Psychiatric genetics and the structure of psychopathology

For over a century, psychiatric disorders have been defined by expert opinion and clinical observation. The modern DSM has relied on a consensus of experts to define categorical syndromes based on clusters of symptoms and signs, and, to some extent, external validators, such as longitudinal course and response to treatment. In the absence of an established etiology, psychiatry has struggled to validate these descriptive syndromes, and to define the boundaries between disorders and between normal and pathologic variation. Recent advances in genomic research, coupled with large-scale collaborative efforts like the Psychiatric Genomics Consortium, have identified hundreds of common and rare genetic variations that contribute to a range of neuropsychiatric disorders. At the same time, they have begun to address deeper questions about the structure and classification of mental disorders: To what extent do genetic findings support or challenge our clinical nosology? Are there genetic boundaries between psychiatric and neurologic illness? Do the data support a boundary between disorder and normal variation? Is it possible to envision a nosology based on genetically informed disease mechanisms? This review provides an overview of conceptual issues and genetic findings that bear on the relationships among and boundaries between psychiatric disorders and other conditions. We highlight implications for the evolving classification of psychopathology and the challenges for clinical translation

Genetic and Environmental Structure of DSM-IV Criteria for Antisocial Personality Disorder: A Twin Study

Results from previous studies on DSM-IV and DSM-5 Antisocial Personality Disorder (ASPD) have suggested that the construct is etiologically multidimensional. To our knowledge, however, the structure of genetic and environmental influences in ASPD has not been examined using an appropriate range of biometric models and diagnostic interviews. The 7 ASPD criteria (section A) were assessed in a population-based sample of 2794 Norwegian twins by a structured interview for DSM-IV personality disorders. Exploratory analyses were conducted at the phenotypic level. Multivariate biometric models, including both independent and common pathways, were compared. A single phenotypic factor was found, and the best-fitting biometric model was a single-factor common pathway model, with common-factor heritability of 51% (95% CI 40–67%). In other words, both genetic and environmental correlations between the ASPD criteria could be accounted for by a single common latent variable. The findings support the validity of ASPD as a unidimensional diagnostic construct

Longitudinal Stability of Genetic and Environmental Influences on Irritability: From Childhood to Young Adulthood.

OBJECTIVE: Little is known about genetic influences on juvenile irritability and whether such influences are developmentally stable and/or dynamic. This study examined the temporal pattern of genetic and environmental effects on irritability using data from a prospective, four-wave longitudinal twin study. METHOD: Parents and their twin children (N=2,620 children) from the Swedish Twin Study of Child and Adolescent Development reported on the children's irritability, defined using a previously identified scale from the Child Behavior Checklist. RESULTS: Genetic effects differed across the sexes, with males exhibiting increasing heritability from early childhood through young adulthood and females exhibiting decreasing heritability. Genetic innovation was also more prominent in males than in females, with new genetic risk factors affecting irritability in early and late adolescence for males. Shared environment was not a primary influence on irritability for males or females. Unique, nonshared environmental factors suggested strong effects early for males followed by an attenuating influence, whereas unique environmental factors were relatively stable for females. CONCLUSIONS: Genetic effects on irritability are developmentally dynamic from middle childhood through young adulthood, with males and females displaying differing patterns. As males age, genetic influences on irritability increase while nonshared environmental influences weaken. Genetic contributions are quite strong in females early in life but decline in importance with age. In girls, nonshared environmental influences are fairly stable throughout development.The National Institutes of Health/National Institute of Mental HealthPublishe

The Genesis 12–19 (G1219) Study: A Twin and Sibling Study of Gene–Environment Interplay and Adolescent Development in the UK

The Genesis 12–19 (G1219) Study is an ongoing longitudinal study of a sample of UK twin pairs, non-twin sibling pairs, and their parents. G1219 was initially designed to examine the role of gene–environment interplay in adolescent depression. However, since then data have continued to be collected from both parents and their offspring into young adulthood. This has allowed for longitudinal analyses of depression and has enabled researchers to investigate multiple phenotypes and to ask questions about intermediate mechanisms. The study has primarily focused on emotional development, particularly depression and anxiety, which have been assessed at multiple levels of analysis (symptoms, cognitions, and relevant environmental experiences). G1219 has also included assessment of a broader range of psychological phenotypes ranging from antisocial behaviors and substance use to sleep difficulties, in addition to multiple aspects of the environment. DNA has also been collected. The first wave of data collection began in the year 1999 and the fifth wave of data collection will be complete before the end of 2012. In this article, we describe the sample, data collection, and measures used. We also summarize some of the key findings to date

The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies

Bone and mineral researc

Caffeine Consumption, Toxicity, Tolerance and Withdrawal; Shared Genetic Influences With Normative Personality and Personality Disorder Traits

