Statistical Methods for Health Care Research

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Psychopharmacology: The Fourth Generation of Progress.

The term 'Borderline Personality Disorder' (BPD) refers to a psychiatric syndrome that is characterized by emotion dysregulation, impulsivity, risk-taking behavior, irritability, feelings of emptiness, self-injury and fear of abandonment, as well as unstable interpersonal relationships. BPD is not only common in psychiatric populations but also more prevalent in the general community than previously thought, and thus represents an important public health issue. In contrast to most psychiatric disorders, some symptoms associated with BPD may improve over time, even without therapy, though impaired social functioning and interpersonal disturbances in close relationships often persist. Another counterintuitive and insufficiently resolved question is why depressive symptoms and risk-taking behaviors can occur simultaneously in the same individual. Moreover, there is an ongoing debate about the nosological position of BPD, which impacts on research regarding sex differences in clinical presentation and patterns of comorbidity.In this review, it is argued that many features of BPD may be conceptualized within an evolutionary framework, namely behavioral ecology. According to Life History Theory, BPD reflects a pathological extreme or distortion of a behavioral 'strategy' which unconsciously aims at immediate exploitation of resources, both interpersonal and material, based on predictions shaped by early developmental experiences. Such a view is consistent with standard medical conceptualizations of BPD, but goes beyond classic 'deficit'-oriented models, which may have profound implications for therapeutic approaches.

Borderline Personality Disorder Why ‘fast and furious’?

Borderline personality disorder (BPD) is characterized by interpersonal difficulties, whereby patients are negatively biased concerning the evaluation of others' trustworthiness. Here, we examined the effect of oxytocin on interpersonal behavior of BPD patients in a trust game, emphasizing the assessment of facial attractiveness of the patients' counterparts in the game, and patients' history of childhood trauma. Thirteen BPD patients and thirteen healthy controls played a trust game after receiving oxytocin or placebo in a randomized, double-blind crossover design. Childhood trauma was evaluated using the Childhood Trauma Questionnaire (CTQ). Patients transferred less money in the oxytocin condition compared to placebo. While healthy controls transferred more money units (MUs) to attractive counterparts than to unattractive ones only after the administration of oxytocin, BPD patients showed this pattern in both conditions. Emotional neglect during childhood negatively correlated with the amount of MUs transferred by patients under oxytocin, but not placebo. Oxytocin had a trust-lowering effect in BPD, which was correlated with patients' history of childhood trauma. Patients' evaluation of interpersonal trust seems to depend more on attractiveness features of their counterparts than in controls, a finding that may have important implications for further research on the usefulness of "prosocial" peptides as an adjunct to psychotherapeutic interventions.

Modulation of interpersonal trust in borderline personality disorder by intranasal oxytocin and childhood trauma.

Effects of acute oral Δ9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.

Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists

Acute effects of Δ9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity

Impaired social cognition has been associated with interpersonal problems and with the development of and relapse into alcohol abuse. In the present study, self-reported trait empathy, decoding of complex mental states and cognitive and affective mental state reasoning were assessed in alcohol-dependent participants, and the association with executive function and psychopathological characteristics was investigated. Twenty recently detoxified alcohol-dependent patients and 20 matched healthy controls were assessed with an abbreviated German version of the Interpersonal Reactivity Index, the Revised Reading the Mind in the Eyes Test, the Faux Pas Story Test, the Trail Making Test and the Letter–Number-Sequencing Test. Patients were impaired relative to controls with regard to mental state decoding on the Eyes Test and showed reduced faux pas detection and impaired mental state reasoning reflected by lower faux pas understanding and faux pas empathy scores. There were no group differences regarding self-reported trait empathy. Performance on the sociocognitive measures was related to executive functioning and the severity of depressive symptoms. Although self-report measures might not always reliably detect impairments of social cognition, behavioural measures suggest pronounced impairments of mental state decoding and mental state reasoning in association with alcohol dependence. Findings ought to be incorporated into current treatment strategies.

Patrik Roser

Papers

Modulation of interpersonal trust in borderline personality disorder by intranasal oxytocin and childhood trauma.

Effects of acute oral Δ9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers

Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists

Acute effects of Δ9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity

Mental state decoding and mental state reasoning in recently detoxified alcohol-dependent individuals.