Depression Polygenic Risk Scores Research Articles

Investigating attention‐deficit hyperactivity disorder and autism spectrum disorder traits in the general population: What happens in adult life?

BackgroundAttention‐deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are generally considered early‐onset disorders so most research has therefore tended to focus on children. Differences between ADHD/ASD in adult life and childhood have been noted, but few population‐based studies have examined them in adulthood. Furthermore, the interpretation of findings is hampered by changes in measure and from parent report to self‐report.MethodWe examined continuous/trait measures of parent‐ and self‐rated ADHD and ASD in adulthood (age 25 years) in a UK prospective longitudinal sample ALPSAC (the Avon Longitudinal Study of Parents and Children), using many of the same measures that parents reported on in childhood (N = 6,064). Our aim was to investigate these traits in this population for mean‐level sex differences, overlaps with other cognitive, learning and communication problems and their associations with polygenic risk scores (PRS) for neuropsychiatric disorders (ADHD, ASD, schizophrenia, depression and anxiety).ResultsADHD and ASD traits in adulthood, as in childhood, showed associations with childhood cognitive, learning and communication problems and adult communication/language measures, although less so for self‐ratings than parent‐ratings. Males had higher ADHD and ASD trait levels, but this was not as marked as in childhood. In adulthood, ADHD (both parent‐ and self‐rated) and ASD (parent‐rated) symptoms showed associations with ADHD PRS; self‐reported ADHD also showed association with depression PRS, whereas self‐reported ASD did not show strong PRS associations.ConclusionsOur findings suggest that in young adults, ADHD and ASD symptoms have similar characteristics as they do in childhood. Associations with other cognitive, learning and communication problems, and ADHD PRS were somewhat less pronounced for self‐reported adult ADHD and ASD symptoms, suggesting that even at age 25, parent reports, where available, could be clinically useful.

Familial risk for depressive and anxiety disorders: associations with genetic, clinical, and psychosocial vulnerabilities.

In research and clinical practice, familial risk for depression and anxiety is often constructed as a simple Yes/No dichotomous family history (FH) indicator. However, this measure may not fully capture the liability to these conditions. This study investigated whether a continuous familial loading score (FLS), incorporating family- and disorder-specific characteristics (e.g. family size, prevalence of depression/anxiety), (i) is associated with a polygenic risk score (PRS) for major depression and with clinical/psychosocial vulnerabilities and (ii) still captures variation in clinical/psychosocial vulnerabilities after information on FH has been taken into account. Data came from 1425 participants with lifetime depression and/or anxiety from the Netherlands Study of Depression and Anxiety. The Family Tree Inventory was used to determine FLS/FH indicators for depression and/or anxiety. Persons with higher FLS had higher PRS for major depression, more severe depression and anxiety symptoms, higher disease burden, younger age of onset, and more neuroticism, rumination, and childhood trauma. Among these variables, FH was not associated with PRS, severity of symptoms, and neuroticism. After regression out the effect of FH from the FLS, the resulting residualized measure of FLS was still associated with severity of symptoms of depression and anxiety, rumination, and childhood trauma. Familial risk for depression and anxiety deserves clinical attention due to its associated genetic vulnerability and more unfavorable disease profile, and seems to be better captured by a continuous score that incorporates family- and disorder-specific characteristics than by a dichotomous FH measure.

Does urbanicity modify the relationship between a polygenic risk score for depression and mental health symptoms? Cross-sectional evidence from the observational HUNT Study in Norway

BackgroundResearch suggests that genetic predisposition for common mental disorders may be moderated by the environment. This study examines whether a polygenic risk score (PRS) for depression is moderated by the...

Using major depression polygenic risk scores to explore the depressive symptom continuum.

