Testing Quantitative and Qualitative Sex Effects in a National Swedish Twin-Sibling Study of Posttraumatic Stress Disorder.

OBJECTIVE: Twin studies have demonstrated that posttraumatic stress disorder (PTSD) is moderately heritable, and the pattern of findings across studies suggests higher heritability in females compared with males. Formal testing of sex differences has yet to be done in twin studies of PTSD. The authors sought to estimate the genetic and environmental contributions to PTSD, and to formally test for sex differences, in the largest sample to date of both sexes, among twins and siblings. METHODS: Using the Swedish National Registries, the authors performed structural equation modeling to decompose genetic and environmental variance for PTSD and to formally test for quantitative and qualitative sex differences in twins (16,242 pairs) and in full siblings within 2 years of age of each other (376,093 pairs), using diagnostic codes from medical registries. RESULTS: The best-fit model suggested that additive genetic and unique environmental effects contributed to PTSD. Evidence for a quantitative sex effect was found, such that heritability was significantly greater in females (35.4%) than males (28.6%). Evidence of a qualitative sex effect was found, such that the genetic correlation was high but less than complete (rg=0.81, 95% CI=0.73-0.89). No evidence of shared environment or special twin environment was found. CONCLUSIONS: This is the first demonstration of quantitative and qualitative sex effects for PTSD. The results suggest that unique environmental effects, but not the shared environment, contributed to PTSD and that genetic influences for the disorder are stronger in females compared with males. Although the heritability is highly correlated, it is not at unity between the sexes.

Extended Swedish Adoption Study of Adverse Stress Responses and Posttraumatic Stress Disorder.

Importance: Twin studies have found that posttraumatic stress disorder (PTSD) is influenced by both genetic and environmental factors within a generation. No study has used an adoption design, which can address questions about the degree and sources of cross-generational transmission of adverse stress responses (ASRs) and PTSD. Objectives: To examine whether ASRs or PTSD are transmitted from parents to offspring, and to clarify the relative importance of genes and rearing. Design, Setting, and Participants: This cohort study used nationwide Swedish registry data from parents and offspring (n = 2 194 171, born 1960-1992) of 6 types of families (intact; had not lived with biological father; had not lived with biological mother; lived with stepfather; lived with stepmother; and adoptive). Follow-up occurred on December 31, 2018, and data were analyzed from March 3, 2023, to January 16, 2024. Exposures: Three sources of parent-offspring resemblance: genes plus rearing, genes only, and rearing only. Main Outcomes and Measures: Diagnoses of ASRs or PTSD were obtained from national inpatient, outpatient, and primary care medical registries. Parent-child resemblance was assessed by tetrachoric correlation. Sensitivity analyses were conducted to control for possible shared traumatic events. Results: The study population included 2 194 171 individuals of 6 family types (1 146 703 [52.3%] male; median [range] age, 42 [20-63] years). The weighted tetrachoric correlations across family types were 0.15 (95% CI, 0.15-0.16) for genes plus rearing, 0.08 (95% CI, 0.06-0.11) for genes only, and 0.10 (95% CI, 0.07-0.12) for rearing only. Controlling for potential shared traumatic events, sensitivity analyses found that the correlation for rearing decreased, with the most conservative control (exclusion of parent-offspring dyads with onset of ASRs or PTSD within 1 year) suggesting equal correlations with genes and rearing. Conclusions and Relevance: Diagnosis of ASRs or PTSD demonstrated cross-generational transmission, including both genetic and rearing correlations. Sensitivity analyses suggested that shared traumatic events partially accounted for the observed rearing correlations.

Functional classes of SNPs related to psychiatric disorders and behavioral traits contrast with those related to neurological disorders.

We investigated the functional classes of genomic regions containing SNPS contributing most to the SNP-heritability of important psychiatric and neurological disorders and behavioral traits, as determined from recent genome-wide association studies. We employed linkage-disequilibrium score regression with several brain-specific genomic annotations not previously utilized. The classes of genomic annotations conferring substantial SNP-heritability for the psychiatric disorders and behavioral traits differed systematically from the classes associated with neurological disorders, and both differed from the classes enriched for height, a biometric trait used here as a control outgroup. The SNPs implicated in these psychiatric disorders and behavioral traits were highly enriched in CTCF binding sites, in conserved regions likely to be enhancers, and in brain-specific promoters, regulatory sites likely to affect responses to experience. The SNPs relevant for neurological disorders were highly enriched in constitutive coding regions and splice regulatory sites.

