Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Survey of genetic counselors identifies a knowledge gap discerning properly regulated cell and gene therapy trials.

BACKGROUND AND AIMS: As cell and gene therapy (CGT) has grown in availability and scope, more unapproved regenerative medicine is being marketed to the public. It is essential that health care providers have sufficient knowledge and comfort to determine whether treatments are properly regulated and address these topics with patients. Due to the applicability of CGT to genetic disease, genetic counselors could be key in providing education and answering patients' questions about these topics. However, previous studies have focused only on physicians' knowledge and comfort with CGT and unapproved regenerative medicine. The purpose of this study was to assess genetic counselors' self-reported knowledge and comfort discussing these topics with patients and to explore what factors predict increased knowledge and comfort. METHODS: The authors designed an online survey distributed to genetic counselors who were part of the National Society of Genetic Counselors Student Research Program e-mail list. The survey addressed genetic counselors' demographics, practice experience with CGT, education about CGT, knowledge and comfort. RESULTS: The survey was completed by 144 genetic counselors. The best predictor of increased knowledge and comfort was experience discussing CGT in practice. In addition, those who worked at an institution at which CGT trials were offered had greater knowledge and comfort. However, most genetic counselors reported their knowledge was not sufficient to address questions from patients, and most had little-to-no knowledge or comfort determining whether a trial was properly regulated. There was no correlation between education and either knowledge or comfort; however, most participants desired more education about these topics. CONCLUSIONS: This study suggests that genetic counselors who (i) have experience with CGT in practice or (ii) work at institutions at which CGT trials are offered may have better knowledge regarding CGT. These results may help identify individuals and/or institutions in whom increasing knowledge regarding CGT could be beneficial. This is crucial as CGT becomes mainstream, leading to more widely marketed unapproved regenerative medicine. Several gaps in knowledge and comfort were identified, including participants' ability to determine whether a treatment is properly regulated. Further research is needed to better characterize the educational needs of genetic counselors surrounding these topics to address these gaps.

The majority of parents of children undergoing genetic testing report preference for earlier genetic counseling appointments.

In the Indiana University Health (IUH) Medical Genetics clinic, certified genetic counselors disclose genetic test results to patients by telephone. The wait-time between a result call-out and a follow-up appointment can vary from weeks to months depending on the medical geneticist's availability. Understanding the experiences that families face during these waiting periods can inform the field regarding what clinical improvements can be made to enhance patients' experiences. Our study explored three topics: the effects of wait-times on parents or patients between a result disclosure and medical genetics follow-up appointment, their anxiety levels during those wait-times, and suggestions for improving parents' and patients' experiences with genetics clinics. Patients or parents who were over 18 years old, who received an initial result call-out between May 2020 and September 2022 prior to a medical genetics follow-up appointment, and who had a diagnostic or a variant of uncertain significance (VUS) genetic test result were recruited for study participation. Individuals were surveyed on their diagnosis, wait-time following result disclosure, feelings during the wait-time, and preferences for result disclosures. The results showed that length of wait-time after a result call-out was not associated with increased anxiety; however, a background in genetics and support group involvement were associated with increased anxiety. The majority of respondents reported that if a genetic counseling-only appointment could occur closer to the time of results call-out, they would prefer to have a genetic counseling-only appointment with a second appointment for medical management with a geneticist later (58.1%). Based on these results, medical genetics clinics should consider implementing genetic counseling-only appointments to reduce wait-times for follow-up appointments.

Genetic counseling program remediation practices for students underperforming in clinical skills: An exploratory study.