Public Health Significance Both the amount of caffeine people consume and their response to caffeine is heritable. A modest proportion of the genetic influences underlying caffeine use and response is shared with personality and personality disorder traits. Our main aim was to estimate the extent of overlapping etiology between caffeine consumption and response and normative and pathological personality. Linear mixed-effects models were used to identify normative personality domains and personality disorder (PD) traits for inclusion in multivariate twin analyses together with individual caffeine related measures. Data were obtained from Norwegian adult twins in a face-to-face interview conducted in 1999-2004 as part of a population-based study of mental health and through self-report in 2010-2011 and 2015-2017. Personality disorder data was available for 2,793 twins, normative personality for 3,889 twins, and caffeine for 3,862 twins (mean age 43.0 years). Normative personality was assessed using the self-reported Big Five Inventory, PD traits were assessed by the Structured Interview for DSM-IV Personality, and caffeine consumption, toxicity, tolerance, and withdrawal were assessed through a self-report questionnaire developed at the Norwegian Institute of Public Health. Caffeine measures were found to be moderately heritable, h(2) = 30.1%-45.0%. All normative personality domains and four PD traits, antisocial, borderline, dependent and paranoid, were significantly associated with at least one caffeine variable. A small proportion of variance in caffeine consumption was attributable to genetic factors shared with normative personality (1.3%) and personality disorders (11.4%). A modest proportion of variance in caffeine tolerance and toxicity was attributable to genetic factors shared with both normative personality (26.9%, 24.8%) and personality disorders (21.0%, 36.0%). The present study found caffeine consumption and response to be heritable and provides evidence that a small to-modest proportion of this genetic etiology is shared with both normative and pathological personality.Peer reviewe

Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity

BACKGROUND: Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-alpha induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines. OBJECTIVES: To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing. METHODS: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression. RESULTS: Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6. CONCLUSIONS: Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokine

A genetic analysis of coffee consumption in a sample of Dutch twins

Caffeine is by far the most commonly used psycho-active substance. Caffeine is consumed regularly as an ingredient of coffee. Coffee consumption and coffee preference was explored in a sample of 4,495 twins (including 1,231 pairs) registered with the Netherlands Twin Registry. Twin resemblance was assessed by tetrachoric correlations and the influence of both genetic and environmental factors was explored with model fitting analysis in MX. Results showed moderate genetic influences (39%) on coffee consumption. The remaining variance was explained by shared environmental factors (21%) and unique environmental factors (40%). The variance in coffee preference (defined as the proportion of coffee consumption relative to the consumption of coffee and tea in total) was explained by genetic factors (62%) and unique environmental factors (38%)

The Silent Side of the Spectrum: Schizotypy and the Schizotaxic Self

The identification of individuals carrying unexpressed genetic liability to schizophrenia is crucial for both etiological research and clinical risk stratification. Subclinical psychopathological features detectable in the nonpsychotic part of the schizophrenia spectrum could improve the delineation of informative vulnerability phenotypes. Inspired by Meehl's schizotaxia-schizotypy heuristic model, we tested anomalous subjective experiences (self-disorders, SDs) as a candidate vulnerability phenotype in a sample of nonpsychotic, genetically high-risk subjects. A total of 218 unaffected members of 6 extended multiplex families (assessed between 1989 and 1999 during the Copenhagen Schizophrenia Linkage Study) were stratified into 4 groups of increasing psychopathological expressivity: no mental illness (NMI), no mental illness with schizotypal traits (NMI-ST), personality disorders not fulfilling other personality disorders (OPDs), and schizotypal personality disorder (SPD). We tested the distribution of SDs among the subgroups, the effect of SDs on the risk of belonging to the different subgroups, and the effect of experimental grouping and concomitant psychopathology (ie, negative symptoms (NSs) and subpsychotic formal thought disorder [FTD]) on the chances of experiencing SDs. SDs distribution followed an incremental pattern from NMI to SPD. SDs were associated with a markedly increased risk of NMI-ST, OPDs, or SPD. The odds of SDs increased as a function of the diagnostic category assignment, independently of sociodemographics and concomitant subclinical psychopathology (NSs and FTD). The results support SDs as an expression of schizotaxic vulnerability and indicate a multidimensional model of schizotypy—characterized by SDs, NSs, FTD—as a promising heuristic construct to address liability phenotypes in genetically high-risk studies

The role of osteoanabolic agents in the management of patients with osteoporosis

Reducing fracture risk is the objective of osteoporosis treatment. Bone-forming osteoporosis drugs increase bone mass, restore bone microarchitecture, and reduce fracture risk more effectively than oral bisphosphonates, providing strong justification for the use of these agents as the initial therapy or after anti-remodeling agents in patients at very high risk of fracture. At the end of a 12-to-24-month course of osteoanabolic therapy, transitioning to a potent anti-remodeling agent maintains and enhances the treatment benefit. This review describes the clinical applications of osteoanabolic therapy for osteoporosis