Personality correlates of past-year alcohol use in individuals with severe alcohol use disorder and a lifetime history of involvement in alcoholics anonymous.

BACKGROUND: Alcohol use disorder (AUD) is a highly impairing condition with important public health impacts. Despite the availability of treatment options for AUD, research shows that few people receive treatment, and even fewer can maintain abstinence/low-drinking levels. This study investigated the role of personality traits in past-year alcohol use among individuals with severe AUD who ever attended Alcoholics Anonymous (AA), a widespread and easily accessible self-help group for alcohol problems. METHODS: Univariable and multivariable regressions were performed separately in females and males with alcohol consumption as an outcome. Socioeconomic factors, genetic liability, and psychopathology were included as covariates in the analyses. RESULTS: Results from the multivariable model indicated that in females who attended AA, greater alcohol use was related to both positive and negative urgency and low sensation seeking, while in males, greater alcohol use was related to positive urgency. Results also showed that, in both sexes, younger age and lower educational levels were associated with greater alcohol use. Moreover, single males and individuals with lower AUD severity were at higher risk of using alcohol in the past year. CONCLUSIONS: These findings highlight sex-specific correlates of drinking in individuals with AUD who engaged in self-help groups. These findings may help to improve treatment options, as personality encompasses modifiable traits that can be targeted in psychological interventions.

A Dynamical Systems View of Psychiatric Disorders-Theory: A Review.

Importance: Psychiatric disorders may come and go with symptoms changing over a lifetime. This suggests the need for a paradigm shift in diagnosis and treatment. Here we present a fresh look inspired by dynamical systems theory. This theory is used widely to explain tipping points, cycles, and chaos in complex systems ranging from the climate to ecosystems. Observations: In the dynamical systems view, we propose the healthy state has a basin of attraction representing its resilience, while disorders are alternative attractors in which the system can become trapped. Rather than an immutable trait, resilience in this approach is a dynamical property. Recent work has demonstrated the universality of generic dynamical indicators of resilience that are now employed globally to monitor the risks of collapse of complex systems, such as tropical rainforests and tipping elements of the climate system. Other dynamical systems tools are used in ecology and climate science to infer causality from time series. Moreover, experiences in ecological restoration confirm the theoretical prediction that under some conditions, short interventions may invoke long-term success when they flip the system into an alternative basin of attraction. All this implies practical applications for psychiatry, as are discussed in part 2 of this article. Conclusions and Relevance: Work in the field of dynamical systems points to novel ways of inferring causality and quantifying resilience from time series. Those approaches have now been tried and tested in a range of complex systems. The same tools may help monitoring and managing resilience of the healthy state as well as psychiatric disorders.

A Dynamical Systems View of Psychiatric Disorders-Practical Implications: A Review.

Importance: Dynamical systems theory is widely used to explain tipping points, cycles, and chaos in complex systems ranging from the climate to ecosystems. It has been suggested that the same theory may be used to explain the nature and dynamics of psychiatric disorders, which may come and go with symptoms changing over a lifetime. Here we review evidence for the practical applicability of this theory and its quantitative tools in psychiatry. Observations: Emerging results suggest that time series of mood and behavior may be used to monitor the resilience of patients using the same generic dynamical indicators that are now employed globally to monitor the risks of collapse of complex systems, such as tropical rainforest and tipping elements of the climate system. Other dynamical systems tools used in ecology and climate science open ways to infer personalized webs of causality for patients that may be used to identify targets for intervention. Meanwhile, experiences in ecological restoration help make sense of the occasional long-term success of short interventions. Conclusions and Relevance: Those observations, while promising, evoke follow-up questions on how best to collect dynamic data, infer informative timescales, construct mechanistic models, and measure the effect of interventions on resilience. Done well, monitoring resilience to inform well-timed interventions may be integrated into approaches that give patients an active role in the lifelong challenge of managing their resilience and knowing when to seek professional help.

Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories.

Divorce, genetic risk, and suicidal thoughts and behaviors in a sample with recurrent major depressive disorder.

BACKGROUND: Theories of risk for suicidal thoughts and behaviors (STB) implicate both interpersonal and biological factors. Divorce/separation and aggregate genetic liability are robustly associated with STB, but have seldom been evaluated in conjunction with one another. Furthermore, whether these factors are effective predictors in high-risk populations is not clear. METHODS: Analyses were conducted in a sample of Han Chinese women with severe recurrent major depressive disorder (maximum N = 4380). Logistic regressions were used to evaluate the associations between divorce/separation and polygenic scores (PGS) for suicidal ideation or behavior with STB. Where appropriate, additive interactions between divorce and PGS were tested. RESULTS: Divorce/separation was significantly associated with increased risk of suicidal ideation, plans, and attempts (odds ratios = 1.28-1.61). PGS for suicidal ideation were not associated with STB, while PGS for suicidal behavior were associated with ideation and plans (odds ratios = 1.08-1.09). There were no significant interactions between divorce/separation and PGS. CONCLUSIONS: Consistent with theories of suicidality, the disruption or end of an important interpersonal relationship is an indicator of risk for STB. Aggregate genetic liability for suicidal behavior more modestly contributes to risk, but does not exacerbate the negative impact of divorce. Thus, even within a high-risk sample, interpersonal and biological exposures distinguish between those who do and do not experience STB, and could motivate targeted screening. Further research is necessary to evaluate whether and how the context of divorce contributes to variation in its effect on STB risk.

Socioeconomic position indicators and risk of alcohol-related medical conditions: A national cohort study from Sweden.

BACKGROUND: Alcohol consumption contributes to excess morbidity and mortality in part through the development of alcohol-related medical conditions (AMCs, including alcoholic cardiomyopathy, hepatitis, cirrhosis, etc.). The current study aimed to clarify the extent to which risk for these outcomes differs as a function of socioeconomic position (SEP), as discrepancies could lead to exacerbated health disparities. METHODS AND FINDINGS: We used longitudinal Swedish national registries to estimate the individual and joint associations between 2 SEP indicators, educational attainment and income level, and risk of AMC based on International Classification of Diseases codes, while controlling for other sociodemographic covariates and psychiatric illness. We conducted Cox proportional hazards models in sex-stratified analyses (N = 1,162,679 females and N = 1,196,659 males), beginning observation at age 40 with follow-up through December 2018, death, or emigration. By the end of follow-up, 4,253 (0.37%) females and 11,183 (0.93%) males had received an AMC registration, corresponding to overall AMC incidence rates among females and males of 2.01 and 5.20, respectively. In sex-stratified models adjusted for birth year, marital status, region of origin, internalizing and externalizing disorder registrations, and alcohol use disorder (AUD) registration, lower educational attainment was associated with higher risk of AMC in both females (hazard ratios [HRs] = 1.40 to 2.46 for low- and mid-level educational attainment across 0 to 15 years of observation) and males (HRs = 1.13 to 1.48). Likewise, risk of AMC was increased for those with lower income levels (females: HRs = 1.10 to 5.86; males: HRs = 1.07 to 6.41). In secondary analyses, we further adjusted for aggregate familial risk of AUD by including family genetic risk scores for AUD (FGRSAUD), estimated using medical, pharmacy, and criminal registries in extended families, as covariates. While FGRSAUD were associated with risk of AMC in adjusted models (HR = 1.17 for females and HR = 1.21 for males), estimates for education and income level remained largely unchanged. Furthermore, FGRSAUD interacted with income level, but not education level, such that those at higher familial liability to AUD were more susceptible to the adverse effect of low income. Limitations of these analyses include the possibility of false negatives for psychiatric illness registrations, changes in income after age 40 that were not accounted for due to modeling restrictions, restriction to residents of a high-income country, and the inability to account for individual-level alcohol consumption using registry data. CONCLUSIONS: Using comprehensive national registry data, these analyses demonstrate that individuals with lower levels of education and/or income are at higher risk of developing AMC. These associations persist even when accounting for a range of sociodemographic, psychiatric, and familial risk factors. Differences in risk could contribute to further health disparities, potentially warranting increased screening and prevention efforts in clinical and public health settings.