Program-level clinical remediation in genetic counseling training programs aims to help students who are underperforming gain clinical skills to successfully manage clinical counseling sessions with patients. Student remediation often requires intervention, including discussions with program leadership and/or a formal remediation plan through the program. This study surveyed genetic counseling program leaders to explore the remediation landscape by identifying skills in which students underperformed, program remediation activities to improve skills, and remediation outcomes. Thirteen participants indicated their program required at least one student to complete program-level clinical remediation during the last 10 years. Eight of the 13 programs (61.5%) required at least one student to participate in clinical remediation for underperformance in professionalism, seven (53.8%) for underperformance in educating patients, six (46.2%) for underperformance in critical thinking, and two (15.4%) for underperformance in demonstrating empathy. Nineteen students were remediated for underperformance in critical thinking. Of those 19 students, one student (5.2%) was dismissed from the training program, and five students (26.3%) chose to withdraw from their program. One of 13 (7.7%) students remediated for underperformance in educating patients and one of 11 (9.1%) students remediated for underperformance in professionalism chose to withdraw from their programs. All students remediated for underperformance in demonstrating empathy successfully completed program-level clinical remediation and graduated. The most frequently endorsed factor positively associated with remediation success was completion of additional in-person patient encounters. The most frequent barrier was a student's poor mental health. Participants most frequently endorsed identification of resources for specific areas of remediation to improve their programs' efficacy in clinical remediation practices. This exploratory study provides valuable information describing clinical skills that require remediation in genetic counseling graduate training, the remediation practices utilized by training programs, and resources that may increase remediation success.

Factors that influence genetic counselors' participation in research.

Genetic counselors have skills and expertise in genetics and patient care that make them an asset to research and research teams. However, the National Society of Genetic Counselors (NSGC) found in 2020 that more than half of practicing genetic counselors do not participate in research activities. Information describing factors that influence their research participation is lacking in the literature. This study ascertained genetic counselors' workplace and graduate training experiences to provide insight into factors that increase or decrease participation in research activities. A survey was distributed through the NSGC Student Research Survey Program. Practicing genetic counselors that graduated in or before 2020 were eligible to participate. The survey included questions about demographics, implementation of student research projects, research-specific resources in their graduate programs, perceived barriers and motivations, and current research activities. Interestingly, the majority of respondents participated in research activities between 2017 and 2021; the most common activities included: recognizing a gap(s) in knowledge (68%) and presenting an abstract or poster (64%). Factors that most significantly influenced genetic counselors' research participation included their interest in research (p = 0.0037), their motivation to do research (p = 0.0014), and their perceived intimidation by the research process (p < 0.001). These results provide insight into solutions for the workplace and graduate programs that could increase genetic counselors' research participation.

An investigation of preceptors' perceptions of behavioral elements of "professionalism" among genetic counseling students.

Professionalism in health care is a loosely defined but increasingly studied concept. In genetic counseling, "professional development" expectations for entry-level genetic counselors are described in the "Practice-Based Competencies for Genetic Counselors," but the teaching and evaluation of "professionalism" among genetic counseling students is relatively unexplored. This study investigated program leaders' and clinical supervisors' perceptions of professionalism demonstrated by genetic counseling graduate students to learn about their associated strengths and lapses. Members of program leadership and clinical supervisors at Accreditation Council for Genetic Counseling (ACGC) accredited genetic counseling graduate programs in the United States and Canada were surveyed regarding their observations of genetic counseling students for the years 2017-2019 regarding four domains of professional behavior: integrity, accountability/conscientiousness, teamwork, and patient care, with the Merriam-Webster definition of each behavior provided for each domain. Participants also provided open-text descriptions. Descriptive results showed that the 263 participants found all facets of these professional behaviors to be essential. Patient care had the highest importance and was the domain with the most strengths observed among genetic counseling students. Lapses in professional behavior were identified for self-awareness, time management, and thoroughness. Free responses noted that suggestions or strategies for education about professional behavior from ACGC may improve the professional behavior of genetic counseling students and in turn, genetic counselors. Participants voiced the importance of consideration of diverse professional and cultural backgrounds in setting the expectations for professional behavior among genetic counseling students and genetic counselors so that "professionalism" in genetic counseling is not defined through a White lens. Further investigation into challenges that genetic counseling students face regarding professional behavior during their graduate training and strategies for education about these behaviors will aid in the growth and improvement of the training of genetic counselors. Given the sensitive nature of this topic, portions of this discussion may be triggering for some readers.

