZ was also related to global cortical thinning for patients. ERS effects remained significant when including PGRS-SCZ as a fixed effect. No relationship which survived FDR correction was found for ERS and PGRS-SCZ in controls.\ud \ud Environmental risk for SCZ was related to localised cortical thinning in patients with SCZ and BD, while increased PGRS-SCZ was associated with global cortical thinning. Genetic and environmental risk factors for SCZ appear therefore to have differential effects. This provides a mechanistic means by which different risk factors may contribute to the development of SCZ and BD.

Objective: Knee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo). Methods: We performed a genome-wide association study of knee pain in the UK Biobank, where knee pain was ascertained through self-report and defined as "knee pain in the last month interfering with usual activities". A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 x 10-8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of knee pain using Genome-wide Complex Trait Analysis (GCTA). Results: We identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 x 10-12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 x 10-8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 x 10-18; rs2808772: P = 2.56 x 10-11). The narrow sense heritability of knee pain was 0.08. Conclusion: In this first reported genome-wide association meta-analysis of knee pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with knee pain. Funding Statement: This work was supported by the STRADL project (Wellcome Trust, grant number: 104036/Z/14/Z). The Osteoarthritis Initiative (OAI) was public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01- AR-2-2261; N01-AR-2-2262) funded by the NIH. The the Johnston County Osteoarthritis Study (JoCo) was supported in part by S043, S1734, & S3486 from the CDC/Association of Schools of Public Health; 5-P60-AR30701 & 5-P60- AR49465-03 from NIAMS/NIH; genotyping was supported by Algynomics, Inc. Additional support was obtained from NIH grant P30-DK072488. Declaration of Interests: J.S., A.A., and members of the 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. Other coauthors have no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the National Health Service National Research Ethics Service (reference 11/NW/0382). All participants included in the analyses provided informed consent and answered surveys online according to 23andMe’s human subjects protocol, which was reviewed and approved by Ethical & Independent Review Services, a private institutional review board.

Background There is an established link between childhood adversity (CA) and schizophrenia. Hippocampus and amygdala abnormalities pre-date onset in those at high familial risk (fHR) of schizophrenia, but it is not clear whether these alterations are associated with CA in those at elevated risk of schizophrenia. Methods We examined hippocampal and amygdala volumes in those at fHR who had been referred to a social worker or the Children's Panel compared to those who had not. Results The right hippocampus and left amygdala were significantly smaller in those that had been referred to social work and Children's Panel. Conclusions Our findings suggest that CA can influence structural changes in the brain in a cohort at fHR of schizophrenia. These findings provide further evidence that while genetic factors contribute to the structural changes found in schizophrenia, environmental factors such as CA can have a lasting impact on specific brain regions.

BackgroundGeneral cognitive function predicts psychiatric illness across the life course. This study examines the role of pleiotropy in explaining the link between cognitive function and psychiatric disorder.MethodsWe use two large genome-wide association study (GWAS) data sets on cognitive function. One from older age, n=53,949, and one from childhood, n=12,441. We also GWAS data on educational attainment, n = 95,427, to examine the validity of its use as a proxy phenotype for cognitive function. Using a new method, linkage disequilibrium (LD) regression, we derive genetic correlations, free from the confounding of clinical state between psychiatric illness and cognitive function.ResultsWe find a genetic correlation of 0.711, (p=2.26e-12) across the life course for general cognitive function. We also show a positive genetic correlation between Autism Spectrum Disorder (ASD) and cognitive function in childhood (rg = 0.360, p = 0.0009), for educational attainment (rg = 0.322, p=1.37e-5), but not in older age. In schizophrenia we find a negative genetic correlation between older age cognitive function (rg =-0.231, p=3.81e-12) but not in childhood or for educational attainment. For Alzheimer’s disease we find negative genetic correlations with childhood cognitive function (rg = -0.341, p = 0.001), educational attainment (rg = -0.324, p=1.15e-5), and with older age cognitive function (rg = -0.324, p=1.78e-5).ConclusionsThe pleiotropy exhibited between cognitive function and psychiatric disorders was changes across the life course. These age-dependent associations might explain why negative selection has not removed variants causally associated with ASD or schizophrenia.