Alcohol use disorder and risk of specific methods of suicide death in a national cohort.

INTRODUCTION: Alcohol use disorder (AUD) is among the strongest correlates of suicide death, but it is unclear whether AUD status is differentially associated with risk of suicide by particular methods. METHODS: The authors used competing risks models to evaluate the association between AUD status and risk of suicide by poisoning, suffocation, drowning, firearm, instruments, jumping, or other means in a large Swedish cohort born 1932-1995 (total N = 6,581,827; 48.8% female). Data were derived from Swedish national registers, including the Cause of Death Register and a range of medical registers. RESULTS: After adjusting for sociodemographic factors and familial liability to suicidal behavior, AUD was positively associated with risk of suicide for each method evaluated (cumulative incidence differences: 0.006-1.040 for females, 0.046-0.680 for males), except the association with firearm suicide in females. AUD was most strongly associated with risk of suicide by poisoning. Sex differences in the effects of AUD and family liability were observed for some, but not all, methods. Furthermore, high familial liability for suicidal behavior exacerbated AUD's impact on risk for suicide by poisoning (both sexes) and suffocation and jumping (males only), while the inverse interaction was observed for firearm suicide (males only). CONCLUSIONS: AUD increases risk of suicide by all methods examined and is particularly potent with respect to risk of suicide by poisoning. Differences in risk related to sex and familial liability to suicidal behavior underscore AUD's nuanced role in suicide risk. Future research should investigate targeted means restriction effectiveness among persons with AUD.

Environmental risk factors for schizophrenia and bipolar disorder from childhood to diagnosis: a Swedish nested case-control study.

BACKGROUND: Shared genetic risk between schizophrenia (SCZ) and bipolar disorder (BD) is well-established, yet the extent to which they share environmental risk factors remains unclear. We compare the associations between environmental exposures during childhood/prior to disorder onset with the risk of developing SCZ and BD. METHODS: We conducted a Swedish register-based nested case-control study using 4184 SCZ cases and 18 681 BD cases diagnosed 1988-2013. Cases were matched to five controls by birth year, birth region, and sex. Conditional logistic regression was used to estimate incidence rate ratios (IRR) for SCZ and BD for each exposure (severe childhood infections, adverse childhood experiences (ACEs), substance use disorders (SUDs), urban birth/longest residence). RESULTS: All SUD types were associated with very high risk (IRR 4.9-25.5), and all forms of ACEs with higher risk (IRR 1.5-4.3) for both disorders. In the mutually adjusted models, ACEs demonstrated slightly higher risk for BD (SCZ IRR 1.30, 1.19-1.42; BD IRR 1.49, 1.44-1.55), while for SUD, risk was higher for SCZ (SCZ IRR 9.43, 8.15-10.92; BD IRR 5.50, 5.15-5.88). Infections were associated with increased risk of BD (IRR 1.21, 1.17-1.26) but not SCZ. Urban birth and urban longest residence were associated with higher risk of SCZ (IRR 1.19, 1.03-1.37), while only the combination of urban birth and rural longest residence showed higher risk for BD (IRR 1.24, 1.13-1.35). CONCLUSIONS: There were both shared and unique environmental risk factors: SUDs and ACEs were risk factors for both disorders, while infections were more strongly associated with BD and urbanicity with SCZ.

Luxenburger's 1939 Essay on "Schizophrenia and its Hereditary Circle".