Mode of delivery preference in prenatal genetic counseling between English- and Spanish-speaking patients at two US medical institutions.

Although Hispanic individuals are at an increased risk for various genetic conditions, they have lower uptake of genetic counseling and genetic testing. Virtual appointments have many advantages that may help Spanish-speaking patients access genetic services more readily. Despite these benefits, there are limitations that may make them less attractive options for these individuals. This study aimed to determine if satisfaction with genetic counseling or mode of delivery preference differs between English- and Spanish-speaking individuals who have had a virtual prenatal genetic counseling session. Participants were recruited from prenatal genetic counseling clinics at Indiana University Health and Eskenazi Hospital. A REDCap survey was sent to all eligible participants. Survey questions included mode of delivery preference for future genetic counseling sessions (virtual versus in-person), the validated Genetic Counseling Satisfaction Scale, and questions inquiring about the importance of various factors affecting mode of delivery preference. Spanish-speaking individuals preferred future visits to be in-person, while English-speaking individuals preferred future visits to be virtual (Fisher's exact p = 0.003). Several factors were associated with these preferences, including waiting time, ability to leave/take off work for an appointment, length of session, childcare arrangements, and people attending the appointment (all p < 0.05). Both language groups reported similar mean satisfaction with the genetic counseling provided during their previous virtual appointments (p = 0.51). This study found that certain aspects of virtual genetic counseling appointments make them less appealing to Spanish-speaking individuals. Making virtual genetic counseling appointments more appealing while continuing to offer in-person appointments may help Spanish-speaking individuals receive necessary genetics services. Continued research into disparities and barriers to telemedicine for Spanish-speaking patients is necessary to increase access to this service delivery model for genetic counseling.

Evaluation of US Medical Student Bias Toward Mental Health Before and After First-Year Pre-clinical Psychiatry Education.

OBJECTIVE: Much of mental health care is provided by non-psychiatric providers, and unfortunately, bias toward patients with mental health conditions leads to worsened outcomes. The authors endeavored to determine if pre-clinical medical student psychiatry education had an impact on these perceptions. METHODS: All 366 first-year medical students at Indiana University were invited to participate in a survey that consisted of the Mental Illness: Clinician's Attitudes version 2 (MICA-2) and six supplemental questions, pre- and post-course. RESULTS: One hundred seventeen students completed both surveys. The pre- and post-course means were 36.6 and 33.6, a change of - 2.9 (paired t-test p-value < 0.001), indicating a reduction in bias. CONCLUSIONS: These results suggest that pre-clinical education can lead to a measurable decrease in bias in medical students early in training. Unfortunately, individual question results and free responses continue to highlight significant bias in US medical students against mental illness and the field of psychiatry. Health care educators should be aware of these biases and their potential impact on patient outcomes so that these harmful perceptions can be targeted.

A genome-wide association study of interhemispheric theta EEG coherence: implications for neural connectivity and alcohol use behavior.

Aberrant connectivity of large-scale brain networks has been observed among individuals with alcohol use disorders (AUDs) as well as in those at risk, suggesting deficits in neural communication between brain regions in the liability to develop AUD. Electroencephalographical (EEG) coherence, which measures the degree of synchrony between brain regions, may be a useful measure of connectivity patterns in neural networks for studying the genetics of AUD. In 8810 individuals (6644 of European and 2166 of African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Multi-Trait Analyses of genome-wide association studies (MTAG) on parietal resting-state theta (3-7 Hz) EEG coherence, which previously have been associated with AUD. We also examined developmental effects of GWAS findings on trajectories of neural connectivity in a longitudinal subsample of 2316 adolescent/young adult offspring from COGA families (ages 12-30) and examined the functional and clinical significance of GWAS variants. Six correlated single nucleotide polymorphisms located in a brain-expressed lincRNA (ENSG00000266213) on chromosome 18q23 were associated with posterior interhemispheric low theta EEG coherence (3-5 Hz). These same variants were also associated with alcohol use behavior and posterior corpus callosum volume, both in a subset of COGA and in the UK Biobank. Analyses in the subsample of COGA offspring indicated that the association of rs12954372 with low theta EEG coherence occurred only in females, most prominently between ages 25 and 30 (p < 2 × 10-9). Converging data provide support for the role of genetic variants on chromosome 18q23 in regulating neural connectivity and alcohol use behavior, potentially via dysregulated myelination. While findings were less robust, genome-wide associations were also observed with rs151174000 and parieto-frontal low theta coherence, rs14429078 and parieto-occipital interhemispheric high theta coherence, and rs116445911 with centro-parietal low theta coherence. These novel genetic findings highlight the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Evaluating risk for alcohol use disorder: Polygenic risk scores and family history.

