Polygenic Risk Scores For Major Depressive Disorder Research Articles

Familial aggregation and shared genetic loading for major psychiatric disorders and type 2 diabetes.

Psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MDD) and bipolar disorder (BPD), are highly comorbid with type 2 diabetes. However, the mechanisms underlying such comorbidity are understudied. This study explored the familial aggregation of common psychiatric disorders and type 2 diabetes by testing family history association, and investigated the shared genetic loading between them by testing the polygenic risk score (PRS) association. A total of 105,184 participants were recruited from the Taiwan Biobank, and genome-wide genotyping data were available for 95,238 participants. The Psychiatric Genomics Consortium-derived PRS for SCZ, MDD and BPD was calculated. Logistic regression was used to estimate the OR with CIs between a family history of SCZ/MDD/BPD and a family history of type 2 diabetes, and between the PRS and the risk of type 2 diabetes. A family history of type 2 diabetes was associated with a family history of SCZ (OR 1.23, 95% CI 1.08, 1.40), MDD (OR 1.19, 95% CI 1.13, 1.26) and BPD (OR 1.26, 95% CI 1.15, 1.39). Compared with paternal type 2 diabetes, maternal type 2 diabetes was associated with a higher risk of a family history of SCZ. SCZ PRS was negatively associated with type 2 diabetes in women (OR 0.92, 95% CI 0.88, 0.97), but not in men; the effect of SCZ PRS reduced after adjusting for BMI. MDD PRS was positively associated with type 2 diabetes (OR 1.04, 95% CI 1.00, 1.07); the effect of MDD PRS reduced after adjusting for BMI or smoking. BPD PRS was not associated with type 2 diabetes. The comorbidity of type 2 diabetes with psychiatric disorders may be explained by shared familial factors. The shared polygenic loading between MDD and type 2 diabetes implies not only pleiotropy but also a shared genetic aetiology for the mechanism behind the comorbidity. The negative correlation between polygenic loading for SCZ and type 2 diabetes implies the role of environmental factors.

Polygenic risk scores for neuropsychiatric, inflammatory, and cardio-metabolic traits highlight possible genetic overlap with suicide attempt and treatment-emergent suicidal ideation.

Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co‐occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio‐metabolic traits/diseases with suicide attempt (SA) or treatment‐worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome‐wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta‐analyzed across samples, including a total of 688 patients with SA (N eff = 2,258) and 214 with TWESI (N eff = 785). Stratified genetic covariance analyses were performed to investigate functionally cross‐phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11–1.38; p = 1.73 × 10−4). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p = 4.6 × 10−3), loneliness (p = .009), or chronic pain (p = .016) and SA, PRSs for MDD or CAD and TWESI (p = .043 and p = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.

Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth

Establishing genetic contributions to the transmission of bipolar disorder (BD) from parents to offspring may inform the risk of developing this disorder and further serve to validate BD in youth. To evaluate the specific association of BD polygenic risk scores (PRSs) on the familial transmission and validity of pediatric BD. This community-based case-control longitudinal study (Pittsburgh Biological Offspring Study) included parents with BD I/II and their offspring and parents without BD (healthy or non-BD psychopathology) and their offspring. Participants were recruited between March 2001 and May 2007, and analysis took place from December 2020 to September 2021. PRSs for BD, major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder. Participants were prospectively evaluated using standardized interviews blind to parental diagnosis. DNA was extracted from saliva and genotyped. PRSs were constructed based on independent large-scale genome-wide association studies. A total of 156 parents with BD I/II and 180 parents without BD (mean [SD] age, 39.6 [7.9] years; 241 female [72%]) as well as 251 offspring of parents with BD and 158 offspring of parents without BD (mean [SD] age, 10.4 [4.7] years; 213 female [52%]) of European ancestry were analyzed. Participants were assessed a mean of 6.7 times during a mean (SD) of 13 (3.4) years of follow-up (84% retention). More offspring of parents with BD developed BD (58 [23.1%] vs 8 [5.1%]; P < .001) and depression (126 [50.2%] vs 52 [32.9%]; P < .001) compared with offspring of parents without BD. BD PRS was higher in both parents and offspring with BD than parents and offspring without BD (parents: odds ratio, 1.50; 95% CI, 1.19-1.89; P < .001; explained 4.8% of the phenotypic variance vs offspring: hazard ratio, 1.34; 95% CI, 1.03-1.7; P = .02; explained 5.0% of the phenotypic variance). BD PRS did not differ across BD subtypes. In a model combining parental and offspring BD PRS, the parental BD PRS association with offspring BD was fully mediated by offspring BD PRS (hazard ratio, 1.40; 95% CI, 1.05-1.86; P = .02). Parental BD had a stronger direct association than parental or offspring BD PRS with offspring BD risk (hazard ratio, 5.21; 95% CI, 1.86-14.62; P = .002), explaining 30% of the variance. Parental and offspring BD PRS explained 6% of the BD onset variance beyond parental diagnosis. There were no significant between-group differences in PRSs for major depressive disorder, schizophrenia, and attention-deficit/hyperactivity disorder in parents or offspring and they were not significantly associated with BD onset. The findings of this study add to the extant clinical validation of BD in youth. Parental BD and offspring BD PRS independently associated with the risk of BD in offspring. Although this is promising, the association of BD PRS was relatively small and cannot be used alone to determine BD risk until further developments occur.