Major depression (MD) is often characterised as a categorical disorder; however, observational studies comparing sub-threshold and clinical depression suggest MD is continuous. Many of these studies do not explore the full continuum and are yet to consider genetics as a risk factor. This study sought to understand if polygenic risk for MD could provide insight into the continuous nature of depression. Factor analysis on symptom-level data from the UK Biobank (N = 148 957) was used to derive continuous depression phenotypes which were tested for association with polygenic risk scores (PRS) for a categorical definition of MD (N = 119 692). Confirmatory factor analysis showed a five-factor hierarchical model, incorporating 15 of the original 18 items taken from the PHQ-9, GAD-7 and subjective well-being questionnaires, produced good fit to the observed covariance matrix (CFI = 0.992, TLI = 0.99, RMSEA = 0.038, SRMR = 0.031). MD PRS associated with each factor score (standardised β range: 0.057-0.064) and the association remained when the sample was stratified into case- and control-only subsets. The case-only subset had an increased association compared to controls for all factors, shown via a significant interaction between lifetime MD diagnosis and MD PRS (p value range: 2.23 × 10-3-3.94 × 10-7). An association between MD PRS and a continuous phenotype of depressive symptoms in case- and control-only subsets provides support against a purely categorical phenotype; indicating further insights into MD can be obtained when this within-group variation is considered. The stronger association within cases suggests this variation may be of particular importance.

S178. SHOULD SCHIZOAFFECTIVE DISORDER DEPRESSED-TYPE BE DISTINCT FROM SCHIZOPHRENIA? ANALYSIS OF GENETIC LIABILITY AND LIFETIME CLINICAL CHARACTERISTICS

BackgroundSchizoaffective disorder depressed type (SAD) has been considered a distinct diagnostic entity since 1987, yet it is rarely recognised in clinical and research settings as it is considered analogous to schizophrenia with comorbid depression. However, these assumptions are often based on anecdotal evidence, as little research has attempted to examine differences between the two disorders. We aimed to establish the validity of SAD as a diagnosis, by investigating phenotypic and genotypic differences between schizophrenia and SAD.MethodsParticipants were from the Cardiff Cognition study and included if they met ICD-10 criteria for schizophrenia (n=713) or SAD (n=151). Diagnosis was determined via consensus assessment by trained researchers using lifetime symptom data from the SCAN interview alongside patient medical records. Polygenic risk scores were derived for schizophrenia and major depressive disorder using PRSice. Logistic regressions were used to measure the association between diagnosis and lifetime clinical characteristics across five categories: demographics, premorbid functioning, illness progression, psychosis, and depression. Sex and age at interview were included as covariates. Logistic regressions were used to measure the association between diagnosis and polygenic risk scores for schizophrenia and depression at a threshold of p<.05, covarying for sex and principal components.ResultsCompared to schizophrenia, SAD was significantly associated with female sex (OR= 3.19, 95% CI= 2.23 - 4.59, p=5.0x10-9), lower global assessment score in worst episode of depression (OR= 0.47, 95% CI= 0.37 – 0.59, p=5.0x10-9), higher global assessment score in worst episode of psychosis (OR= 1.44, 95% CI= 1.20 – 1.72, p= 6.8x10-4), a greater likelihood of an admission for depression (OR= 2.24, 95% CI= 1.48 – 3.40, p= 1.2x10-3), greater alcohol abuse or dependence (OR= 2.12, 95% CI= 1.41 – 3.20, p= 2.3x10-3), longer duration of depression (OR= 1.46, 95% CI= 1.19 - 1.84, p= 3.5x10-3), experiencing childhood abuse (OR= 2.07, 95% CI = 1.35 – 3.17, p= 3.9x10-3), a reduced likelihood of an involuntary admission for psychosis (OR= 0.40, 95% CI= 0.22 – 0.75, p= 0.01), depression onset occurring prior to psychosis onset (OR= 2.40, 95% CI= 1.37 – 4.43, p= 0.01), having a higher number of children (OR= 1.34, 95% CI= 1.08 – 1.67, p= 0.03), and better cognitive functioning (OR= 1.20, 95% CI= 1.04 – 1.40, p= 0.05).Depression polygenic risk score was higher in participants with SAD (OR= 1.33, 95% CI= 1.06 – 1.66, R2= 0.015, p= 0.01); schizophrenia polygenic risk score was not associated with diagnosis (OR= 0.94, 95% CI= 0.75 – 1.17, R2= 0.001, p= 0.58). Secondary analyses were conducted to investigate sex-specific effects. A significant difference in schizophrenia polygenic risk was observed between males and females, which indicated that males with SAD have lower schizophrenia polygenic risk scores than females with SAD (OR= 0.46, 95% CI= 0.28 – 0.74, R2= 0.143, p=1.5x10-3). Sex-specific effects were not observed for depression PRS or phenotypes.DiscussionOur results indicate a number of differences between individuals with schizophrenia and SAD. Primarily, the results demonstrate a greater burden of depression in those with SAD, both phenotypically and genotypically. Our results also suggest that the genetic contribution to SAD may differ between males and females. The findings indicate that schizophrenia research, particularly genetic research, needs to consider the impacts of sex-specific effects and comorbid depression before combining patient samples for analysis.