BACKGROUND: Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD. METHODS: We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity. RESULTS: AUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E-11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E-10 ). CONCLUSIONS: Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits.

Binge and high-intensity drinking-Associations with intravenous alcohol self-administration and underlying risk factors.

Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.

Diversity training experiences and factors associated with implicit racial bias among recent genetic counselor graduates of accredited programs in the United States and Canada.

Implicit racial bias in healthcare settings can impact delivery of patient care. Exploration of this bias is necessary to improve patient experiences. We sought to understand implicit racial bias among graduates of accredited genetic counseling programs in the United States and Canada in the class of 2020 as they enter the genetics workforce and assess how this bias is associated with training and life experiences. Implicit racial bias was quantified through use of the Black-White Implicit Association Test (BW-IAT). Participants also completed an online survey focused on didactic and clinical training and personal experiences with diverse populations. Participants (n = 100) were majority White (88%), and 44% demonstrated an implicit bias favoring White individuals. Respondents reported a lack of interaction with Black healthcare professionals during their training. A concerning proportion (38%) reported experiencing or witnessing racial insensitivity perpetrated by genetic counselors or physicians in supervisory roles. Graduates reported diversity coursework as significantly less effective overall than other general genetic counseling coursework. This study reveals prevalence of implicit racial bias among genetic counselor graduates, lack of exposure to diverse populations within and outside of graduate training, and concerns regarding racial insensitivity and effectiveness of didactic and clinical genetic counseling training. Employers and program directors should implement revisions to ongoing training and graduate curriculum with consideration of these findings.

Management of amended variant classification laboratory reports by genetic counselors in the United States and Canada: An exploratory study.

For the past two decades, the guidelines put forth by the American College of Medical Genetics and Genomics (ACMG) detailing providers' clinical responsibility to recontact patients have remained mostly unchanged, despite evolving variant interpretation practices which have yielded substantial rates of reclassification and amended reports. In fact, there is little information regarding genetic counselors' roles in informing patients of reclassified variants, or the process by which these amended reports are currently being handled. In this study, we developed a survey to measure current experiences with amended variant reports and preferences for ideal management, which was completed by 96 genetic counselors from the United States and Canada. All respondents indicated they were the individuals responsible for disclosing initial positive genetic testing results and any clinically actionable reclassified variant reports, and over half (56%) received at least a few amended variant reports each year. Nearly a quarter (20/87) of respondents reported having a standard operating procedure (SOP) for managing amended reports and all were very satisfied (12/20) or satisfied (8/20) with the SOP. Of those without a protocol, 76% (51/67) would prefer to have an SOP implemented. Respondents reported a preference for (1) laboratories to send amended variant reports directly to the genetic counselor or ordering physician through email or an online portal, and (2) notification to patients ideally occurring through a phone call. In the event that the original genetic counselor is inaccessible, respondents reported a preference for reports to be sent directly to another genetic counselor (36%) on the team or the clinic in general (27%). Information from this study provides insight into the current practices of genetic counselors as applied to amended reports and what improvements may increase the efficiency of the reporting process. Moreover, these results suggest a need for an updated statement addressing duty to recontact, specifically as it applies to amended variant reports.

