Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Patients' perspectives regarding induction of labor in the absence of maternal and fetal indications: are our patients ready for the ARRIVE trial?

BACKGROUND: After careful review of the ARRIVE trial (A Randomized Trial of Induction Versus Expectant Management) data, induction of labor prior to one's due date in the absence of maternal and fetal indications (which the American College of Obstetricians and Gynecologists currently refers to as "elective") is now endorsed as a "reasonable" option by the American College of Obstetricians and Gynecologists (ACOG). As a result, there has been much discussion among providers regarding how best to operationalize this ACOG recommendation into shared decision making regarding delivery planning. However, we lack a formal understanding of the perspectives of patients themselves on this topic. OBJECTIVE: To assess patient understanding and preference for induction of labor prior to one's due date. MATERIALS AND METHODS: We conducted an anonymous, cross-sectional survey of women in their third trimester of pregnancy presenting for routine obstetric care in August 2018. The survey included a series of questions designed to assess basic demographics, obstetric history, and patient understanding and opinions about the practice of induction of labor, with a focus on induction of labor prior to one's due date in the absence of maternal and fetal indications. RESULTS: A total of 108 women were approached for participation, and 100 women participated in this survey (93% participation). Of the participants, 99% were supportive of induction of labor for fetal indications, and 96% were supportive for maternal indications prior to one's due date. In contrast, 54% of participants were not interested in induction of labor in the absence of maternal and fetal indications prior to one's due date. Women opposed to induction of labor in the absence of maternal and fetal indications were almost 4 times more likely to be concerned about the possibility that induction of labor in the absence of maternal and fetal indications could cause fetal harm (odds ratio, 3.9; confidence interval, 1.2-13.2). CONCLUSION: Nearly all women surveyed in our pilot study were interested in induction of labor prior to one's due date for maternal or fetal indications. 46% of those surveyed were interested in induction of labor in the absence of maternal and fetal indications prior to their due date. Concern about potential fetal harm was more likely among women opposed to induction of labor in the absence of maternal and fetal indications. As providers discuss delivery planning with their patients, these results may provide a useful context for operationalizing and individualizing the results of the ARRIVE trial for their patients.

Interaction between genetic variants and exposure to Hurricane Katrina on post-traumatic stress and post-traumatic growth: a prospective analysis of low income adults.

BACKGROUND: There is considerable variation in psychological reactions to natural disasters, with responses ranging from relatively mild and transitory symptoms to severe and persistent posttraumatic stress (PTS). Some survivors also report post-traumatic growth (PTG), or positive psychological changes due to the experience and processing of the disaster and its aftermath. Gene-environment interaction (GxE) studies could offer new insight into the factors underlying variability in post-disaster psychological responses. However, few studies have explored GxE in a disaster context. METHODS: We examined whether ten common variants in seven genes (BDNF, CACNA1C, CRHR1, FKBP5, OXTR, RGS2, SLC6A4) modified associations between Hurricane Katrina exposure and PTS and PTG. Data were from a prospective study of 205 low-income non-Hispanic Black parents residing in New Orleans prior to and following Hurricane Katrina. RESULTS: We found a significant association (after correction) between RGS2 (rs4606; p=0.0044) and PTG, which was mainly driven by a cross-over GxE (p=0.006), rather than a main genetic effect (p=0.071). The G (minor allele) was associated with lower PTG scores for low levels of Hurricane exposure and higher PTG scores for moderate and high levels of exposure. We also found a nominally significant association between variation in FKBP5 (rs1306780, p=0.0113) and PTG, though this result did not survive correction for multiple testing. LIMITATIONS: Although the inclusion of low-income non-Hispanic Black parents allowed us to examine GxE among a highly vulnerable group, our findings may not generalize to other populations or groups experiencing other natural disasters. Moreover, not all participants invited to participate in the genetic study provided saliva. CONCLUSIONS: To our knowledge, this is the first study to identify GxE in the context of post-traumatic growth. Future studies are needed to clarify the role of GxE in PTS and PTG and post-disaster psychological responses, especially among vulnerable populations.

