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.

Factors Influencing Patient Disclosure of Parkinson's Disease Genetic Testing Results to Relatives.

BACKGROUND: Persons with Parkinson's disease (PD) who have received genetic test results are faced with the decision of whether, and how, to share that information with family. Studies in other specialties have shown high rates of disclosure motivated by a sense of responsibility. Rates of, and attitudes surrounding, disclosure have yet to be reported in this population. OBJECTIVES: To explore the disclosure practices and motivations of patients with PD regarding genetic test results, allowing insight to guide genetic counseling and navigation of test result discussions. METHODS: A cross-sectional online survey was distributed to adults with PD and previous genetic test results. Survey questions assessed demographics, genetic testing results and delivery, sharing behaviors, perceptions of PD, and motivations and barriers to family disclosure. RESULTS: Among respondents, 88.9% shared results with at least one family member, most often a child (73.5%) or sibling (65.4%). Seventy-four percent reported sharing results with someone outside of their family, most frequently a friend (88.4%). The most common motivation for disclosure was the perception that family members would want to know. Barriers to disclosure were lack of close relationships, understanding results, and perceived utility. CONCLUSIONS: Disclosure rates in this PD population were consistent with those in previously reported populations. Motivations were anchored in perceptions of utility and family desire for information, suggesting a need to adjust patient education to improve retention and to explore family dynamics and perceptions of results.

Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) conducted a genome-wide association study (GWAS) of SA and performed downstream analyses to determine whether we could identify specific biological pathways of risk, and 2) explored risk in aggregate across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning between those with AD who have and have not reported a lifetime suicide attempt. The GWAS and downstream analyses did not produce any significant associations. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22-1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.

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.

Polymorphisms in the choline transporter SLC44A1 are associated with reduced cognitive performance in normotypic but not prenatal alcohol-exposed children.

BACKGROUND: Choline is essential for healthy cognitive development. Single nucleotide polymorphisms (SNPs; rs3199966(G), rs2771040(G)) within the choline transporter SLC44A1 increase risk for choline deficiency. In a choline intervention trial of children who experienced prenatal alcohol exposure (PAE), these alleles are associated with improved cognition. OBJECTIVE: This study aimed to determine if SNPs within SLC44A1 are differentially associated with cognition in children with PAE compared with normotypic controls (genotype × exposure). A secondary objective tested for an association of these SNPs and cognition in controls (genotype-only). DESIGN: This is a secondary analysis of data from the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Participants (163 normotypic controls, 162 PAE) underwent psychological assessments and were genotyped within SLC44A1. Choline status was not assessed. Association analysis between genotype × exposure was performed using an additive genetic model and linear regression to identify the allelic effect. The primary outcome was the interaction between SLC44A1 genotype × exposure status with respect to cognition. The secondary outcome was the cognitive-genotype association in normotypic controls. RESULTS: Genotype × exposure analysis identified 7 SNPs in SLC44A1, including rs3199966(G) and rs2771040(G), and in strong linkage (D' ≥ 0.87), that were associated (adjusted P ≤ 0.05) with reduced performance in measures of general cognition, nonverbal and quantitative reasoning, memory, and executive function (ß, 1.92-3.91). In controls, carriers of rs3199966(GT or GG) had worsened cognitive performance than rs3199966(TT) carriers (ß, 0.46-0.83; P < 0.0001), whereas cognitive performance did not differ by rs3199966 genotype in those with PAE. CONCLUSIONS: Two functional alleles that increase vulnerability to choline deficiency, rs3199966(G) (Ser644Ala) and rs2771040(G) (3' untranslated region), are associated with worsened cognition in otherwise normotypic children. These alleles were previously associated with greater cognitive improvement in children with PAE who received supplemental choline. The findings endorse that choline benefits cognitive development in normotypic children and those with PAE.

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.

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.

Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank.

BACKGROUND: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. METHODS: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. RESULTS: In COGA EA, PGSAUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, ßs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, ß = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, ß = 0.15). CONCLUSIONS: PGSAUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life.

Relationship satisfaction in adults with phenylketonuria is positively associated with following recommended treatment, having a partner involved in management, and maintaining good health.

RATIONALE: Phenylketonuria (PKU) is a metabolic condition that requires treatment for life. There is increasing evidence that chronic illnesses put strain on relationships and marriages. However, no studies have examined the unique factors that metabolic conditions have on affected individuals and their relationship satisfaction. We surveyed a population of adult patients with PKU and assessed how management, treatment, and lifestyle factors impact their relationship satisfaction. PURPOSE: The purpose of our study was to explore whether factors such as involvement of partner in PKU management, impact of challenges unique to PKU (e.g., diet, family planning, mood disturbances), and PKU treatment types were associated with the degree of relationship satisfaction. METHOD: We surveyed adult patients with PKU (n = 82) who were either currently in or had previously been in a long-term relationship. We developed a 78-question survey that included unique questions regarding lifestyle, treatment, and management of their PKU in addition to a validated Relationship Assessment Score. Questions included single choice, multiple choice, and 3 open-ended questions. RESULTS: We found that higher relationship satisfaction was associated with increased partner involvement, increased health, and adherence to recommended PKU treatments. Participants utilizing both diet and pharmaceutical treatment had the highest relationship satisfaction. Finally, participants who reported that their PKU did not contribute to the ending of a previous relationship reported higher relationship satisfaction scores. CONCLUSION: This study suggests that involvement of partners in the management and treatment of a chronic illness and adherence to recommended treatments can significantly improve relationship satisfaction.