Background Major Depressive Disorder (MDD) is substantially heritable but has been late to reveal its genetic associations. New data available from UK Biobank (UKB) presents a new opportunity to test for common genetic associations with MDD and to compare different phenotype definitions. Methods We conducted a genome-wide association study of broad and relatively narrow depression phenotypes in UKB and the Psychiatric Genomics Consortium MDD Working Group. Data were meta-analysed and the heritability and genetic correlations between different phenotypic definitions was estimated. Results The full results of our analyses are expected to be available within the next 30 days. Preliminary data analyses suggest that the genetic correlation of all but one depression phenotype in UKB and operationally defined 'clinical' MDD is indistinguishable from 1. Narrower definitions tend to have higher heritabilities, but at the expense of a high number of missing values. Genome-wide significant variants were identified in the first 110 K subjects. We will provide updated results for the meeting. Discussion Our preliminary findings suggest that a broad phenotypic definition of MDD is likely to be the most productive for GWAS studies in future. These definitions include self-declared depression and self-declared treatment with antidepressants amongst others.

Background Major Depressive Disorder (MDD) is a common psychiatric illness. Neuroimaging studies have indicated the involvement functional networks in the disorder. Resting-state functional magnetic resonance imaging (rs-fMRI) provides a non-invasive, task-free way of studying such distributed functional dynamics of the brain. Previous studies have found significant alteration in rs-fMRI functional connectivity in MDD patients. Hyperactivity of default mode network (DMN) has been reported to be associated with rumination of negative emotional stimuli, and abnormal connectivity between DMN and task-positive networks was associated with cognitive impairment within MDD, however other studies do not report such effects. Previous rs-fMRI studies were however often conducted on small sample sizes which may account for inconsistency in the literature, and few studies were conducted on the association between genetic risk of MDD and rs-fMRI functional connectivity. Therefore, the present study used imaging data from a large-population based sample from UK Biobank to test the association of brain functional connectivity with MDD status and its genetic risk. Methods We used IDPs (Imaging-Derived Phenotypes) from UK Biobank imaging project. The imaging data was collected on a single scanner and preprocessed using FSL packages by UK Biobank. Data was parcelled into 21 non-noise functional networks, and the L2-regularised partial correlation was estimated between each pair of networks. These estimated connections were then used for further analysis in the current study. MDD status was derived based on self-reported depressive symptoms and history of hospital admission data (Case: N=256, Control: N=488,). Polygenic risk of MDD (MDD-pgrs) was calculated based on the summary statistics from the PGC (N=914). Regression models were applied to test the MDD case-control difference and the associations of MDD-pgrs with rs-fMRI functional connectivity. Age, age2, sex and assessment centre were controlled for in the model of case-control differences, and genotype batch and the first 15 principal component of genetic variance were additionally controlled for MDD-pgrs. FDR correction was applied. All effect sizes reported were standardised. Results MDD cases showed higher positive connectivity between the precuneus, the bilateral superior posterior cingulate cortex and temporal-parietal junction (β=0.292, pcorr=0.047); all components of DMN. Higher MDD-pgrs was associated with less connectivity between posterior motor area and posterior parietal gyrus (PPG) (β=-0.123, pcor=0.045), less negative connectivity between precuneus and PPG (β=0.122, pcor=0.045) and higher negative connection of right fronto-temporal network (FTN) and left fronto-parietal network (FPN) (β=-0.124, pcor=0.045). Discussion In the present study, MDD cases exhibited significantly higher connection between two DMN components, and a higher negative connection between FTN and FPN. Conversely, higher genetic risk for MDD was associated with decreased connectivity between DMN regions and task-positive networks. These results were highly consistent with previous studies which found that altered functioning of DMN was related with MDD status. The present study also found functional connections that involve with DMN, FTN and FPN associated with MDD-pgrs.

