Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations.

Background: The prevalence of co-occurring heavy alcohol consumption and obesity is increasing in the United States. Despite neurobiological overlap in the regulation of alcohol consumption and eating behavior, alcohol- and body mass index (BMI)-related phenotypes show no or minimal genetic correlation. We hypothesized that the lack of genetic correlation is due to mixed effect directions of variants shared by AUD and BMI. Methods: We applied MiXeR, to investigate shared genetic architecture between AUD and BMI in individuals of European ancestry. We used conjunctional false discovery rate (conjFDR) analysis to detect loci associated with both phenotypes and their directional effect, Functional Mapping and Annotation (FUMA) to identify lead single nucleotide polymorphisms (SNPs), Genotype-Tissue Expression (GTEx) samples to examine gene expression enrichment across tissue types, and BrainXcan to evaluate the shared associations of AUD and BMI with brain image-derived phenotypes. Results: MiXeR analysis indicated polygenic overlap of 80.9% between AUD and BMI, despite a genetic correlation (r g ) of -.03. ConjFDR analysis yielded 56 lead SNPs with the same effect direction and 76 with the opposite direction. Of the 132 shared lead SNPs, 53 were novel for both AUD and BMI. GTEx analyses identified significant overexpression in the frontal cortex (BA9), hypothalamus, cortex, anterior cingulate cortex (BA24), hippocampus, and amygdala. Amygdala and caudate nucleus gray matter volumes were significantly associated with both AUD and BMI in BrainXcan analyses. Conclusions: More than half of variants significantly associated with AUD and BMI had opposite directions of effect for the traits, supporting our hypothesis that this is the basis for their lack of genetic correlation. Follow-up analyses identified brain regions implicated in executive functioning, reward, homeostasis, and food intake regulation. Together, these findings clarify the extensive polygenic overlap between AUD and BMI and elucidate several overlapping neurobiological mechanisms.

N-acetylcysteine as a treatment for substance use cravings: A meta-analysis.

N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. There were no between-group differences in risk of AEs. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.

Perceived control is significantly associated with psychological adaptation in individuals with known or suspected inborn errors of immunity.

Inborn errors of immunity (IEIs) are rare genetic disorders characterized by increased susceptibility to infection and immune system dysregulation. Despite the significant physical toll of IEIs, there is less information on clinical and patient-reported biopsychosocial outcomes and how these individuals psychologically adapt. We invited adults with IEIs or suspected IEIs (sIEIs) enrolled on a protocol at the National Institutes of Health to complete a cross-sectional survey measuring patient-reported biopsychosocial outcomes, psychological adaptation, and perceived control. We received responses from 312 individuals. Levels of adaptation to illness were similar to previously published cohorts of individuals with chronic health conditions. Participants reported significantly increased levels of anxiety, pain, sleep disturbance, and fatigue and significantly lower levels of physical functioning compared to the general population (p < 0.05). Multiple linear regression analysis indicated that perceived present control was significantly positively associated with adaptation (ß = 0.26, p < 0.05). We found that perceived present control was significantly associated with psychological adaptation. Individuals with sIEIs in our sample struggled with poorer biopsychosocial outcomes than the general population, although these may not ultimately be directly related to psychological adaptation. Interventions to increase perceived control may be beneficial to this patient population. Clinicians should also consider screening and management for psychological and physical concerns including anxiety, depression, sleep disturbance, pain, and fatigue.

Research participants' perspectives about the return of uninformative genomic test results in a clinical research setting.

The majority of genomic sequencing and microarray results are clinically uninformative, meaning that they do not suggest a need for any behavioral action or medical intervention. Prior studies have shown that recipients of uninformative genomic testing results ("uninformative results" hereafter) may incorrectly interpret them to imply a lowered risk of disease or false reassurance about future health risks. Few studies have examined how patients understand uninformative results when they are returned in a research setting, where there is wide variation in analytical specifications of testing, interpretation and reporting practices, and resources to support the return of results. We conducted cross-sectional interviews (N = 17) to explore how a subset of research participants in one genomics study at the National Institutes of Health reacted to and understood their uninformative test results, which were returned to them via a patient portal without genetic counseling. We found that most participants did not remember the details of the informed consent process, including the distinction between "primary" and "secondary" findings. Participants had questions about what genes were tested for and, in most cases, requested a list of the genes covered. Several participants incorrectly assumed that autosomal recessive carrier results would have been reported to them if detected. Some participants interpreted their uninformative results to mean that they could forgo prenatal testing, and participants had mixed expectations about whether their results might be reinterpreted in the future. These themes suggest that there are specific challenges to returning uninformative results in research settings. Educational supplements to uninformative test reports may be most useful if they contextualize results in relation to other types of clinical genetic or genomic testing that may be made available to research participants in their lifetimes.

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.