Mapping the genetic architecture of suicide attempt and suicide death using polygenic risk scores for clinically-related psychiatric disorders and traits.

Suicidal behavior is moderately heritable and a consequence of a combination of the diathesis traits for suicidal behavior and suicide-related major psychiatric disorders. Here, we sought to examine shared polygenic effects between various psychiatric disorders/traits and suicidal behavior and to compare the shared polygenic effects of various psychiatric disorders/traits on non-fatal suicide attempt and suicide death. We used our genotyped European ancestry sample of 260 non-fatal suicide attempters, 317 suicide decedents and 874 non-psychiatric controls to test whether polygenic risk scores (PRSs) obtained from large GWASs for 22 suicide-related psychiatric disorders/traits were associated with suicidal behavior. Results were compared between non-fatal suicide attempt and suicide death in a sensitivity analysis. PRSs for major depressive disorder, bipolar disorder, schizophrenia, ADHD, alcohol dependence, sensitivity to environmental stress and adversity, educational attainment, cognitive performance, and IQ were associated with suicidal behavior (Bonferroni-corrected p < 2.5 × 10-4). The polygenic effects of all 22 psychiatric disorders/traits had the same direction (p for binomial tests = 4.8 × 10-7) and were correlated (Spearman's ρ = 0.85) between non-fatal suicide attempters and suicide decedents. We found that polygenic effects for major psychiatric disorders and diathesis-related traits including stress responsiveness and intellect/cognitive function contributed to suicidal behavior. While we found comparable polygenic architecture between non-fatal suicide attempters and suicide decedents based on correlations with PRSs of suicide-related psychiatric disorders/traits, our analyses are limited by small sample size resulting in low statistical power to detect difference between non-fatal suicide attempt and suicide death.

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness

BackgroundElectroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness. MethodsA total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R2) at the optimal p-value threshold is reported. ResultsIn the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold. ConclusionsA linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry.

Suicidal ideation and planning among Mexican adolescents are associated with depression polygenic risk scores.

Suicide is a major public health problem in Mexico and around the world. Genetic predisposition for major depressive disorder (MDD) has been associated with increased risk for suicidal behaviors (SB) in populations of European ancestry (EA). Here, we examine whether MDD polygenic risk scores (MDD PRS), derived from a genome-wide association study involving EA individuals, predict SB, including ideation, planning, and attempt, among Mexican youth using a longitudinal design. At baseline, participants (N=1,128, 12-17 years, 55% women) were interviewed and genotyped as part of a general population survey on adolescent mental health. Eight years later, they were recontacted for a follow up visit (N=437, 20-25 years, 63% women). At both assessments, individuals reported on their engagement in SB within the past year. MDD PRS were significantly positively associated with SB, particularly suicide ideation and planning during adolescence, accounting for ~4-5% of the variance in these outcomes. In contrast, associations between MDD PRS and SB during young adulthood did not reach statistical significance. Our results suggest that increased genetic liability for depression increased risk for SB, particularly during adolescence, expanding our knowledge of the genetic underpinnings of SB.

Associations between major psychiatric disorder polygenic risk scores and blood-based markers in UK biobank

Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear.We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: ‘minimally adjusted’ controlling for variables such as age and sex, and ‘fully adjusted’ including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake.There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively.This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.