The aim of this study was to test whether bilinear and nonlinear effective connectivity (EC) measures of working memory fMRI data can differentiate between patients with schizophrenia (SZ) and healthy controls (HC). We applied bilinear and nonlinear Dynamic Causal Modeling (DCM) for the analysis of verbal working memory in 16 SZ and 21 HC. The connection strengths with nonlinear modulation between the dorsolateral prefrontal cortex (DLPFC) and the ventral tegmental area/substantia nigra (VTA/SN) were evaluated. We used Bayesian Model Selection at the group and family levels to compare the optimal bilinear and nonlinear models. Bayesian Model Averaging was used to assess the connection strengths with nonlinear modulation. The DCM analyses revealed that SZ and HC used different bilinear networks despite comparable behavioral performance. In addition, the connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area showed differences between SZ and HC. The adoption of different functional networks in SZ and HC indicated neurobiological alterations underlying working memory performance, including different connection strengths with nonlinear modulation between the DLPFC and the VTA/SN area. These novel findings may increase our understanding of connectivity in working memory in schizophrenia.

In schizophrenia, reduced orbitofrontal cortex (OFC) volume is inconsistently reported. To investigate the impact of genetic load on OFC volume, manual MRI-tracing in 23 first-episode schizophrenia patients (FE-SZ) and 23 controls was performed. FE-SZ with genetic load showed a decrease in OFC volume compared to FE-SZ without load and controls.

Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD., Highlights • Measured miRNA expression in unmedicated relatives of bipolar disorder patients. • Identified miR-15b, miR-132 and miR-652 as being significantly up-regulated. • Identified known and predicted targets of these miRNAs. • Targets of these miRNAs are involved in functions implicated in bipolar disorder.

Background Borderline personality disorder (BPD) is a severe psychiatric disorder involving a range of symptoms including marked affective instability and disturbances in interpersonal interactions. Neuroimaging studies are beginning to provide evidence of altered processing in fronto-limbic network deficits in the disorder, however, few studies directly examine structural connections within this circuitry together with their relation to proposed causative processes and clinical features. Methods In the current study, we investigated whether individuals with BPD (n = 20) have deficits in white matter integrity compared to a matched group of healthy controls (n = 18) using diffusion tensor MRI (DTI). We hypothesized that the BPD group would have decreased fractional anisotropy (FA), a measure of white matter integrity, compared to the controls in white matter tracts connecting frontal and limbic regions, primarily the cingulum, fornix and uncinate fasciculus. We also investigated the extent to which any such deficits related to childhood adversity, as measured by the childhood trauma questionnaire, and symptom severity as measured by the Zanarini rating scale for BPD. Results We report decreased white matter integrity in BPD versus controls in the cingulum and fornix. There were no significant relationships between FA and measures of childhood trauma. There were, however, significant associations between FA in the cingulum and clinical symptoms of anger, and in the fornix with affective instability, and measures of avoidance of abandonment from the Zanarini rating scale. Conclusions We report deficits within fronto-limbic connections in individuals with BPD. Abnormalities within the fornix and cingulum were related to severity of symptoms and highlight the importance of these tracts in the pathogenesis of the disorder., Highlights • Decreased white matter integrity was reported in patients with borderline personality disorder in the cingulum and fornix. • Decreases in white matter integrity were related to severity of affective and interpersonal symptoms. • Findings highlight the importance of fronto-limbic tracts in the pathogenesis of the disorder.

Background Psychiatric illnesses are a group of genetically-related disorders with highly polygenic architecture and a significant environmental component. Even within families, these conditions show the attributes of many complex traits: reduced penetrance and phenotypic heterogeneity. An extended pedigree design has several advantages: it avoids population stratification and reduces genetic heterogeneity, narrowing the search for rare and functional variants that segregate with a phenotype. We have analysed a multigenerational pedigree where major mental illness segregates with a balanced translocation between chromosomes 1 and 11. Methods Whole genome sequencing was performed on 49 family members (20 carriers, 29 non-carriers of the translocation). Polygenic risk scores were calculated using summary statistics from the PGC MDD 2011 and used to predict diagnosis. Multipoint linkage analyses were performed using the variance components method implemented in SOLAR. Multiple phenotypic classes were used constructed to reflect the multiple phenotypes within the family. Fine-mapping was performed using two-point linkage analyses across the linked regions and association analyses performed in a Scottish cohort with measures of mental health, cognitive and personality traits (N= 6,555; 2,060 cases and 4,495 controls). Results Two genome-wide significant peaks with LOD > 5.5 were detected on the translocated chromosomes 1 and 11 with maximum linkage to schizophrenia, bipolar disorder, recurrent major depression and cyclothymia; as previously noted for the translocation itself. In addition, two further peaks, a second on chromosome 1 and a peak on chromosome 5, showed genome-wide significant linkage to affective disorder (bipolar disorder, and major depressive disorder). Polygenic risk scores of schizophrenia and bipolar disorder, but not major depressive disorder significantly predict mental illness in the family. Functional annotation of the whole genome sequence, and case-control association for affective disorder in the Scottish population, support a role for GRM5, CNTN5 and PDE4D in the phenotypic heterogeneity seen in the family. Discussion These results suggest that the high density of psychiatric illness in the t(1;11) family may be a combination of: direct effects of the translocation on the genes located at the breakpoint (DISC1, DISC2, DISC1FP), “locking together” of additional familial risk factors and the accumulation of common risk variants. We have identified additional modifying loci that may explain the variance in disease expression. Our findings suggest that pleiotropy may play a significant role and that this is now tractable by whole genome sequencing in families.