A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank

Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (β: 0.125 to 0.868, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (β: 0.014 to 0.180, pFDR: 0.049 to 1.28 × 10−14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.

Neuroanatomical Signature of a Novel Transcriptome-Based Polygenic Risk Score for Depression

A recent meta-analysis of case-control post-mortem transcriptome datasets identified 566 genes associated with depression. We subsequently developed a novel transcriptome-based polygenic risk score (T-PRS) that captures variants partially mimicking this post-mortem transcriptomic signature of MDD and mapped it onto reduced brain reactivity to faces. Here, we aim to further model effects of T-PRS on structural MRI measures, which may be more stable and clinically-accessible.

Nick Martin's Contribution to GxE Research.

The study and identification of genotype-environment interactions (GxE) has been a hot topic in the field of human genetics for several decades. Yet the extent to which GxE contributes to human behavior variability, and its mechanisms, remains largely unknown. Nick Martin has contributed important advances to the field of GxE for human behavior, which include methodological developments, novel analyses and reviews. Here, we will first review Nick's contributions to the GxE research, which started during his PhD and consistently appears in many of his over 1000 publications. Then, we recount a project that led to an article testing the diathesis-stress model for the origins of depression. In this publication, we observed the presence of an interaction between polygenic risk scores for depression (the risk in our 'genotype') and stressful life events (the experiences from our 'environment'), which provided the first empirical support of this model.

Association of Genetic Risk and Lifestyle Factors with Incident Depression: A Prospective Analysis of the UK Biobank Cohort

Background: Genetic factors increase the risk of depression, but the extent to which this can be offset by lifestyle factors is unknown. In the present study, we investigated whether a healthy lifestyle is associated with lower risk of depression regardless of genetic risk. Methods: Data for this prospective analysis were obtained from the UK Biobank and consisted of 339,944 participants (37–73 years old) without depression between 2006 and 2010. Genetic risk was categorized as low (quintile 1), intermediate (quintiles 2–4), or high (quintile 5) according to polygenic risk scores for depression. Healthy lifestyle scores—including no current smoking, regular physical activity, a healthy diet, and a body mass index < 30 kg/m2—was categorized into favorable, intermediate, and unfavorable lifestyles. Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs) of the associations of genetic risk and lifestyle factors with depression. Finding: During a median follow-up of 8.1 years (2,723,692 person-years), 5,749 incidences of depression were ascertained. The risk of depression was 25% higher among those at high genetic risk compared with those at low genetic risk (HR = 1.25, 95% CI: 1.15–1.36). Unfavorable lifestyle was associated with a 70% increased risk of depression compared with that of a favorable lifestyle (HR = 1.70, 95% CI: 1.57–1.84). Of the participants with a high genetic risk and unfavorable lifestyle, 2.75% (95% CI, 2.36%–3.19%) developed depression compared with 1.25% (95% CI: 1.15%–1.36%) of participants with low genetic risk and a favorable lifestyle (HR = 2.06, 95% CI: 1.74–2.45). There was no significant interaction between genetic risk and healthy lifestyle (P for interaction = 0.75). Among participants at high genetic risk, a favorable lifestyle was associated with a 40% lower relative risk of depression than an unfavorable lifestyle (HR = 0.60, 95% CI: 0.51–0.72). Interpretation: Genetic and combined lifestyle factors were independently associated with the incidence of depression. Hence, our findings suggest that a healthy lifestyle may attenuate the risk of depression independent of genetic risk. Funding Statement: The National Natural Science Foundation of China (91746205, 71910107004, 71673199) Declaration of Interests: The authors declare that they have no conflicts of interests.