European Depression Polygenic Risk Score Predicts Suicide Behavior in Mexicans

Depression is frequently linked to suicide behaviors (ideation, plan, and attempt). To date, the association between the Major Depressive Disorder Polygenic Risk Score (MDD-PRS) and suicide behaviors (SB) has been primarily examined in individuals of European ancestry. Nonetheless, the extent to which MDD-PRS can predict SB in populations with a different ethnicity (Mexicans) remains unclear. The current study aimed to assess whether MDD-PRS predict suicide ideation, planning, and attempt in a sample of young Mexican individuals.

Polygenic risk and predominant polarity in individuals with bipolar disorder

IntroductionIndividuals with bipolar disorder often have a ‘predominant polarity’ (e.g. depressive or manic) that characterizes the majority of episodes over the course of the illness. Genome-wide association studies have suggested a relationship between genetic risk and phenotypic heterogeneity in bipolar disorder. However, to date, no study has directly examined the association between polygenic liabilities and predominant polarity in bipolar disorder.ObjectivesTo estimate the associations between the polygenic risk score for major depressive disorder (PRS-MD), bipolar disorder (PRS-BD) and schizophrenia (PRS-SZ), and predominant polarity among individuals with bipolar disorder in hospital-based settings in Denmark.MethodsThe study sample will include all individuals from the Initiative for Integrated Psychiatric Research (iPSYCH2015) sample who received a diagnosis of bipolar disorder and were successfully genotyped (approximately 3,400). Information on polarity will be computed based on data from the Danish Central Psychiatric Research Register. PRS variables will be generated using the most recent results from the Psychiatric Genomics Consortium. Odds ratios for the associations between PRS variables and polarity will be estimated using logistic regression.ResultsWe hypothesize that PRS-MD will be highest among the predominantly depressed patients, that PRS-BD will be highest among those with predominantly manic/mixed episodes, and that PRS-SZ will be highest among those who experience psychotic mania or psychotic bipolar depression. The results will be shown at the conference.ConclusionsA finding of association between genetic liability and predominant polarity in bipolar disorder could pave the way for stratification on genetic liability in future treatment studies and in clinical practice.DisclosureNo significant relationships.

Polygenic risk for depression, anxiety and neuroticism are associated with the severity and rate of change in depressive symptoms across adolescence.

Adolescence marks a period where depression will commonly onset. Twin studies show that genetic influences play a role in how depression develops and changes across adolescence. Recent genome-wide association studies highlight that common genetic variants - which can be combined into polygenic risk scores (PRS) - are also implicated in depression. However, the role of PRS in adolescent depression and changes in adolescent depression is not yet understood. We aimed to examine associations between PRS for five psychiatric traits and depressive symptoms measured across adolescence using cross-sectional and growth-curve models. The five PRS were as follows: depression (DEP), major depressive disorder (MDD), anxiety (ANX), neuroticism (NEU) and schizophrenia (SCZ). We used data from over 6,000 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine associations between the five PRS and self-reported depressive symptoms (Short Mood and Feelings Questionnaire) over 9 occasions from 10 to 24 years. The PRS were created from well-powered genome-wide association studies conducted in adult populations. We examined cross-sectional associations between the PRS at each age and then again with longitudinal trajectories of depressive symptoms in a repeated measures framework using multilevel growth-curve analysis to examine the severity and the rate of change. There was strong evidence that higher PRS for DEP, MDD and NEU were associated with worse depressive symptoms throughout adolescence and into young adulthood in our cross-sectional analysis, with consistent associations observed across all nine occasions. Growth-curve analyses provided stronger associations (as measured by effect sizes) and additional insights, demonstrating that individuals with higher PRS for DEP, MDD and NEU had steeper trajectories of depressive symptoms across development, all with a greater increasing rate of change during adolescence. Evidence was less consistent for the ANX and SCZ PRS in the cross-sectional analysis, yet there was some evidence for an increasing rate of change in adolescence in the growth-curve analyses with the ANX PRS. These results show that common genetic variants as indexed by varying psychiatric PRS show patterns of specificity that influence both the severity and rate of change in depressive symptoms throughout adolescence and then into young adulthood. Longitudinal data that make use of repeated measures designs have the potential to provide greater insights how genetic factors influence the onset and persistence of adolescent depression.

Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71–88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.