In 1939, Hans Luxenburger published a detailed overview of the current status of schizophrenia genetics research, reaching six major conclusions. First, schizophrenia is clearly a hereditary disease. Second, however, schizophrenia is not the hereditary trait itself but rather the consequences of a slowly developing biological progress, the nature of which remains entirely unknown. Third, the full manifestation of the disorder requires certain environmental influences that must come into play. In around 30% of cases, the environment can inhibit hereditary factors so that the predisposition does not manifest in schizophrenia. Fourth, the mode of inheritance of schizophrenia remains unknown, although recessivity is more likely than dominance and monomerism is more likely than polymerism. Fifth, current evidence suggests that schizophrenia is likely etiologically homogenous. Sixth, schizophrenia is part of a hereditary circle that includes "normal" variants of the human personality (schizothymia), a pathological version of this dimension (schizoidia), and other schizophrenia-like delusional syndromes. Luxenburger is skeptical of efforts to clarify further Mendelian transmission models in the absence of pathophysiological markers because schizophrenia cannot serve as a typical phenotype for genetic analysis. By contrast, he strongly supports empirical work on hereditary prognosis, which does not depend on assumptions about any particular phenotype-genotype relationship.

Are Psychiatric Disorders Brain Diseases?-A New Look at an Old Question.

This Viewpoint discusses whether psychiatric disorders are diseases of the brain.

Pattern of Risks for Psychiatric and Substance Use Disorders in the Offspring of Parents With Alcohol Use Disorder.

OBJECTIVE: The authors sought to clarify the components of the familial liability to alcohol use disorder (AUD) by examining parent-offspring transmission in a large Swedish population sample. METHODS: To this end, 1,244,516 offspring in intact families with a mean age at follow-up of 37.7 years (SD=6.8) were examined. Hazard ratios for offspring of parents with AUD were calculated using Cox models for risk of five disorders assessed from Swedish medical and criminal registries: AUD, drug use disorders, attention deficit hyperactivity disorder, major depression, and anxiety disorders. RESULTS: The hazard ratio for the offspring was highest for AUD (hazard ratio=2.36), followed by drug use disorder (hazard ratio=2.04), attention deficit hyperactivity disorder (hazard ratio=1.82), major depression (hazard ratio=1.43), and anxiety disorder (hazard ratio=1.43). The risks for AUD were statistically indistinguishable between the children having mothers with AUD compared with those having fathers with AUD and between sons and daughters of a parent with AUD. All risks for offspring having two parents with AUD were higher than those having one parent with AUD, but the increase with two parents with AUD was greatest for AUD, followed by drug use disorder and attention deficit hyperactivity disorder. Age at AUD onset of the parents predicted risk among the offspring more strongly for AUD and drug use disorder, followed by attention deficit hyperactivity disorder, and then major depression and anxiety disorders. Number of recurrences of the parents with AUD predicted risks for all disorders equally. The risk pattern of disorders for the offspring of not-lived-with fathers with AUD was similar to that in the main analysis of intact families. No evidence was found for sex-specific transmission of AUD or a familial female protective effect. CONCLUSIONS: Familial and likely genetic liability to AUD has three components: a nonspecific risk of common internalizing and externalizing disorders, a moderately specific risk of externalizing disorders, and a highly specific risk of AUD.

Genome-wide association analyses using machine learning-based phenotyping reveal genetic architecture of occupational creativity and overlap with psychiatric disorders.

Creativity is known to be heritable and exhibits familial aggregation with psychiatric disorders; however, the complex nature of their relationship has not been well-established. In the present study, we demonstrate that using an expanded and validated machine learning (ML)-based phenotyping of occupational creativity (OC) can allow us to further understand the trait of creativity, which was previously difficult to define and study. We conducted the largest genome-wide association study (GWAS) on OC with 241,736 participants from the UK Biobank and identified 25 lead variants that have not yet been reported and three candidate causal genes that were previously associated with educational attainment and psychiatric disorders. We found extensive genetic overlap between OC and psychiatric disorders with mixed effect direction through various post-GWAS analyses, including the bivariate causal mixture model. In addition, we discovered a strongly genetic correlation between our original GWAS and the GWAS adjusted for education years (rg = 0.95). Our GWAS analysis via ML-based phenotyping contributes to the understanding of the genetic architecture of creativity, which may inform genetic discovery and genetic prediction in human cognition and psychiatric disorders.

The genetic epidemiology of schizotypal personality disorder.

