BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, antisocial behavior, and measures of suicide and self-harm.
Abstract
Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions. Genome-wide association analyses identify risk variants for borderline personality disorder and find genetic correlations with psychiatric disorders, behavioral traits and somatic diseases.
Schizophrenia and bipolar disorder are diagnostically distinct categories that overlap substantially in clinical features and genetic aetiology. Understanding genetic variants that contribute liability specifically to each disorder can offer insights into biological processes that differentiate them. Here we used Case-Case GWAS (CC-GWAS) to identify common genetic variants differentially associated with schizophrenia and bipolar disorder, analysing 67,390 schizophrenia cases and 41,917 bipolar disorder cases. We identified 19 genome-wide significant loci, of which 16 (84%) demonstrated divergent genetic effects with risk alleles showing opposite directions of association between disorders. The CC-GWAS summary statistics had detectable disorder-differentiating heritability (10.27%, SE=0.01) and showed genetic correlations indicating that SCZ-differentiating alleles were associated with lower educational attainment, lower cognitive performance, and increased risk of ADHD, anorexia, autism, BD1 (though not BD2), cannabis use disorder, and OCD. Four loci showed divergent effects despite not reaching genome-wide significance in either individual disorder GWAS, demonstrating enhanced power to detect opposite-direction effects. Functional annotation identified 102 mapped genes significantly enriched for expression across all 13 tested brain regions, with no significant enrichment in peripheral tissues, and gene set enrichment analysis implicated neuronal projection and synaptic compartments as the strongest biological themes differentiating the two disorders. Polygenic risk scores derived from these disorder-differentiating variants were associated with earlier age at onset and more severe negative symptoms in schizophrenia, consistent with these variants marking neurodevelopmental dimensions of illness. Our findings provide targets for understanding pathogenic differences between schizophrenia and bipolar disorder and demonstrate that genuine divergent genetic effects exist beyond the substantial shared liability.
I. Willcocks, A. Richards, S. Legge et al.· medRxiv· 0 citations
Social anxiety disorder (SAD) is a common anxiety disorder (ANX) with moderate heritability that often co-occurs with other mental disorders. Until now, sample sizes in genetic analyses of SAD have been limited, so that the genetic basis of SAD and its subphenotypes is still largely unknown. In a large cohort comprising n = 1,194 SAD patients derived from five German cohorts and n = 3,409 controls from the Heinz Nixdorf Recall Study, we computed polygenic risk scores (PRS) at six p-thresholds using PRSice-2 based on large-scale genome-wide association studies for depression, major depressive disorder (MDD), ANX, schizophrenia (SCZ), bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), anorexia nervosa (AN), autism spectrum disorder (ASD), and alcohol dependence (AD). We used general linear models to examine the association between the PRS and SAD status. In SAD subsamples, we investigated whether the PRS are associated with SAD subphenotypes (i.e., SAD severity, current depressive symptoms, comorbid MDD) using correlation analyses and a general linear model. Results were corrected for multiple testing. The SAD status was significantly associated with PRS for depression, MDD, ANX, SCZ, BD, AN, and ASD (pBH-adjusted<0.05), but not with PRS for ADHD and AD. In SAD subsamples, the subphenotype analyses revealed no significant associations after correction for multiple testing (pBH-adjusted>0.05). Our results support that SAD seems to be genetically highly overlapping with other mental disorders, which might underline a common psychopathological factor. No significant association was found with SAD severity, current depressive symptoms or comorbid MDD. A better understanding of the genetic architecture of SAD may help to develop new diagnostic and treatment approaches.
L. Sindermann, Angelina Röhrig, F. David et al.· Translational Psychiatry· 0 citations
Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.
Jet D Termorshuizen, Helena L Davies, Sang-Hyuck Lee et al.· Nature Mental Health· 0 citations
It is found that schizophrenia and ADHD show distinct genetic patterns: schizophrenia shares more genetic factors with brain structure and diabetes, while ADHD is more strongly linked to metabolic pathways.
J. Kopal, A. Shadrin, Dennis van der Meer et al.· Communications Medicine· 0 citations
BACKGROUND
Prior twin studies have shown genetic and environmental overlap between autistic traits and internalising symptoms. However, it remains unknown whether this overlap reflects a common latent liability or similar aetiological influences operating through independent pathways. We investigated the genetic and environmental origins of the co-occurrence of autistic traits and internalising symptoms with a meta-analysis and an empirical twin study.
METHODS
Study 1 meta-analysed six twin studies examining autistic traits and internalising symptoms, predominantly in Western child and adolescent samples. Study 2 applied multivariate genetic modelling to a Chinese community sample of 178 twin pairs (109 monozygotic and 69 dizygotic, aged 24-35).
RESULTS
Study 1 showed genetic (rA = 0.42) and non-shared environmental (rE = 0.15) overlap between autistic traits and internalising symptoms, although substantial heterogeneity was observed across estimates. Study 2 was broadly consistent with the findings of Study 1. It further suggested that the co-occurrence of autistic traits, anxiety and depressive symptoms may be partly explained by a common latent factor shaped by genetic and non-shared environmental influences, although the common pathway model was only tentatively favoured over the independent pathway model.
CONCLUSION
Across meta-analytic and empirical twin studies, the co-occurrence of autistic traits, anxiety and depressive symptoms appears to be shaped in part by shared genetic and non-shared environmental influences across these three traits. This generally aligns with the transdiagnostic framework of psychopathology. It also highlights that individuals presenting autistic traits may benefit from screening for internalising symptoms, and vice versa.
Yuxuan Han, Xinying Li, Ruo-lei Gu et al.· Journal of Affective Disorde...· 0 citations
BACKGROUND
Major Depressive Disorder (MDD) is heritable and polygenic, yet the relative diagnostic specificity, developmental impact, and cross-ancestry generalizability of MDD polygenic risk scores (MDD-PRS) remain unclear.
METHODS
In two sites of the Brazilian High-Risk Cohort (N=2,163; ages 6-23; 45.6% female), we used a discovery-replication design to test associations between MDD-PRS and (i) lifetime DSM-IV diagnoses; (ii) longitudinal depressive-symptom trajectories from latent growth-curve models; and (iii) late-adolescent/young-adult depressive symptoms and nonsuicidal self-injury (NSSI). Analyses used weighted ordinary least squares and quantile regression, adjusting for age, sex, socioeconomic status, genetic principal components, and psychiatric comorbidity.
RESULTS
MDD-PRS showed relative specificity for MDD in both sites, explaining approximately 2.6-3.6% of liability-scale variance; no other diagnostic category survived false-discovery-rate correction. Longitudinally, higher MDD-PRS predicted higher initial level (β=0.10-0.18; p<0.001 in both sites), faster rate of increase (β=0.07-0.10; p=0.004 and p<0.001), and higher time-averaged level (β=0.13-0.20; p<0.001 in both sites) of depressive symptoms, with effects strengthening at higher quantiles. Cross-sectionally, MDD-PRS were associated with more depressive symptoms (β=0.15-0.17; p<0.001 in both sites). For NSSI, a main-effect association was observed (β=0.09; p<0.001), but it remained significant only in a post-hoc MDD-PRS×lifetime-MDD interaction among individuals with MDD (β=0.24; p=0.014).
CONCLUSIONS
In this deeply phenotyped, admixed cohort, MDD-PRS showed relative diagnostic specificity and marked a more severe developmental course of depression, with NSSI associations contingent on MDD diagnosis, supporting the relative specificity, developmental utility, and cross-ancestry relevance of MDD-PRS.
M. Brañas, L. T. Ito, M. Croci et al.· Biological Psychiatry· 0 citations