Genetic Risk, Incident Depression, and the Benefits of Adhering to a Healthy Lifestyle: A Prospective Analysis of the UK Biobank Cohort

Background: Genetic factors increase the risk of depression, but the extent to which this can be offset by lifestyle factors is unknown. In the present study, we investigated whether a healthy lifestyle is associated with lower risk of depression regardless of genetic risk. Methods: Data for this prospective analysis were obtained from the UK Biobank and consisted of 339,944 participants (37-73 years old) without depression between 2006 and 2010. Genetic risk was categorized as low (quintile 1), intermediate (quintiles 2-4), or high (quintile 5) according to polygenic risk scores for depression. Healthy lifestyle scores — including no current smoking, regular physical activity, a healthy diet, and a body mass index < 30 kg/m2 — was categorized into favorable, intermediate, and unfavorable lifestyles. Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs) of the associations of genetic risk and lifestyle factors with depression. Finding: During a median follow-up of 8.1 years (2,723,692 person-years), 5,749 incidences of depression were ascertained. The risk of depression was 25% higher among those at high genetic risk compared with those at low genetic risk (HR = 1.25, 95% CI: 1.15-1.36). Unfavorable lifestyle was associated with a 70% increased risk of depression compared with that of a favorable lifestyle (HR = 1.70, 95% CI: 1.57-1.84). Of the participants with a high genetic risk and unfavorable lifestyle, 2.75% (95% CI, 2.36%-3.19%) developed depression compared with 1.25% (95% CI: 1.15%-1.36%) of participants with low genetic risk and a favorable lifestyle (HR = 2.06, 95% CI: 1.74-2.45). There was no significant interaction between genetic risk and healthy lifestyle (P for interaction = 0.75). Among participants at high genetic risk, a favorable lifestyle was associated with a 40% lower relative risk of depression than an unfavorable lifestyle (HR = 0.60, 95% CI: 0.51-0.72). Interpretation: Genetic and combined lifestyle factors were independently associated with the incidence of depression. Hence, our findings suggest that a healthy lifestyle may lower the risk of depression across different genetic risk categories, emphasizing the benefit of adherence to a healthy lifestyle independent of genetic risk. Funding Statement: National Natural Science Foundation of China (91746205, 71910107004, 71673199). Declaration of Interests: The authors declare that they have no conflicts of interests. Ethics Approval Statement: Not required.

EXPLORATORY ANALYSIS OF POLYGENIC RISK SCORES FOR PSYCHIATRIC DISORDERS: APPLIED TO DUAL DIAGNOSIS.

Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.

Maternal vitamin D status during pregnancy and offspring risk of childhood/adolescent depression: Results from the Avon Longitudinal Study of Parents and Children (ALSPAC)

BackgroundLow maternal vitamin D levels [serum 25-hydroxyvitamin D (25(OH)D)] during pregnancy have been linked to offspring neuropsychiatric outcomes such as schizophrenia and autism, but studies on depression are lacking. We examined the association between maternal vitamin D status during pregnancy and offspring depression during childhood and adolescence and investigated whether any associations were modified by offspring genetic risk for depression. MethodsMother-singleton birth offspring pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC) that had maternal 25(OH)D measurements, offspring genetic data, and offspring depression measures collected in childhood (mean age=10.6 years; n = 2938) and/or adolescence (mean age=13.8 years; n = 2485) were included in the analyses. Using multivariable logistic regression, we assessed associations between maternal vitamin D status and offspring polygenic risk score (PRS) for depression on childhood/adolescent depression risk. ResultsThere was no evidence for an association between maternal vitamin D status during pregnancy and offspring depression in childhood (p = 0.72) or adolescence (p = 0.07). Offspring depression PRS were independently associated with childhood depression (p = 0.003), but did not interact with maternal vitamin D status. These results were robust to adjustments for potential confounders and different cut-offs for vitamin D insufficiency/deficiency. Limitations25(OH)D measurements were only available at a single time point during pregnancy. ConclusionThese findings suggest that maternal vitamin D status during pregnancy does not affect an offspring's risk for early life depression.