Purpose: Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI. Methods: We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. Results: Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone. Conclusion: Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

The contribution of rare copy number variants in FAS toward pathogenesis of autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphadenopathy, splenomegaly, cytopenias, and other autoimmune manifestations. ALPS is caused by lymphocyte accumulation from defects in FAS-mediated apoptosis. Heterozygous germline or somatic pathogenic single nucleotide variants in FAS are the most common molecular etiology of ALPS. Through the Centralized Sequencing Program at the National Institute of Allergy and Infectious Diseases, we performed exome sequencing on subjects with a clinical diagnosis of ALPS, with a subset receiving copy number variant (CNV) analysis. In this cohort, we identified 3 subjects from unrelated families with CNVs at the FAS locus. One subject had a de novo ∼0.828 Mb copy number loss encompassing all of FAS. The second subject had a maternally inherited ∼1.004 Mb copy number loss encompassing all of FAS. The third subject had a paternally inherited ∼0.044 Mb copy number loss encompassing exons 7 through 9 of FAS. Subjects with deletions in FAS had clinical presentations and biomarker profiles similar to those with ALPS and with germline and somatic FAS variants. We demonstrate that CNV analysis should be pursued if there is clinical and biomarker evidence of ALPS because it can lead to a molecular diagnosis and appropriate treatment when FAS sequencing is inconclusive.

Assessing genetic counselor communication in response to virtual, asynchronous simulated video prompts.

Online methods of teaching and assessing communication skills meet not only the need for remote education during the COVID-19 pandemic but also future demand for flexible training methods. This study aimed to explore the utility of standardized video prompts intended to elicit samples of genetic counselors' (GCs') interpersonal, psychosocial, and counseling skills by describing variation in GCs' socioemotional communication during their responses to a series of videotaped communication challenges. We analyzed the previously recorded communication of 43 GCs responding to a set of videotaped simulated client prompts related to a cancer or prenatal counseling session. We applied the Roter Interaction Analysis System to the prompts and GCs' responses, focusing on the proportion of socioemotional content as an indicator of interpersonal, psychosocial, and counseling skill use. We analyzed the responses of 21 GCs to the cancer prompts and 22 GCs to the prenatal prompts. Two-sample t tests explored differences in the proportion of socioemotional content in GCs' responses to prompts within and across the two scenarios. Overall, socioemotional statements accounted for 31% (SD = 8%) of all GC statements in response to the prenatal prompts and 36% (SD = 9%) of statements in response to the cancer prompts (Bonferroni-adjusted p=.49). The proportion of socioemotional communication in individual prompt responses varied from 4% (SD = 12%) to 76% (SD = 26%) across the cancer prompt series and 10% (SD = 13%) to 76% (SD = 30%) across the prenatal prompt series. Across the two scenarios, two of 10 matched prompts showed significant differences in the proportion of GCs' socioemotional content of the prompt responses (p's < 0.001). These differences appear related to differences in the socioemotional nature of the prompts. These findings inform online methods of communication assessment that are useful during restrictions to in-person learning due to COVID-19, as well as future hybrid training and research efforts.

Exome sequencing study in a clinical research setting finds general acceptance of study returning secondary genomic findings with little decisional conflict.

The most appropriate strategies for managing secondary genomic findings (SF) in clinical research are being developed and evaluated. We surveyed patients at the National Institute of Allergy and Infectious Diseases (NIAID) to evaluate decisional conflict regarding enrolling in a study that returns SF. Responses were collected using a cross-sectional survey after informed consent but before return of SF. Sixty-six adults of 116 eligible participants responded. No participant explicitly declined because they did not want to possibly receive a SF. Sixty-five of 66 (98%) participants thought it was appropriate to return SFs in research; one participant was unsure. Decisional conflict regarding enrolling in a study returning SF was low overall with 68% of participants reporting a score of less than 10 on a 100-point decisional conflict scale, implying that they felt informed, clear on what they wanted, and supported. Lower genetic literacy was weakly associated with higher decisional conflict (Spearman's rho = -0.297, p = .015). Six participants reported confusion related to the choices about SFs. Our data suggest that participants in our study feel it is appropriate to receive SF and have little decisional conflict about potentially receiving such information; however, some participants may need further education and counseling.

Feasibility, face validity, and sensitivity of a web-based simulation tool for assessing genetic counseling communication.

We conducted a test of concept study to explore feasibility, face validity, and sensitivity of an interactive web-based video tool designed to assess communication practices of genetic counselors in response to standardized video prompts. A convenience sample of genetic counselors was recruited from the National Society of Genetic Counselors to respond verbally to a set of brief standardized video prompts from a virtual client in a prenatal genetic counseling session and a cancer genetic counseling session, embedded in an interactive online platform. Participant verbal responses to prompts were captured through a secure voicemail service. A total of 89 participants attempted to use the online tool and 51 (57%) successfully completed the simulation and produced an audio record of their responses. The average length of recordings was 12.2 min. Face validity was high; participants rated the virtual client as similar to clients seen in practice (75% agree; 12% strongly agree, 7% neutral, 6% disagree) and rated their own responses to the virtual client prompts as similar to those in practice (63% agree; 19% strongly agree; 12% neutral, 6% disagree). Feasibility was assessed by ratings of ease of use (57% agreed, 24% strongly agreed, 17% were neutral, and none disagreed). Content checklists showed that the tool was sensitive enough to detect variation in frequency of certain topics discussed by participants that was similar to previous descriptive studies. The test of concept demonstrated feasibility, face validity, and sensitivity of this communication tool with possible applications in research, training, and program evaluation.