Browsing by Author "Wetherill, Leah"
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Item A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53(Springer Nature, 2013) Wang, Jen-Chyong; Foroud, Tatiana; Hinrichs, Anthony L.; Le, Nhung X. H.; Bertelsen, Sarah; Budde, John P.; Harari, Oscar; Koller, Daniel L.; Wetherill, Leah; Agrawal, Arpana; Almasy, Laura; Brooks, Andrew I.; Bucholz, Kathleen; Dick, Danielle; Hesselbrock, Victor; Johnson, Eric O.; Kang, Sun; Kapoor, Manav; Kramer, John; Kuperman, Samuel; Madden, Pamela A. F.; Manz, Niklas; Martin, Nicholas G.; McClintick, Jeanette N.; Montgomery, Grant W.; Nurnberger, John I., Jr.; Rangaswamy, Madhavi; Rice, John; Schuckit, Marc; Tischfield, Jay A.; Whitfield, John B.; Xuei, Xiaoling; Porjesz, Bernice; Heath, Andrew C.; Edenberg, Howard J.; Bierut, Laura J.; Goate, Alison M.; Medical and Molecular Genetics, School of MedicineSeveral studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.Item A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks(Springer, 2013) Kapoor, Manav; Wang, Jen-Chyong; Wetherill, Leah; Le, Nhung; Bertelsen, Sarah; Hinrichs, Anthony L.; Budde, John; Agrawal, Arpana; Bucholz, Kathleen; Dick, Danielle; Harari, Oscar; Hesselbrock, Victor; Kramer, John; Nurnberger, John I., Jr.; Rice, John; Saccone, Nancy; Schuckit, Marc; Tischfield, Jay; Porjesz, Bernice; Edenberg, Howard J.; Bierut, Laura; Foroud, Tatiana; Goate, Alison; Medical and Molecular Genetics, School of MedicineMaximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10(-7)) and PLCL1 genes (p = 4.1 × 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10(-3), 3 × 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.Item Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking(Wiley Blackwell (Blackwell Publishing), 2015-07) Kosobud, Ann E. K.; Wetherill, Leah; Plawecki, Martin H.; Kareken, David A.; Liang, Tiebing; Nurnberger, John L.; Windisch, Kyle; Xuei, Xiaoling; Edenberg, Howard J.; Foroud, Tatiana M.; O’Connor, Sean J.; Department of Psychiatry, IU School of MedicineBACKGROUND: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. METHODS: One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. RESULTS: Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. CONCLUSIONS: Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.Item An ADH1B variant and peer drinking in progression to adolescent drinking milestones: Evidence of a gene-by-environment interaction(Wiley Online Library, 2014-10) Olfson, Emily; Edenberg, Howard J.; Nurnberger Jr., John; Agrawal, Arpana; Bucholz, Kathleen K.; Almasy, Laura A.; Chorlian, David; Dick, Danielle M.; Hesselbrock, Victor M.; Kramer, John R.; Kuperman, Samuel; Porjesz, Bernice; Schuckit, Marc A.; Tischfield, Jay A.; Wang, Jen-Chyong; Wetherill, Leah; Foroud, Tatiana M.; Rice, John; Goate, Alison; Bierut, Laura J.; Department of Biochemistry & Molecular Biology, IU School of MedicineBACKGROUND: Adolescent drinking is an important public health concern, one that is influenced by both genetic and environmental factors. The functional variant rs1229984 in alcohol dehydrogenase 1B (ADH1B) has been associated at a genome-wide level with alcohol use disorders in diverse adult populations. However, few data are available regarding whether this variant influences early drinking behaviors and whether social context moderates this effect. This study examines the interplay between rs1229984 and peer drinking in the development of adolescent drinking milestones. METHODS: One thousand five hundred and fifty European and African American individuals who had a full drink of alcohol before age 18 were selected from a longitudinal study of youth as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Cox proportional hazards regression, with G × E product terms in the final models, was used to study 2 primary outcomes during adolescence: age of first intoxication and age of first DSM-5 alcohol use disorder symptom. RESULTS: The minor A allele of rs1229984 was associated with a protective effect for first intoxication (HR = 0.56, 95% CI 0.41 to 0.76) and first DSM-5 symptom (HR = 0.45, 95% CI 0.26 to 0.77) in the final models. Reporting that most or all best friends drink was associated with a hazardous effect for first intoxication (HR = 1.81, 95% CI 1.62 to 2.01) and first DSM-5 symptom (HR = 2.17, 95% 1.88 to 2.50) in the final models. Furthermore, there was a significant G × E interaction for first intoxication (p = 0.002) and first DSM-5 symptom (p = 0.01). Among individuals reporting none or few best friends drinking, the ADH1B variant had a protective effect for adolescent drinking milestones, but for those reporting most or all best friends drinking, this effect was greatly reduced. CONCLUSIONS: Our results suggest that the risk factor of best friends drinking attenuates the protective effect of a