Exercise May Offset Genetic Risk for Depression

Back to table of contents Previous article Next article Clinical & ResearchFull AccessExercise May Offset Genetic Risk for DepressionTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:3 Jan 2020https://doi.org/10.1176/appi.pn.2020.1a27AbstractBoth high-intensity and low-intensity physical activity may offer protection from depressive episodes.Regular exercise may help prevent depression in people who have a higher genetic risk for the disorder, according to a study posted November 5, 2019, in Depression & Anxiety. Moreover, patients do not have to run marathons to derive any benefit: Gentler forms of exercise such as walking and yoga also appear to offer some protection.Some patients may find exercise daunting, so psychiatrists should explain that it is OK to start slowly, says Jordan W. Smoller, M.D., Sc.D.Massachusetts General HospitalAlthough prior research has suggested that physical activity has positive effects on depression, this study answers two key questions in a more concrete way, said researcher Jordan W. Smoller, M.D. Sc.D., a professor of psychiatry at Harvard Medical School and a professor of epidemiology at Harvard T.H. Chan School of Public Health.“Can we see a preventive effect of physical activity on new-onset depression in a real-world health care setting? And if so, do we see that effect even in people who may be genetically predisposed to develop depression?” asked Smoller, who is also the director of the Psychiatric and Neurodevelopmental Genetics Unit at Massachusetts General Hospital. “The answer to both questions is yes.”To arrive at their conclusions, Smoller and colleagues analyzed data from 7,968 adults in the Partners Biobank, an ongoing study of patients in the Partners HealthCare hospital system in Massachusetts. The database contains patients’ electronic health records, genomic data, and data from lifestyle surveys to help researchers understand how genes, lifestyle, and environment affect health. Overall, roughly 8% of patients in the study were diagnosed with depression within two years of completing a baseline lifestyle survey that asked how much physical activity they engaged in each week.First, the researchers divided the patients according to their polygenic risk score for depression.“The polygenic risk score is a sum of the many small effects of genetic variations that may contribute to a trait, in this case, depression,” Smoller explained. The more variations people have, the greater their risk. Indeed, those with higher polygenic risk scores were significantly more likely to develop a new episode of depression over the two years.Next, the researchers looked at the effect of physical activity. They found that the more physical activity patients reported, the less likely they were to develop depression. This effect was seen even in those with the highest polygenic risk for depression. For example, 12.7% of those in the high genetic risk group who exercised less than an hour a week developed depression, compared with 8.1% of those in the same group who exercised at least 3.2 hours a week, or an average of about 45 minutes a day. Both low-intensity exercise such as yoga and stretching and high-intensity exercise such as dancing, aerobics, and using exercise machines were associated with a lower risk of having a depressive episode, even after the researchers accounted for the patients’ polygenic risk score.Combined with prior research to date, this study demonstrates that “there is now pretty compelling evidence that physical activity of many different kinds may reduce the risk of new-onset depression and symptoms of depression,” Smoller said.He said he includes a discussion of exercise and physical activity in his visits with his patients and encourages other psychiatrists to do the same.“[Psychiatrists] should be trained and educated to support physical activity as part of what we do in counseling our patients,” he said. Yet he acknowledged that the prospect of exercising may seem daunting to patients, so it is important to stress that they can start slowly.This study was funded by the National Genome Research Institute and the National Institute of Mental Health. ■“Physical Activity Offsets Genetic Risk for Incident Depression Assessed Via Electronic Health Records in a Biobank Cohort Study” is posted here. ISSUES NewArchived

GWAS-based polygenic risk scores for depression with clinical validation: methods and study design in the Russian population

Depression is one of the leading causes of decreased quality of life and social functioning of patients. In the context of preventive medicine, the prevention of depression becomes a priority. To achieve the goals of prevention, it is necessary to identify specific population risk groups - individuals with a high genetic risk of depression. The paper describes the project aimed at developing a genetic test system based on polygenic risk scores (PRS) for depression, considering the multi-ethnicity and multicultural diversity of the Russian population. As a result of the study, data on the genetic architecture of depression (GWAS) and PRS for depression will be obtained for the first time. The emergence of a genetic test system developed in the study of the Russian population and in the conditions of a constant decrease in the cost of genetic research will allow an effective transition to preventive medicine in the area of mental health.

