The genetics of trichotillomania and excoriation disorder: A systematic review.

BACKGROUND: Trichotillomania (TTM) and excoriation disorder (ED) are impairing obsessive-compulsive related disorders that are common in the general population and for which there are no clear first-line medications, highlighting the need to better understand the underlying biology of these disorders to inform treatments. Given the importance of genetics in obsessive-compulsive disorder (OCD), evaluating genetic factors underlying TTM and ED may advance knowledge about the pathophysiology of these body-focused repetitive behaviors. AIM: In this systematic review, we summarize the available evidence on the genetics of TTM and ED and highlight gaps in the field warranting further research. METHOD: We systematically searched Embase, PsycInfo, PubMed, Medline, Scopus, and Web of Science for original studies in genetic epidemiology (family or twin studies) and molecular genetics (candidate gene and genome-wide) published up to June 2023. RESULTS: Of the 3536 records identified, 109 studies were included in this review. These studies indicated that genetic factors play an important role in the development of TTM and ED, some of which may be shared across the OCD spectrum, but there are no known high-confidence specific genetic risk factors for either TTM or ED. CONCLUSIONS: Our review underscores the need for additional genome-wide research conducted on the genetics of TTM and ED, for instance, genome-wide association and whole-genome/whole-exome DNA sequencing studies. Recent advances in genomics have led to the discovery of risk genes in several psychiatric disorders, including related conditions such as OCD, but to date, TTM and ED have remained understudied.

Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene.

Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children ("primary" stereotypies, pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries.

Prevalence and gender distribution of excoriation (skin-picking) disorder: A systematic review and meta-analysis.

Epidemiological studies of excoriation disorder have reported different prevalence estimates for this condition, limiting our understanding of its public health impact. We performed a systematic review and meta-analysis to collate epidemiological studies of excoriation disorder. We aimed to estimate the pooled prevalence and the female-to-male ratio of excoriation disorder in the general population. We searched Embase, PsycInfo, and PubMed up to May 2020 and updated the PubMed search in October 2021. Studies which reported the frequency of excoriation disorder in a sample from the general population were included in our meta-analyses. We made no restrictions regarding the definition or assessment of excoriation disorder. Data were pooled through random-effects meta-analyses. Of the 677 records identified through database searches, 19 studies involving 38,038 participants met our inclusion criteria. Meta-analyses demonstrated that excoriation disorder has an overall prevalence of 3.45% (95% CI 2.55, 4.65%) and impacts women more than men (female-to-male OR = 1.45; 95% CI 1.15, 1.81, p = 0.001). These findings underscore the public health impact of excoriation disorder, which will hopefully motivate future research focused on advancing our understanding and management of this condition.

Characteristics of trichotillomania and excoriation disorder across the lifespan.

Trichotillomania (hair-pulling disorder) and excoriation (skin-picking) disorder are body-focused repetitive behaviors, which often first present in adolescence and cause distress and impairment into adulthood. Few studies have examined the clinical characteristics of the co-occurrence of these conditions across the lifespan. We examined cross-sectional survey responses collected from April 2018-February 2020 to evaluate the relationship between trichotillomania, excoriation disorder, and their co-occurrence. Responses from individuals with trichotillomania (n = 50), excoriation disorder (n = 52), and both conditions (n = 50) ages 4-67 years old were compared for co-occurring conditions and current symptoms. Self-report measures of hair-pulling and skin-picking severity and subtypes were assessed. Gender, race, and co-occurring conditions were generally similarly distributed across the three groups with high rates of self-reported anxiety (63-82%), depression (34-50%), obsessive-compulsive disorder (16-29%), and attention-deficit/hyperactivity disorder (12-32%). Among individuals with both trichotillomania and excoriation disorder, significant positive correlations were observed between hair-pulling and skin-picking severity scores as well as hair-pulling and skin-picking subtypes. Hair-pulling and skin-picking severity peaked at the transition from adolescence to adulthood and hair-pulling/skin-picking styles appeared to shift across the lifespan. Our results support several similarities between trichotillomania and excoriation disorder, providing new insight into the clinical characteristics of these conditions.

Prevalence and gender distribution of trichotillomania: A systematic review and meta-analysis.