well-established ADH1B variant for 2 adolescent drinking behaviors. These findings illustrate the interplay between genetic and environmental factors in the development of drinking milestones during adolescence.Item Alcohol Affects the P3 Component of an Adaptive Stop Signal Task ERP(Elsevier, 2017) Plawecki, Martin H.; Windisch, Kyle A.; Wetherill, Leah; Kosubud, Ann E. K.; Dzemidzic, Mario; Kareken, David A.; O'Connor, Sean J.; Department of Psychiatry, School of MedicineBACKGROUND The P3 component of the event-related potential (ERP) has been particularly useful in alcohol research for identifying endophenotypes of alcohol use disorder (AUD) risk in sober subjects. However, practice and/or fatigue reduces P3 amplitude, limiting the ability to ascertain acute and adaptive effects of alcohol exposure. Here, we report acute alcohol effects on P3 amplitude and latency using an adaptive stop signal task (aSST). METHODS One hundred and forty eight nondependent moderate to heavy social drinkers, age 21 to 27, participated in 2 single-blind, alcohol or placebo, counterbalanced sessions approximately one week apart. During each session, subjects performed an adaptive stop signal task (aSST) at (1) baseline, (2) upon reaching the target 60 mg/dL breath alcohol concentration or at the equivalent time during the placebo session, and (3) approximately 135 minutes later while the breath alcohol concentration was clamped. Here, we report on differences between baseline and first subsequent measurements across the experimental sessions. During each aSST run, the stop signal delay (SSD, the time between stop and go signals) adjusted trial-by-trial based on the subject’s performance. RESULTS The aSST reliably generated a STOP P3 component that did not change significantly with repeated task performance. The pre-infusion SSD distribution was bimodal, with mean values several hundred msec apart (FAST: 153 msec and SLOW: 390 msec). This suggested different response strategies: FAST SSD favoring “going” over “stopping,” and SLOW SSD favoring “stopping” over “going”. Exposure to alcohol at 60 mg/dL differentially affected the amplitude and latency of the STOP P3 according to SSD group. Alcohol significantly reduced P3 amplitude in the SLOW SSD compared to FAST SSD group, but significantly increased P3 latency in the FAST SSD compared to SLOW SSD group. CONCLUSIONS The aSST is a robust and sensitive task for detecting alcohol induced changes in inhibition behavior as measured by the P3 component in a within subject design. Alcohol was associated with P3 component changes which varied by SSD group, suggesting a differential effect as a function of task strategy. Overall, the data support the potential utility of the aSST in the detection of alcohol response related AUD risk.Item Alcohol-Related, Drug-Related, and Non-Substance-Related Aggression: Three Facets of a Single Construct or Three Distinct Constructs?(Wiley, 2020-09) Chester, David S.; Bucholz, Kathleen K.; Chan, Grace; Kamarajan, Chella; Pandey, Ashwini K.; Wetherill, Leah; Kramer, John R.; Nurnberger, John I., Jr.; Salvatore, Jessica E.; Dick, Danielle M.; Medical and Molecular Genetics, School of MedicineBackground: Aggression often occurs alongside alcohol and drug misuse. However, it is not clear whether the latent and manifest relations among alcohol-related, drug-related, and non-substance-related aggression are separate manifestations of a single construct or instead are 3 distinct constructs. Methods: To examine these associations, we conducted a preregistered analysis of 13,490 participants in the Collaborative Study on the Genetics of Alcoholism. In a structured interview, participants reported their lifetime perpetration of these 3 aggression phenotypes. Results: The data were better fit by a model that treated these aggression phenotypes as 3 distinct latent factors, as compared to models in which the items all loaded onto 1 ("general") or 2 ("substance-related" and "non-substance-related") aggression factors. This 3-factor model fit better for men than women. Subsequent exploratory analyses then showed that among these 3 factors, alcohol-related aggression explained the variance of overall aggression better than the other 2 factors. Conclusions: Our findings suggest that these 3 forms of aggression are distinct phenotypes (especially among men). Yet, people's alcohol-related aggression can accurately characterize their overall aggressive tendencies across these domains. Future research will benefit from articulating the unique and shared pathways and risk factors underlying each of these facets of aggression.Item An exploration of delegation practices regarding the utilization of genetic counseling assistants for disclosure of genetic testing results(Wiley, 2025) Ranson, David; Allison, Camille O.; Wetherill, Leah; Delk, Paula