Readiness for Parkinson's disease genetic testing and counseling in patients and their relatives in urban settings in the Dominican Republic.

Genetic testing for Parkinson's disease (PD) is increasing globally, and genetic counseling is an important service that provides information and promotes understanding about PD genetics and genetic testing. PD research studies have initiated outreach to underrepresented regions in North America, including regions in Latin America, such as the Dominican Republic (DR); some studies may include return of genetic test results. Thus, understanding what individuals know about PD, genetic testing for PD, and their interest in speaking with a genetic counselor, is crucial when assessing readiness. In this cross-sectional study, a survey was distributed to people with Parkinson's disease (PwP) and their unaffected biological relatives in the DR. Questions assessed genetics knowledge, attitude toward genetic testing, and interest in genetic testing and counseling. Of 45 participants, 69% scored the maximum on the attitude scale, indicating an overall positive attitude toward genetic testing; 95% indicated interest in genetic testing for PD, and 98% were at least somewhat interested in meeting with a genetic counselor. The mean PD genetics knowledge score was similar to previously published data. Through free text responses, participants expressed a desire to know more about PD treatment and management, prevention, cause, and their personal risk for PD. These results provide further evidence of readiness for genetic testing in this country but also underscore some gaps in knowledge that should be addressed with targeted educational efforts, as part of building genetic testing and counseling capacities.

Mutation in the Bone Morphogenetic Protein signaling pathway sensitize zebrafish and humans to ethanol-induced jaw malformations.

Fetal Alcohol Spectrum Disorders (FASD) describe ethanol-induced developmental defects including craniofacial malformations. While ethanol-sensitive genetic mutations contribute to facial malformations, the impacted cellular mechanisms remain unknown. Bmp signaling is a key regulator of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. Integrating FASD patient data, we provide the first evidence that variants in the human Bmp receptor gene BMPR1B associate with ethanol-related differences in jaw volume. Our results show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, facial epithelia that mirror overall viscerocranial shape changes and are predictive for Bmp-ethanol associations in human jaw development. Our data provide a mechanistic paradigm linking ethanol to disrupted epithelial cell behaviors that underlie facial defects in FASD.

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.

The collaborative study on the genetics of alcoholism: Genetics.

This review describes the genetic approaches and results from the family-based Collaborative Study on the Genetics of Alcoholism (COGA). COGA was designed during the linkage era to identify genes affecting the risk for alcohol use disorder (AUD) and related problems, and was among the first AUD-focused studies to subsequently adopt a genome-wide association (GWAS) approach. COGA's family-based structure, multimodal assessment with gold-standard clinical and neurophysiological data, and the availability of prospective longitudinal phenotyping continues to provide insights into the etiology of AUD and related disorders. These include investigations of genetic risk and trajectories of substance use and use disorders, phenome-wide association studies of loci of interest, and investigations of pleiotropy, social genomics, genetic nurture, and within-family comparisons. COGA is one of the few AUD genetics projects that includes a substantial number of participants of African ancestry. The sharing of data and biospecimens has been a cornerstone of the COGA project, and COGA is a key contributor to large-scale GWAS consortia. COGA's wealth of publicly available genetic and extensive phenotyping data continues to provide a unique and adaptable resource for our understanding of the genetic etiology of AUD and related traits.

Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder, despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) explored clinical risk factors associated with SA, 2) conducted a genome-wide association study of SA, 3) examined whether individuals with a SA had elevated polygenic scores for comorbid psychiatric conditions (e.g., alcohol use disorders, lifetime suicide attempt, and depression), and 4) explored differences in electroencephalogram neural functional connectivity between those with and without a SA. One gene-based finding emerged, RFX3 (Regulatory Factor X, located on 9p24.2) which had supporting evidence in prior research of SA among individuals with major depression. Only the polygenic score for suicide attempts was associated with reporting a suicide attempt (OR = 1.20, 95% CI = 1.06, 1.37). Lastly, we observed decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences among those participants who reported a SA relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.

Motivations and expectations of parents seeking genetic testing for their children with ocular genetic disease.

BACKGROUND: To date, almost 600 genes have been associated with ocular genetic diseases. As these discoveries are made, clinical genetic testing continues to grow and become a more common element in the diagnostic workup of children with blindness and reduced vision. However, few studies have explored the motivations of parents of pediatric patients for pursuing genetic testing or the topics they would like to discuss during their visit. This study explored these gaps in the existing knowledge of clinical care for children with vision loss. MATERIALS AND METHODS: We distributed a REDCap survey to parents of pediatric patients in the Indiana University Ocular Genetics Clinic and through the Foundation Fighting Blindness MyRetinaTracker database to examine factors that motivate families to undergo genetic testing, topics they are interested in discussing, and satisfaction with their current care. RESULTS: Parents were primarily motivated by the opportunity to learn about their child's prognosis, formal diagnosis, and possible treatment options. Parents were most interested in discussing prognosis, adaptations for vision loss, and testing logistics. Parents reported satisfaction with the care received; however, less than half were very satisfied with their understanding of prognosis and the support resources provided. CONCLUSIONS: Parents seem to be generally satisfied by the care from their ocular genetics team. However, families' desires are not being fully met, especially with information about prognosis and support resources. As the field of ocular genetics continues to grow, it is important we improve these offerings and optimize care for this patient population.

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.

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.

High Polygenic Risk Scores Are Associated With Early Age of Onset of Alcohol Use Disorder in Adolescents and Young Adults at Risk.

Background: Genome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations. Methods: A total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS. Results: European ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p = 3 × 10-7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile). Conclusions: Predictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.