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Genetic counseling for advanced paternal age: A survey of genetic counselors' current practice.

Advanced paternal age (APA) has no formal definition, though many publications utilize the cutoff of fathers >40 years of age. The literature demonstrates an association between APA and certain conditions including de novo autosomal dominant disorders, birth defects, and neuropsychiatric conditions. This study surveyed 165 genetic counselors within the National Society of Genetic Counselors to assess their current approach to APA. t Tests, analysis of variance, logistic regression, and chi-squared tests were performed on quantitative data, and content analysis was applied to qualitative data. Although most respondents have discussed APA with a patient (88%), there was no consensus on what age cutoff constitutes APA: >40 (N = 53, 37.9%), >45 (N = 61, 43.6%), >50 (N = 24, 17.1%), or >55 (N = 2, 1.4%). Those who discussed APA were more likely to be prenatal counselors, see more patients per week, be board certified, or be familiar with current APA guidelines. Respondents agreed the literature supports the association of APA with deleterious outcomes (mean agreement = 8.2, median = 8 on a 1 = strongly disagree to 10 = strongly agree). Individuals who discussed APA and were board certified had higher agreement. Content analysis confirmed agreement that the literature supports an association between APA and deleterious outcomes (documented in responses from 31.5% of prenatal respondents, 17.8% others) but noted that available testing and screening options for associated conditions are limited (34.4% of prenatal respondents, 17.4% others). Prenatal and non-prenatal respondents reported similar agreement with the statement that APA is associated with deleterious outcomes. However, most non-prenatal respondents were unfamiliar with current guidelines (80%), and presumably as a result, were also less likely to discuss APA with their patients. Our study identified a need to disseminate information regarding APA and current guidelines to genetic counselors, particularly non-prenatal and those with less experience.

Outcomes of genetic test disclosure and genetic counseling in a large Parkinson's disease research study.

Genetic testing for Parkinson's disease (PD) is growing as interventional clinical trials begin to enroll participants with PD who carry pathogenic variants in the LRRK2 or GBA genes. However, the impact of receiving genetic test results and the satisfaction with receiving genetic counseling among PD populations have not yet been studied. The purpose of this study was to evaluate (1) the psychological impact of genetic testing for PD and (2) satisfaction with genetic counseling. Surveyed participants (N = 875) were individuals with PD or at risk of developing PD, initially recruited for the Parkinson's Progression Marker Initiative (PPMI) study and currently enrolled in the Widespread Recruitment Initiative (WRI) at Indiana University. Individuals were surveyed following genetic test disclosure and genetic counseling regarding results from targeted testing for pathogenic variants in the LRRK2 and GBA genes. Participants were surveyed via two tools: a modified version of the Multidimensional Impact of Cancer Risk Assessment Survey (M-MICRA), which measured the psychological impact of genetic testing and the Genetic Counseling Satisfaction Survey (GCSS). Participants were divided into affected/unaffected and variant positive/negative groups for subset analyses. The majority of participants had favorable M-MICRA scores and were satisfied with the disclosure of the genetic test results and genetic counseling for PD. However, participants with PD and those with pathogenic variants had less favorable M-MICRA scores and lower satisfaction scores compared to those without disease or pathogenic variants. This information is valuable to providers performing genetic testing of and genetic counseling to people and families affected with PD. Individuals with PD and individuals with pathogenic variants may benefit from additional interventions.

Positive and negative professionalism experiences of genetic counseling students in the United States and Canada.