Background Stressful Life Events (SLEs) and genetic risk factors both contribute to the aetiology of Major Depressive Disorder (MDD). Although SLEs are considered to be an environmental factor, studies suggest that they may act in part through interaction with the known genetic risk factors in MDD or more unexpectedly, through interaction with novel genetic factors specific to SLEs. Polygenic Risk Scores (PRS) reflect an individual's genetic vulnerability to develop depression. Such vulnerability to MDD has been commonly based on main additive effects, although a genetic contribution has been suggested for SLEs on risk of MDD. We used PRS for MDD and for a novel stress-sensitivity trait, derived from a Genome-Wide Interaction Study (GWEIS), to test these hypotheses. Methods We performed a GWEIS in UK Biobank (N=23,092; UKB), modeling the interaction between SNP allele and MDD status on neuroticism score (EPQ-N). The effect size of the interaction term was used to create a measure of genetic MDD-dependent stress-sensitivity (SS). The genetic vulnerability-stress model was tested using PRS weighted by MDD using Psychiatric GWAS Consortium MDD summary statistics (MDD-PRS), or PRS weighted by MDD-dependent stress-sensitivity effect (SS-PRS) in GS:SFHS STRADL (Stratifying Depression and Resilience Longitudinally; N=4,919). GS:SFHS STRADL has data on symptoms of depression assessed by General Health Questionnaire (GHQ-28) and past 6 month SLEs using the List of Threatening Experiences (LTE-Q). Results MDD-PRS, SS-PRS and main effects of SLEs significantly predicted symptoms of depression (MDD-PRS: P=5.48×10-9; SS-PRS: P=2.63×10-4; SLEs: P=1.01×10–58, using best predictor at full cohort). The MDD-PRS-by-SLEs interaction significantly contributed to the risk of MDD at population level (p-threshold=0.01, β=0.028, SE=0.014, R2=0.077%, P=4.91×10-2), although this was stronger in females (p-threshold=1×10-5, β=0.044, SE=0.018, R2=0.19%, P=1.84×10-2) and not significant in males (p-threshold=0.1, β=0.04, SE=0.022, R2=0.16%, P=6.37×10-2). The SS-PRS-by-SLEs interaction significantly contributed to the risk of MDD in males (p-threshold=0.01, β=0.078, SE=0.022, R2=0.6%, P=3.38×10-4) but not in females (p-threshold=0.05, β=-0.027, SE=0.018, R2=0.075%, P=0.14) or in the full cohort (p-threshold=1×10-5, β=0.025, SE=0.014, R2=0.063%, P=7.75×10-2), This SS-PRS-by-SLEs interaction in males explained almost as much as the variance explained by the main MDD-PRS effect at their best predictor (p-threshold=0.102, β=0.081, SE=0.022, R2=0.66%, P=2.09×10-4). Discussion Significant genetic vulnerability-SLEs interactions predict and additional MDD risk for individuals with high predisposition and high number of reported SLEs. However, the results suggest distinct interactions between genetic vulnerabilities and SLEs on the aetiology of depression in males versus females, although replication on a larger sample would be required.