Genomic prediction of depression risk and resilience under stress.

Advancing ability to predict who is likely to develop depression holds great potential in reducing the disease burden. Here, we utilize the predictable and large increase in depression with physician training stress to identify predictors of depression. Applying the depression polygenic risk score (MDD-PRS) derived from the most recent PGC2/UKB/23andMe GWAS to 5,227 training physicians, we found that MDD-PRS predicted depression under training stress (beta=0.095, p=4.7×10−16) and that MDD-PRS was more strongly associated with depression under stress than at baseline (MDD-PRSxstress interaction beta=0.036, p=0.005). Further, known risk factors accounted for substantially less of the association between MDD-PRS and depression at under stress than at baseline, suggesting that MDD-PRS adds unique predictive power in depression prediction. Finally, we found that low MDD-PRS may have particular utility in identifying individuals with high resilience. Together, these findings suggest that MDD-PRS holds promise in furthering our ability to predict vulnerability and resilience under stress.

Evaluating chronic emotional dysregulation and irritability in relation to ADHD and depression genetic risk in children with ADHD.

A central nosological problem concerns the etiological relationship of emotional dysregulation with ADHD. Molecular genetic risk scores provide a novel method for informing this question. Participants were 514 community-recruited children of Northern European descent age 7-11 defined as ADHD or non-ADHD by detailed research evaluation. Parents-rated ADHD on standardized ratings and child temperament on the Temperament in Middle Childhood Questionnaire (TMCQ) and reported on ADHD and comorbid disorders by semi-structured clinical interview. Categorical and dimensional variables were created for ADHD, emotional dysregulation (implicating disruption of regulation of both anger-irritability and of positive valence surgency-sensation seeking), and irritability alone (anger dysregulation). Genome-wide polygenic risk scores (PRS) were computed for ADHD and depression genetic liability. Structural equation models and computationally derived emotion profiles guided analysis. The ADHD PRS was associated in variable-centered analyses with irritability (β=.179, 95% CI=0.087-0.280; ΔR2 =.034, p<.0002), but also with surgency/sensation seeking (B=.146, 95%CI=0.052-0.240, ΔR2 =.022, p=.002). In person-centered analysis, the ADHD PRS was elevated in the emotion dysregulation ADHD group versus other ADHD children (OR=1.44, 95% CI=1.03-2.20, Nagelkerke ΔR2 =.013, p=.033) but did not differentiate irritable from surgent ADHD profiles. All effects were independent of variation in ADHD severity across traits or groups. The depression PRS was related to oppositional defiant disorder but not to ADHD emotion dysregulation. Irritability-anger and surgency-sensation seeking, as forms of negative and positively valenced dysregulated affect in ADHD populations, both relate principally to ADHD genetic risk and not mood-related genetic risk.

Polygenic risk for psychiatric disorder and singleness in patients with severe mental illness and controls

We aimed to investigate whether the polygenic risk score (PRS) for schizophrenia influences time in couple relationships for patients with severe mental illness and controls. We combined the nationwide Danish registers with genetic information from dried neonatal blood spots. We included 2,599 individuals with schizophrenia, 1,446 with bipolar disorder, 20,315 with depression, and 6,963 controls. PRS for schizophrenia, depression, and bipolar disorder were estimated using data from the Psychiatric Genetics Consortium and analyzed both as a scale-predictor and as highest versus other deciles. The main outcome was number of days in couple relationships. Patients with schizophrenia had markedly fewer days/year in couple relationships: 64 (95% CI; 61–69) than patients with depression: 119 (95% CI; 117–121), bipolar disorder: 103 (95% CI 97–110), and controls: 136 (95% CI 133–139). PRS for schizophrenia was associated with fewer days in couple relationships in patients with schizophrenia (scale-PRS: IRR = 0.95 (0.93–0.97)) or depression (highest decile: IRR = 0.93 (0.87–0.98)). PRS for bipolar disorder (as scale) was also associated with fewer days in couple relationships in patients with depression (IRR = 0.99 (0.99–1.00)) or bipolar disorder (IRR = 0.96 (0.94–0.99)) and controls (IRR = 0.99 (0.97–1.00), and IRR = 0.89 (0.81–0.98) for the highest decile). Due to the number of statistical tests, however, it cannot be concluded definitely that some of these may not be spurious findings. In conclusion, our findings implicate high genetic loading for schizophrenia as a predisposing factor to singleness in patients with schizophrenia or depression, and genetic loading for bipolar disorder a similar predisposing factor in patients with depression, bipolar disorder or controls.