BACKGROUND: The concept of schizotypal personality disorder (SPD) emerged from observations of personality characteristics common in relatives of schizophrenic patients. While often studied in family designs, few studies and none with genetic measures, have examined SPD in epidemiological samples. METHODS: We studied individuals born in Sweden 1940-2000 with an ICD-10 diagnosis of SPD with no prior schizophrenia (SZ) diagnosis (n = 2292). Demographic features, patterns of comorbidity, and Family Genetic Risk Scores (FGRS) were assessed from multiple Swedish registries. Prediction of progression to SZ was assessed by Cox models. RESULTS: SPD was rare, with a prevalence of 0.044%, and had high levels of comorbidity with autism spectrum disorder (ASD), OCD, ADHD, and major depression (MD), and increased rates of being single, unemployed and in receipt of welfare. Affected individuals had elevated levels of FGRS for SZ (+0.42), ASD (+0.30), MD (+0.29), and ADHD (+0.20). Compared to cases of schizophrenia, they had significantly lower rates of FGRSSZ, but significantly elevated rates of genetic risk for ASD, MD, and ADHD. Over a mean follow-up of 8.7 years, 14.6% of SPD cases received a first diagnosis of SZ, the risk for which was significantly increased by levels of FGRSSZ, male sex, young age at SPD diagnosis and an in-patient SPD diagnosis and significantly decreased by comorbidity with MD, ASD, and ADHD. CONCLUSIONS: Our results not only support the designation of SPD as a schizophrenia spectrum disorder but also suggest potentially important etiologic links between SPD and ASD and, to a lesser extent, ADHD, OCD, and MD.

The predictive effect of family genetic risk scores as an indirect measure of causal effects of one disorder on another.

BACKGROUND: One potential cause of comorbidity is the direct causal effect of one disorder - A - on risk for subsequent onset of disorder B. Could genetic risk scores be utilized to test for such an effect? If disorder A causally impacts on risk for disorder B, then genetic risk for disorder A should be lower in cases of disorder A with v. without a prior onset of B. METHODS: In all individuals (n = 905 736) born in Sweden from 1980 to 1990, from six psychiatric and drug use disorders (major depression, anxiety disorders, alcohol use disorder, drug use disorder, bipolar disorder, and schizophrenia), we formed 14 pairs of disorders A and B. In these pairs, we compared, using Cox proportional hazards models, the predictive effect of the familial-genetic risk score (FGRS) for disorder B in those who had v. had not had a prior onset of disorder A. RESULTS: In all pairs, the impact of the FGRS for disorder B was significantly stronger in cases without v. with a prior history of disorder A. These effects were similar across sex, stable across levels of FGRS and not likely due to clinician bias. In many of our disorder pairs, previous clinical studies suggest a mechanism for a causal effect of disorder A on B. CONCLUSIONS: Our findings provide indirect evidence that the occurrence of one psychiatric or substance use disorder often has a causal effect on risk for subsequent disorders. This mechanism may substantially contribute to the widespread comorbidity among psychiatric conditions.

Joseph Guislain's writings on melancholia from 1835 and 1852.

Over the course of the 19th century, the concept of melancholia morphed from a partial insanity defined by disorders of judgment to a disorder characterized primarily by mood disturbances. The francophone Belgian psychiatrist Joseph Guislain, whose work has not been previously translated into English, played an important role in this transition. We translate and comment upon two of his key descriptions of melancholia from 1835 and 1852, emphasizing the following 5 features. First, his concept of melancholia is quite "modern" meeting all DSM-5 criteria for major depression. Second, his clinical descriptions are vivid, often giving voice to his patients. Third, other aspects of his text reflect older concepts, including 17th century melancholic subtypes. Fourth, and of particular historical import, he was, in 1835, likely the first major European alienist to argue that nonpsychotic melancholia was an important form of the disorder and a legitimate mental illness. This represented key step in the transition of melancholia from a psychotic to a mood disorder and also helped expand the 18th century model of insanity which was as restricted solely to disturbances of judgment/imagination. Fifth, beginning with his 1835 writings, but more prominently in his 1852 text, Guislain emphasizes that melancholia is a form of phrenalgia - mental pain. In so doing, he played an important role in helping initiate this influential psychophysiological theory of melancholia that was championed by Wilhelm Griesinger and other important German and English psychiatrists later in the 19th century.

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.