Reconsidering the reasons for heightened inflammation in major depressive disorder

BackgroundIncreased circulating pro-inflammatory markers have repeatedly been associated with major depressive disorder (MDD). However, it remains unclear whether inflammation represents a causal mechanism for MDD, or whether the association is influenced by confounding factors such as body mass index (BMI). MethodsTo better understand this complex relationship, we generated polygenic risk scores (PRS) for MDD and BMI in a population cohort and attempted to isolate the impact these potential risk factors have on adulthood inflammation. Peripheral blood samples were collected as part of the South East London Community Health study, where we generated individualized PRS for MDD and BMI and quantified inflammatory markers using multiplex ELISA-based technology. We performed linear regressions to investigate the effects of PRS for MDD and BMI on inflammatory marker levels. ResultsOut of 35 inflammatory markers, we found a nominal effect of PRS for MDD on interleukin-10. We also found a significant positive effect of BMI on nine inflammatory markers, of which the two most strongly affected markers, interleukin-6 (IL-6) and C-reactive protein (CRP), were also nominally predicted by BMI PRS. LimitationsThe study utilized a cross-sectional design with a moderately sized sample. ConclusionsOur findings suggest there may not be a shared genetic mechanism contributing to MDD and higher inflammatory marker levels. However, there may be shared genetic etiology between BMI and adulthood levels of CRP and IL-6. Therefore, polygenic risk scores for BMI may represent a useful indicator for heightened levels of inflammation in adulthood.

Sex-specific association between infant caudate volumes and a polygenic risk score for major depressive disorder.

Polygenic risk scores for major depressive disorder (PRS-MDD) have been identified in large genome-wide association studies, and recent findings suggest that PRS-MDD might interact with environmental risk factors to shape human limbic brain development as early as in the prenatal period. Striatal structures are crucially involved in depression; however, the association of PRS-MDD with infant striatal volumes is yet unknown. In this study, 105 Finnish mother-infant dyads (44 female, 11-54days old) were investigated to reveal how infant PRS-MDD is associated with infant dorsal striatal volumes (caudate, putamen) and whether PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant striatal volumes. A robust sex-specific main effect of PRS-MDD on bilateral infant caudate volumes was observed. PRS-MDD were more positively associated with caudate volumes in boys compared to girls. No significant interaction effects of genotype PRS-MDD with the environmental risk factor "prenatal maternal depressive symptoms" (genotype-by-environment interaction) nor significant interaction effects of genotype with prenatal maternal depressive symptoms and sex (genotype-by-environment-by-sex interaction) were found for infant dorsal striatal volumes. Our study showed that a higher PRS-MDD irrespective of prenatal exposure to maternal depressive symptoms is associated with smaller bilateral caudate volumes, an indicator of greater susceptibility to major depressive disorder, in female compared to male infants. This sex-specific polygenic effect might lay the ground for the higher prevalence of depression in women compared to men.

Clock gene polygenic risk score and seasonality in major depressive disorder and bipolar disorder.

Seasonal changes in mood and diurnal preference are two well-characterized chronobiological phenotypes in major depressive disorder (MDD) and bipolar disorder (BD). The biological mechanisms regulating physiological changes related to seasonality and chronotype involve several genes known as "clock" or circadian genes. Our goal was to study the relationship between the polygenic risk score (PRS) obtained from a set of clock genes and chronobiological traits in patients with mood disorders. The sample included 445 patients with mood disorders (256 MDD; 189 BD). Seasonality was assessed using the Seasonal Pattern Assessment Questionnaire (SPAQ), and chronotype was assessed using the Horne and Östberg Morningness-Eveningness Questionnaire. We selected 248 single nucleotide polymorphisms located within 19 genes. PRS for both MDD and BD was calculated using the Psychiatric Genetics Consortium latest datasets as discovery samples. Another PRS was calculated using results from a genome-wide association study focusing on chronotype. SPAQ results were significantly associated with MDD-PRS (p = 0.037) and chronotype-PRS (p = 0.019), which also showed a significant interaction with age (p = 0.039). No significant association was observed between the measured PRS and chronotype. Our results reflect that small effect variants associated with MDD and chronotype within clock genes are associated with seasonality traits in patients with mood disorders, further explaining the mechanism through which the circadian system might influence mood disorder clinical presentation. Future studies measuring PRS from specific gene sets and focusing on biological endophenotypes will help to elucidate the pathways from genetic variations to clinical outcome.

Partial Support for an Interaction Between a Polygenic Risk Score for Major Depressive Disorder and Prenatal Maternal Depressive Symptoms on Infant Right Amygdalar Volumes.