Epidemiological studies have provided varying prevalence estimates of trichotillomania (TTM) and other hair-pulling behaviors. We performed a systematic review and meta-analysis to provide data-driven prevalence estimates of TTM and hair-pulling. PubMed, PsycInfo and Embase were searched on June 2020 (updated in November 2021). Studies reporting the frequency of TTM defined by Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria or hair-pulling behaviors were included. Prevalence data was extracted for both genders, and female-to-male odds ratios (OR) were computed for TTM and any hair-pulling behaviors. Data were pooled through random-effects meta-analyses. Of the 713 records identified through database searches, 30 studies involving 38,526 participants were included. Meta-analyses indicated TTM had a prevalence of 1.14% (95% CI 0.66%, 1.96%), while any hair-pulling behavior had a prevalence of 8.84% (95% CI 6.33%, 12.20%). Meta-analyses demonstrated females were at an increased risk of any hair-pulling when noticeable hair loss was required (OR = 2.23, 95% CI 1.60, 3.10, p < 0.0001), but not of any hair-pulling when noticeable hair loss was not required (OR = 0.90, 95% CI 0.72, 1.64, p = 0.33). Meta-analyses did not indicate female preponderance in TTM (k = 10; N = 22,775; OR = 1.29; 95% CI 0.91, 1.83; I2 = 28%, p = 0.15), although there was considerable heterogeneity across studies. This study demonstrates that TTM impacts ∼1% of the population, while general hair-pulling behaviors affects ∼8%, highlighting the significant public health impact of this understudied condition. Additional research should clarify the gender distribution of TTM in epidemiological samples.

Whole-exome DNA sequencing in childhood anxiety disorders identifies rare de novo damaging coding variants.

BACKGROUND: Genetic factors contribute to the development of anxiety disorders, yet few risk genes have been previously identified. One genomic approach that has achieved success in identifying risk genes in related childhood neuropsychiatric conditions is investigations of de novo variants, which has yet to be leveraged in childhood anxiety disorders. METHODS: We performed whole-exome DNA sequencing in 76 parent-child trios (68 trios after quality control) recruited from a childhood anxiety disorder clinic and compared rates of rare and ultra-rare de novo variants with 790 previously sequenced control trios (783 trios after quality control). We then explored overlap with risk genes for other neuropsychiatric conditions and enrichment in biologic pathways. RESULTS: Rare and ultra-rare de novo likely gene disrupting and predicted damaging missense genetic variants are enriched in anxiety disorder probands compared with controls (rare variant rate ratio 1.97, 95% confidence interval [CI]: 1.11-3.34, p = .03; ultra-rare variant rate ratio 2.59, 95% CI: 1.35-4.70, p = .008). These de novo damaging variants occur in individuals with a variety of childhood anxiety disorders and impact genes that have been associated with other neuropsychiatric conditions. Exploratory network analyses reveal enrichment of deleterious variants in canonical biological pathways. CONCLUSIONS: These findings provide a path for identifying risk genes and promising biologic pathways in childhood anxiety disorders by de novo genetic variant detection. Our results suggest the discovery potential of applying this approach in larger anxiety disorder cohorts to advance our understanding of the underlying biology of these common and debilitating conditions.

Pharmacological and behavioral treatment for trichotillomania: An updated systematic review with meta-analysis.

BACKGROUND: Trichotillomania (TTM) is a difficult-to-treat psychiatric condition with no first-line medications approved by the Food and Drug Administration. Individuals with TTM often feel that clinicians know little about this disorder. Here, we present an updated meta-analysis of randomized controlled trials (RCTs) examining treatments for TTM. METHODS: Pubmed, PsychINFO, Embase, and CENTRAL were searched with the terms "Trichotillomania OR Hair Pulling Disorder" to identify randomized controlled clinical trials evaluating treatments for TTM. RESULTS: Twenty-four trials involving 26 comparisons and 857 participants were included in this meta-analysis. Behavioral therapy with habit-reversal training components (BT-HRT) demonstrated a large benefit compared to control conditions (standardized mean difference [SMD] [95% CI] = -1.22 [-1.71, -0.73], p < .0001) for improving TTM symptoms. Clomipramine (SMD [95% CI] = -0.71 [-1.38, -0.05], p = .036), N-acetylcysteine (SMD [95% CI] = -0.75 [-1.36, -0.13], p = .017) and olanzapine (SMD [95% CI] = -0.94 [-1.77, -0.12], p = .025) demonstrated significant benefits compared to placebo in RCTs. CONCLUSIONS: BT-HRT has demonstrated the largest treatment effects and has the strongest evidence base for reducing TTM symptoms. In contrast, several pharmacological agents have demonstrated efficacy in single randomized clinical trials that would benefit from replication. Additional trials are needed to identify other effective medications for TTM and determine the relative efficacy of available agents.

Measuring Treatment Response in Pediatric Trichotillomania: A Meta-Analysis of Clinical Trials.