Identifying Novel Types of Irritability Using a Developmental Genetic Approach.

Irritability, which is strongly associated with impairment and negative outcomes, is a common reason for referral to mental health services but is a nosological and treatment challenge. A major issue is how irritability should be conceptualized. The authors used a developmental approach to test the hypothesis that there are several forms of irritability, including a "neurodevelopmental/ADHD-like" type, with onset in childhood, and a "depression/mood" type, with onset in adolescence. Data were analyzed from the Avon Longitudinal Study of Parents and Children, a prospective U.K. population-based cohort. Irritability trajectory classes were estimated for 7,924 individuals with data at multiple time points across childhood and adolescence (four possible time points from approximately ages 7 to 15). Psychiatric diagnoses were assessed at approximately ages 7 and 15. Psychiatric genetic risk was indexed by polygenic risk scores (PRSs) for attention deficit hyperactivity disorder (ADHD) and depression, derived using large genome-wide association study results. Five irritability trajectory classes were identified: low (81.2%), decreasing (5.6%), increasing (5.5%), late-childhood limited (5.2%), and high-persistent (2.4%). The early-onset high-persistent trajectory was associated with male preponderance, childhood ADHD (odds ratio=108.64, 95% CI=57.45-204.41), and ADHD PRS (odds ratio=1.31, 95% CI=1.09-1.58). The adolescent-onset increasing trajectory was associated with female preponderance, adolescent depression (odds ratio=5.14, 95% CI=2.47-10.73), and depression PRS (odds ratio=1.20, 95% CI=1.05-1.38). Both the early-onset high-persistent and adolescent-onset increasing trajectory classes were associated with adolescent depression diagnosis and ADHD PRS. The developmental context of irritability may be important in its conceptualization: early-onset persistent irritability may be more neurodevelopmental/ADHD-like and later-onset irritability more depression/mood-like. These findings have implications for treatment as well as nosology.

GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.

More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Polygenic Risk: Predicting Depression Outcomes in Clinical and Epidemiological Cohorts of Youths.

Identifying risk factors for major depression and depressive symptoms in youths could have important implications for prevention efforts. This study examined the association of polygenic risk scores (PRSs) for a broad depression phenotype derived from a large-scale genome-wide association study (GWAS) in adults, and its interaction with childhood abuse, with clinically relevant depression outcomes in clinical and epidemiological youth cohorts. The clinical cohort comprised 279 youths with major depression (mean age=14.76 years [SD=2.00], 68% female) and 187 healthy control subjects (mean age=14.67 years [SD=2.45], 63% female). The first epidemiological cohort included 1,450 youths (mean age=13.99 years [SD=0.92], 63% female). Of those, 694 who were not clinically depressed at baseline underwent follow-ups at 6, 12, and 24 months. The replication epidemiological cohort comprised children assessed at ages 8 (N=184; 49.2% female) and 11 (N=317; 46.7% female) years. All cohorts were genome-wide genotyped and completed measures for major depression, depressive symptoms, and/or childhood abuse. Summary statistics from the largest GWAS to date on depression were used to calculate the depression PRS. In the clinical cohort, the depression PRS predicted case-control status (odds ratio=1.560, 95% CI=1.230-1.980), depression severity (β=0.177, SE=0.069), and age at onset (β=-0.375, SE=0.160). In the first epidemiological cohort, the depression PRS predicted baseline depressive symptoms (β=0.557, SE=0.200) and prospectively predicted onset of moderate to severe depressive symptoms (hazard ratio=1.202, 95% CI=1.045-1.383). The associations with depressive symptoms were replicated in the second epidemiological cohort. Evidence was found for an additive, but not an interactive, effect of the depression PRS and childhood abuse on depression outcomes. Depression PRSs derived from adults generalize to depression outcomes in youths and may serve as an early indicator of clinically significant levels of depression.