Dissociable genetic contributions to error processing: a multimodal neuroimaging study.

BACKGROUND: Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation. METHODS: We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response. RESULTS: We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant. CONCLUSIONS: DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.

The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function.

BACKGROUND: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. METHODS: We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals. RESULTS: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age ≤ 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048). CONCLUSIONS: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD.

An experimental evaluation of patient decision aid design to communicate the effects of medications on the rate of progression of structural joint damage in rheumatoid arthritis.

OBJECTIVE: To explore how effectively information presentation formats used in a patient decision aid communicated the ability of a disease modifying anti-rheumatic drug to slow the rate of progression of rheumatoid arthritis related structural joint damage (SJD). METHODS: 91 first year psychology students and 91 RA patients participated in a prospective randomized, single blind, factorial experimental design evaluating the effect of four information formats on: satisfaction with risk communication, verbatim and gist recall of a hypothetical anti-rheumatic drug's ability to slow the rate of progression of SJD. RESULTS: Both groups underestimated the hypothetical drug's ability to slow SJD. Formats that supported the narrative statement with a reinforcing graphic element resulted in recall closer to the true value. Comparison of the results from testing of RA patients and college students were remarkably similar across formats. CONCLUSION: Rate of progression as communicated by narrative statement plus a graphic element (i.e. speedometer metaphor or pictograph) aided recall better than a narrative statement alone. Our results suggest that testing decision aid components with non-patients may provide data generalizable to patient populations. PRACTICE IMPLICATIONS: Graphics must be used carefully in patient decision aids as they can enhance recall, but may also introduce unintended recall bias.

Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants.

OBJECTIVE: To examine the association between exposure to newer antidepressants and risk of gastrointestinal (GI) and other bleeding complications among individuals with major depressive disorder (MDD). DESIGN: This study uses an incident user cohort design to compare associations between incidence of vascular/bleeding events and the relative affinity (low, moderate or high) of the antidepressant for the serotonin transporter during an exposure risk period for each patient. SETTING: New England healthcare system electronic medical record database. PARTICIPANTS: 36 389 individuals with a diagnosis of MDD and monotherapy with a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor or other new-generation antidepressant were identified from among 3.1 million patients in a New England healthcare system. PRIMARY AND SECONDARY OUTCOME MEASURES: Rates of bleeding or other vascular complications, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures. RESULTS: 601 GI bleeds were observed in the 21 462 subjects in the high-affinity group versus 333 among the 14 927 subjects in the lower affinity group (adjusted RR: 1.17, 95% CI 1.02 to 1.34). Similarly, 776 strokes were observed in the high-affinity group versus 434 in the lower affinity treatment group (adjusted RR: 1.18, 95% CI 1.06 to 1.32). No significant association with risk for a priori negative control outcomes, including acute liver failure, acute renal failure, asthma, breast cancer and hip fractures, was identified. CONCLUSIONS: Use of antidepressants with high affinity for the serotonin transporter may confer modestly elevated risk for GI and other bleeding complications. While multiple methodologic limitations must be considered, these results suggest that antidepressants with lower serotonin receptor affinity may be preferred in patients at greater risk for such complications.

Antidepressant response in patients with major depression exposed to NSAIDs: a pharmacovigilance study.

OBJECTIVE It has been suggested that there is a mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with antidepressant response, and poorer outcomes among NSAID-treated patients were reported in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. To attempt to confirm this association in an independent population-based treatment cohort and explore potential confounding variables, the authors examined use of NSAIDs and related medications among 1,528 outpatients in a New England health care system. METHOD Treatment outcomes were classified using a validated machine learning tool applied to electronic medical records. Logistic regression was used to examine the association between medication exposure and treatment outcomes, adjusted for potential confounding variables. To further elucidate confounding and treatment specificity of the observed effects, data from the STAR*D study were reanalyzed. RESULTS NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio=1.55, 95% CI=1.21-2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables. CONCLUSIONS These results support an association between NSAID use and poorer antidepressant outcomes in major depressive disorder but indicate that some of the observed effect may be a result of confounding.