Objectives: In clinical trials of pediatric trichotillomania (TTM), three instruments are typically employed to rate TTM severity: (1) the Massachusetts General Hospital Hair Pulling Scale (MGH-HPS), (2) the National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS), and (3) the Trichotillomania Scale for Children (TSC). These instruments lack standardized definitions of treatment response, which lead researchers to determine their own definitions of response post hoc and potentially inflate results. We performed a meta-analysis to provide empirically determined accuracy measures for percentage reduction cut points in these three instruments. Methods: MEDLINE was searched for TTM clinical trials. A total of 67 studies were initially identified, but only 5 were clinical trials focused on TTM in pediatric populations and therefore were included in this meta-analysis (n = 180). A Clinical Global Impressions Improvement score ≤2 was used to define clinical response. Receiver operating characteristic principles were employed to determine accuracy measures for percentage reduction cut points on each one of the instruments. Meta-DiSc software was employed to provide pooled accuracy measures for each cut point for each instrument. The Youden Index and the distance to corner methods were used to determine the optimal cut point. Results: The optimal cut points to determine treatment response were a 45% reduction on the MGH-HPS (Youden Index 0.40, distance to corner 0.20), a 35% reduction on the NIMH-TSS (Youden Index 0.42, distance to corner 0.17), a 25% reduction on the TSC child version (TSC-C; Youden Index 0.40, distance to corner 0.18), and a 45% (distance to corner 0.30) or 50% reduction (Youden Index 0.33) on the TSC parent version (TSC-P). The TSC-C had less discriminative ability at determining response in younger children in comparison to older children; no age-related differences were observed on the TSC-P. Conclusions: This study provides empirically determined cut points of treatment response on three instruments that rate TTM severity. These data-driven cut points will benefit future research on pediatric TTM.

De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. In recent years, risk gene discovery in other complex psychiatric disorders has been achieved by studying rare de novo (DN) coding variants. METHODS: We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), comparing DN variant frequencies with 777 previously sequenced unaffected trios. We estimated the contribution of DN mutations to OCD risk and the number of genes involved. Finally, we looked for gene enrichment in other datasets and canonical pathways. RESULTS: DN likely gene disrupting and predicted damaging missense variants are enriched in OCD probands (rate ratio, 1.52; p = .0005) and contribute to risk. We identified 2 high-confidence risk genes, each containing 2 DN damaging variants in unrelated probands: CHD8 and SCUBE1. We estimate that 34% of DN damaging variants in OCD contribute to risk and that DN damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring DN damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly Tourette's disorder and autism spectrum disorder. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways, biological processes, and disease networks. CONCLUSIONS: Our findings show a pathway toward systematic gene discovery in OCD via identification of DN damaging variants. Sequencing larger cohorts of OCD parent-child trios will reveal more OCD risk genes and will provide needed insights into underlying disease biology.

Identifying standardized definitions of treatment response in trichotillomania: A meta-analysis.

BACKGROUND: Symptom severity in trichotillomania clinical trials is typically rated using the Massachusetts General Hospital Hair Pulling Scale (MGH-HPS) and the National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS). There are no universal definitions of treatment response on these scales. The absence of empirically supported definitions of treatment response hampers advances in trichotillomania treatment. METHODS: PubMed and CENTRAL databases were searched for trichotillomania clinical trials. A total of 14 studies were identified and 7 provided adequate data to be included in the meta-analysis (n = 270). Meta-DiSc software was employed. The Youden index and distance to corner were used to determine the optimal cut-point. Response was defined by the Clinical Global Impressions Improvement scale score ≤ 2. RESULTS: The optimal cut-points for identifying response on the MGH-HPS was a 35% percent reduction [Youden Index 0.48; distance to corner 0.37] or a seven-point reduction [Youden Index 0.43; distance to corner 0.40]. The optimal cut-points for the NIMH-TSS was a 50% reduction [Youden Index 0.57; distance to corner 0.34] or a six-point reduction [Youden Index 0.53; distance to corner 0.36]. The optimal cut-points were similar when the analysis was confined to only trichotillomania trials involving adult subjects, but the scales appeared to have improved ability to define treatment response when pediatric subjects were excluded. CONCLUSION: This study provides empirically determined cut-points of treatment response on the MGH-HPS and NIMH-TSS. These data-driven cut-points will benefit future research in trichotillomania by providing definitions of treatment response that can be defined a priori in clinical trials.

CYP2A6 metabolism in the development of smoking behaviors in young adults.

Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones. A total of 1209 European American young adults enrolled in the Collaborative Study on the Genetics of Alcoholism were genotyped for CYP2A6 variants to calculate a previously well-validated metric that estimates nicotine metabolism. This metric was not associated with the transition from never smoking to smoking initiation nor with the transition from initiation to daily smoking (P > 0.4). But among young adults who had become daily smokers (n = 506), decreased metabolism was associated with increased risk of nicotine dependence (P = 0.03) (defined as Fagerström Test for Nicotine Dependence score ≥4). This finding was replicated in the Collaborative Genetic Study of Nicotine Dependence with 335 young adult daily smokers (P = 0.02). Secondary meta-analysis indicated that slow metabolizers had a 53 percent increased odds (OR = 1.53, 95 percent CI 1.11-2.11, P = 0.009) of developing nicotine dependence compared with normal metabolizers. Furthermore, secondary analyses examining four-level response of time to first cigarette after waking (>60, 31-60, 6-30, ≤5 minutes) demonstrated a robust effect of the metabolism metric in Collaborative Study on the Genetics of Alcoholism (P = 0.03) and Collaborative Genetic Study of Nicotine Dependence (P = 0.004), illustrating the important role of this measure of dependence. These findings highlight the complex role of CYP2A6 variation across different developmental stages of smoking behaviors.

The significant impact of education, poverty, and race on Internet-based research participant engagement.

PURPOSE: Internet-based technologies are increasingly being used for research studies. However, it is not known whether Internet-based approaches will effectively engage participants from diverse racial and socioeconomic backgrounds. METHODS: A total of 967 participants were recruited and offered genetic ancestry results. We evaluated viewing Internet-based genetic ancestry results among participants who expressed high interest in obtaining the results. RESULTS: Of the participants, 64% stated that they were very or extremely interested in their genetic ancestry results. Among interested participants, individuals with a high school diploma (n = 473) viewed their results 19% of the time relative to 4% of the 145 participants without a diploma (P < 0.0001). Similarly, 22% of participants with household income above the federal poverty level (n = 286) viewed their results relative to 10% of the 314 participants living below the federal poverty level (P < 0.0001). Among interested participants both with a high school degree and living above the poverty level, self-identified Caucasians were more likely to view results than self-identified African Americans (P < 0.0001), and females were more likely to view results than males (P = 0.0007). CONCLUSION: In an underserved population, engagement in Internet-based research was low despite high reported interest. This suggests that explicit strategies should be developed to increase diversity in Internet-based research.Genet Med 19 2, 240-243.

Implications of Personal Genomic Testing for Health Behaviors: The Case of Smoking.

INTRODUCTION: Direct-to-consumer personal genomic testing has the potential to influence health behaviors, including smoking. Critics of this testing highlight limited evidence to support positive behavioral benefits and caution that genomic results may provide false reassurance, leading to unhealthy behaviors. This study investigates interest in genetic risks of smoking-related diseases and changes in smoking behaviors among genomic testing consumers. METHODS: From 2012 to 2013, a longitudinal series of web surveys was conducted. A total of 1464 customers of 23andMe and Pathway Genomics completed a survey prior to viewing genomic test results, of which 1002 participants provided data on smoking behaviors 6 months after receiving results. RESULTS: At baseline, 64% of participants were never smokers, 29% were former smokers, and 7% were current smokers. Most baseline current smokers were very interested in genetic risk results for lung cancer (65%) and heart disease (72%). For lung cancer, this interest was significantly greater than former (50% very interested) and never smokers (37% very interested) (p < .0001). Even though participants were interested in smoking-related disease genetic risks, 96% reported the same smoking status at baseline and 6-month follow-up. Importantly, only 1% (n = 13/916) of former and never smokers became current smokers at 6 months and 22% (n = 14/64) of current smokers reported quitting. CONCLUSIONS: Overall, smokers show a high level of interest in genetic risks of smoking-related illnesses. The experience of receiving direct-to-consumer genomic health risks does not appear to have obvious harms related to smoking behaviors, with some potential benefits. IMPLICATIONS: In the setting of ongoing controversy surrounding direct-to-consumer genomic testing, this study provides evidence that consumers are interested in genetic risk results of smoking-related diseases. Receiving genomic testing results does not lead to smoking initiation among never smokers or reinitiation among former smokers and may be associated with a higher quit rate among current smokers at 6-month follow-up than the general population. These findings ease concerns that direct-to-consumer genomic testing could lead to false reassurance and unhealthy behaviors related to smoking.

When Does Choice of Accuracy Measure Alter Imputation Accuracy Assessments?