R.; Stone, Kristyne; Medical and Molecular Genetics, School of MedicineGenetic counselors (GCs) play a crucial role in the healthcare system, providing education, support and guidance regarding genetic risk assessment, testing and results interpretation. To help GCs practice at the highest level of their expertise, the role of the genetic counseling assistant (GCA) was introduced, focusing on tasks like administrative support and patient care coordination. Although GCs typically handle the disclosure of test results, there is limited research on the delegation of results disclosure to GCAs. This study explores GCs' perspectives on delegating negative and variant of uncertain significance (VUS) genetic test results disclosures to GCAs. A quantitative survey was conducted among GCs practicing in the United States and Canada. Results revealed that while the majority of GCs were willing to delegate both negative and VUS results, few currently do so. Oncology GCs exhibited greater willingness and actual delegation of VUS disclosures relative to other specialties. Effective communication skills, level of genetics knowledge, and willingness to seek help were identified as the most influential attributes on GCs' confidence in GCAs' abilities to disclose test results. The most frequent concern about GCAs disclosing negative and VUS results was remaining suspicion for an underlying genetic etiology. Additionally, GCs were concerned about delegating VUS disclosures since patients more frequently struggle to understand those results. A triaging system to determine suitable results for a GCA to disclose and extensive shadowing of GCs disclosing results were proposed as methods of building GCs' confidence in the ability of a GCA to disclose test results. Ultimately, a better understanding of the discrepancy between GCs' willingness to delegate results disclosures and actual delegation practices is essential if the GCA scope of practice were to include results disclosure.Item An investigation of preceptors' perceptions of behavioral elements of "professionalism" among genetic counseling students(Wiley, 2023) Delk, Paula; Bowling, Isabella; Schroeder, Courtney; Wilson, Theodore E.; Wesson, Melissa; Wetherill, Leah; Medical and Molecular Genetics, School of MedicineProfessionalism 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.Item Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis(Oxford University Press, 2019-11) Moe, Sharon M.; Long, Jin; Schwantes-An, Tae-Hwi Linus; Decker, Brian S.; Wetherill, Leah; Edenberg, Howard J.; Xuei, Xiaoling; Vatta, Matteo; Foroud, Tatiana M.; Chertow, Glenn M.; Medicine, School of MedicineBACKGROUND: Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. METHODS: We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. RESULTS: Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. CONCLUSIONS: The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD.Item APOL1 G3 variant is associated with cardiovascular mortality and sudden cardiac death in patients receiving maintenance hemodialysis of European Ancestry(Karger, 2022) Schwantes-An, Tae-Hwi; Robinson-Cohen, Cassianne; Liu, Sai; Zheng, Neil; Stedman, Margaret; Wetherill, Leah; Edenberg, Howard J.; Vatta, Matteo; Foroud, Tatiana M.; Chertow, Glenn M.; Moe, Sharon M.; Medical and Molecular Genetics, School of MedicineIntroduction: The G1 and G2 variants in the APOL1 gene convey high risk for the progression of chronic kidney disease in African Americans. The G3 variant in APOL1 is more common in patients of European ancestry (EA); outcomes associated with this variant have not been explored previously in EA patients receiving dialysis. Methods: DNA was collected from approximately half of the patients enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial and genotyped for the G3 variants. We utilized an additive genetic model to test associations of G3 with the EVOLVE adjudicated endpoints of all-cause mortality, cardiovascular mortality, sudden cardiac death (SCD), and heart failure. EA and African ancestry samples were analyzed separately. Validation was done in the Vanderbilt BioVU using ICD codes for cardiovascular events that parallel the adjudicated endpoints in EVOLVE. Results: In EVOLVE, G3 in EA patients was associated with the adjudicated endpoints of cardiovascular mortality and SCD. In a validation cohort from the Vanderbilt BioVU, cardiovascular events and cardiovascular mortality defined by ICD codes showed similar associations in EA participants who had been on dialysis for 2 to <5 years. Discussion/conclusions: G3 in APOL1 variant was associated with cardiovascular events and cardiovascular mortality in the EA patients receiving dialysis. This suggests that variations in the APOL1 gene that differ in populations of different ancestry may contribute to cardiovascular disease.