Psychiatric disease susceptibility partly originates prenatally and is shaped by an interplay of genetic and environmental risk factors. A recent study has provided preliminary evidence that an offspring polygenic risk score for major depressive disorder (PRS-MDD), based on European ancestry, interacts with prenatal maternal depressive symptoms (GxE) on neonatal right amygdalar (US and Asian cohort) and hippocampal volumes (Asian cohort). However, to date, this GxE interplay has only been addressed by one study and is yet unknown for a European ancestry sample. We investigated in 105 Finnish mother-infant dyads (44 female, 11-54days old) how offspring PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant amygdalar and hippocampal volumes. We found a GxE effect on right amygdalar volumes, significant in the main analysis, but nonsignificant after multiple comparison correction and some of the control analyses, whose direction paralleled the US cohort findings. Additional exploratory analyses suggested a sex-specific GxE effect on right hippocampal volumes. Our study is the first to provide support, though statistically weak, for an interplay of offspring PRS-MDD and prenatal maternal depressive symptoms on infant limbic brain volumes in a cohort matched to the PRS-MDD discovery sample.

Shared polygenic risk for ADHD, executive dysfunction and other psychiatric disorders

Many psychiatric disorders are associated with impaired executive functioning (EF). The associated EF component varies by psychiatric disorders, and this variation might be due to genetic liability. We explored the genetic association between five psychiatric disorders and EF in clinically-recruited attention deficit hyperactivity disorder (ADHD) children using polygenic risk score (PRS) methodology. Genome-wide association study (GWAS) summary data for ADHD, major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BIP) and autism were used to calculate the PRSs. EF was evaluated by the Stroop test for inhibitory control, the trail-making test for cognitive flexibility, and the digital span test for working memory in a Chinese ADHD cohort (n = 1147). Exploratory factor analysis of the three measures identified one principal component for EF (EF-PC). Linear regression models were used to analyze the association between each PRS and the EF measures. The role of EF measures in mediating the effects of the PRSs on ADHD symptoms was also analyzed. The result showed the PRSs for MDD, ADHD and BIP were all significantly associated with the EF-PC. For each EF component, the association results were different for the PRSs of the five psychiatric disorders: the PRSs for ADHD and MDD were associated with inhibitory control (adjusted P = 0.0183 and 0.0313, respectively), the PRS for BIP was associated with working memory (adjusted P = 0.0416), and the PRS for SZ was associated with cognitive flexibility (adjusted P = 0.0335). All three EF measures were significantly correlated with ADHD symptoms. In mediation analyses, the ADHD and MDD PRSs, which were associated with inhibitory control, had significant indirect effects on ADHD symptoms through the mediation of inhibitory control. These findings indicate that the polygenic risks for several psychiatric disorders influence specific executive dysfunction in children with ADHD. The results helped to clarify the relationship between risk genes of each mental disorder and the intermediate cognitive domain, which may further help elucidate the risk genes and motivate efforts to develop EF measures as a diagnostic marker and future treatment target.

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.

Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling.

Disordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia.

BackgroundCognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.MethodsWe combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. ResultsPRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. ConclusionsCognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

The effect of genetic vulnerability and military deployment on the development of post-traumatic stress disorder and depressive symptoms

Exposure to trauma strongly increases the risk to develop stress-related psychopathology, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). In addition, liability to develop these moderately heritable disorders is partly determined by common genetic variance, which is starting to be uncovered by genome-wide association studies (GWASs). However, it is currently unknown to what extent genetic vulnerability and trauma interact. We investigated whether genetic risk based on summary statistics of large GWASs for PTSD and MDD predisposed individuals to report an increase in MDD and PTSD symptoms in a prospective military cohort (N = 516) at five time points after deployment to Afghanistan: one month, six months and one, two and five years. Linear regression was used to analyze the contribution of polygenic risk scores (PRSs, at multiple p-value thresholds) and their interaction with deployment-related trauma to the development of PTSD- and depression-related symptoms. We found no main effects of PRSs nor evidence for interactions with trauma on the development of PTSD or depressive symptoms at any of the time points in the five years after military deployment. Our results based on a unique long-term follow-up of a deployed military cohort suggest limited validity of current PTSD and MDD polygenic risk scores, albeit in the presence of minimal severe psychopathology in the target cohort. Even though the predictive value of PRSs will likely benefit from larger sample sizes in discovery and target datasets, progress will probably also depend on (endo)phenotype refinement that in turn will reduce etiological heterogeneity.