Many aspects of genetic counseling training programs have been examined over the years. However, no study has explored professional or unprofessional behaviors genetic counseling graduate students experience during their training, and how these behaviors influence satisfaction with their training. This exploratory study examined students' experiences with program leaders, instructors, supervisors, and other trainees. Specific experiences included actions of favoritism, bias, negativity, abuse of power, and examples of positive role modeling. A survey was sent to all members of the National Society of Genetic Counselors and program directors in order to reach graduates of Accreditation Council for Genetic Counseling (ACGC)-accredited programs from 2015-2019 who were eligible to participate. Responses to questions relating to demographics, satisfaction with graduate education, behaviors experienced or seen during graduate school, and reporting of inappropriate behaviors were collected and analyzed. Results demonstrated that 95% of the genetic counseling graduates were highly satisfied with their graduate education and those who experienced inappropriate behaviors during their training were somewhat less satisfied (p = .04). Individuals who felt more prepared by their graduate education were more satisfied with their graduate education (p < .01). Being publicly embarrassed or humiliated, being made to feel like a burden in clinic, or being subjected to negative or offensive behavior based on their personal beliefs or personal characteristics (excluding areas of gender, race/ethnicity, or sexual orientation) were all negatively associated with satisfaction (all p < .04). We conclude that this survey could serve as a "Genetic Counseling Training Experiences Assessment" which could be incorporated into annual evaluations required by the ACGC. Implementation of this assessment would enhance the current evaluations of genetic counseling training programs and provide important information regarding student experiences during their training.

Genome-wide admixture mapping of DSM-IV alcohol dependence, criterion count, and the self-rating of the effects of ethanol in African American populations.

African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations.

A Family-Based Genome Wide Association Study of Externalizing Behaviors.

Shared genetic factors contribute to the high degree of comorbidity among externalizing problems (e.g. substance use and antisocial behavior). We leverage this common genetic etiology to identify genetic influences externalizing problems in participants from the Collaborative Study on the Genetics of Alcoholism (European ancestry = 7568; African ancestry = 3274). We performed a family-based genome-wide association study (GWAS) on externalizing scores derived from criterion counts of five DSM disorders (alcohol dependence, alcohol abuse, illicit drug dependence, illicit drug abuse, and either antisocial personality disorder or conduct disorder). We meta analyzed these results with a similar measure of externalizing in an independent sample, Spit for Science (combined sample N = 15,112). We did not discover any robust genome-wide significant signals. Polygenic scores derived from the ancestry-specific GWAS summary statistics predicted externalizing problems in an independent European ancestry sample, but not in those of African ancestry. However, these PRS were no longer significant after adjusting for multiple testing. Larger samples with deep phenotyping are necessary for the discovery of SNPs related to externalizing problems.

Identification of Functional Genetic Variants Associated With Alcohol Dependence and Related Phenotypes Using a High-Throughput Assay.

BACKGROUND: Genome-wide association studies (GWAS) of alcohol dependence (AD) and related phenotypes have identified multiple loci, but the functional variants underlying the loci have in most cases not been identified. Noncoding variants can influence phenotype by affecting gene expression; for example, variants in the 3' untranslated regions (3'UTR) can affect gene expression posttranscriptionally. METHODS: We adapted a high-throughput assay known as PASSPORT-seq (parallel assessment of polymorphisms in miRNA target sites by sequencing) to identify among variants associated with AD and related phenotypes those that cause differential expression in neuronal cell lines. Based upon meta-analyses of alcohol-related traits in African American and European Americans in the Collaborative Study on the Genetics of Alcoholism, we tested 296 single nucleotide polymorphisms (SNPs with meta-analysis p values ≤ 0.001) that were located in 3'UTRs. RESULTS: We identified 60 SNPs that affected gene expression (false discovery rate [FDR] < 0.05) in SH-SY5Y cells and 92 that affected expression in SK-N-BE(2) cells. Among these, 30 SNPs altered RNA levels in the same direction in both cell lines. Many of these SNPs reside in the binding sites of miRNAs and RNA-binding proteins and are expression quantitative trait loci of genes including KIF6,FRMD4A,CADM2,ADD2,PLK2, and GAS7. CONCLUSION: The SNPs identified in the PASSPORT-seq assay are functional variants that might affect the risk for AD and related phenotypes. Our study provides insights into gene regulation in AD and demonstrates the value of PASSPORT-seq as a tool to screen genetic variants in GWAS loci for one potential mechanism of action.