Imputation, the process of inferring genotypes for untyped variants, is used to identify and refine genetic association findings. Inaccuracies in imputed data can distort the observed association between variants and a disease. Many statistics are used to assess accuracy; some compare imputed to genotyped data and others are calculated without reference to true genotypes. Prior work has shown that the Imputation Quality Score (IQS), which is based on Cohen's kappa statistic and compares imputed genotype probabilities to true genotypes, appropriately adjusts for chance agreement; however, it is not commonly used. To identify differences in accuracy assessment, we compared IQS with concordance rate, squared correlation, and accuracy measures built into imputation programs. Genotypes from the 1000 Genomes reference populations (AFR N = 246 and EUR N = 379) were masked to match the typed single nucleotide polymorphism (SNP) coverage of several SNP arrays and were imputed with BEAGLE 3.3.2 and IMPUTE2 in regions associated with smoking behaviors. Additional masking and imputation was conducted for sequenced subjects from the Collaborative Genetic Study of Nicotine Dependence and the Genetic Study of Nicotine Dependence in African Americans (N = 1,481 African Americans and N = 1,480 European Americans). Our results offer further evidence that concordance rate inflates accuracy estimates, particularly for rare and low frequency variants. For common variants, squared correlation, BEAGLE R2, IMPUTE2 INFO, and IQS produce similar assessments of imputation accuracy. However, for rare and low frequency variants, compared to IQS, the other statistics tend to be more liberal in their assessment of accuracy. IQS is important to consider when evaluating imputation accuracy, particularly for rare and low frequency variants.

Identification of Medically Actionable Secondary Findings in the 1000 Genomes.

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.

Return of individual genetic results in a high-risk sample: enthusiasm and positive behavioral change.

PURPOSE: The goal of this study was to examine participant responses to disclosure of genetic results in a minority population at high risk for depression and anxiety. METHODS: Eighty-two subjects in a genetic study of nicotine dependence were offered personalized genetic results. All were nicotine-dependent and 64% self-identified as African American. Pathway Genomics was used to evaluate genetic risks for five complex diseases. Participants returned 4-8 weeks after enrollment for in-person genetic counseling interviews and evaluation of baseline measures. A telephone follow-up was performed 4-8 weeks later to assess responses to results. RESULTS: Fifty of the 82 subjects (61%) were interested in receiving genetic results. These participants had multiple risk factors, including high baseline measures of depression (66%) and anxiety (32%), as well as low rates of employment (46%), adequate health literacy (46%), and health insurance (45%). Pathway Genomics reported "increased risk" for at least one disease in 77% of subjects. Ninety-five percent of participants reported that they appreciated the genetic results, and receiving these results was not associated with changes in symptoms of depression or anxiety. Furthermore, after return of genetic results, smoking cessation attempts increased (P = 0.003). CONCLUSION: Even in an underserved population at high risk for adverse psychological reactions, subjects responded positively to personalized genetic results.

An ADH1B variant and peer drinking in progression to adolescent drinking milestones: evidence of a gene-by-environment interaction.

BACKGROUND: 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.

Summaries of oral sessions at the XXI World Congress of Psychiatric Genetics, Boston, Massachusetts, 17-21 October 2013: state of the field.

The XXI World Congress of Psychiatric Genetics (WCPG), sponsored by the International Society of Psychiatric Genetics (ISPG), took place in Boston, Massachusetts, on 17-21 October 2013. Approximately 900 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported.

Convergence of genome-wide association and candidate gene studies for alcoholism.

BACKGROUND: Genome-wide association (GWA) studies have led to a paradigm shift in how researchers study the genetics underlying disease. Many GWA studies are now publicly available and can be used to examine whether or not previously proposed candidate genes are supported by GWA data. This approach is particularly important for the field of alcoholism because the contribution of many candidate genes remains controversial. METHODS: Using the Human Genome Epidemiology (HuGE) Navigator, we selected candidate genes for alcoholism that have been frequently examined in scientific articles in the past decade. Specific candidate loci as well as all the reported single nucleotide polymorphisms (SNPs) in candidate genes were examined in the Study of Addiction: Genetics and Environment (SAGE), a GWA study comparing alcohol-dependent and nondependent subjects. RESULTS: Several commonly reported candidate loci, including rs1800497 in DRD2, rs698 in ADH1C, rs1799971 in OPRM1, and rs4680 in COMT, are not replicated in SAGE (p > 0.05). Among candidate loci available for analysis, only rs279858 in GABRA2 (p = 0.0052, OR = 1.16) demonstrated a modest association. Examination of all SNPs reported in SAGE in over 50 candidate genes revealed no SNPs with large frequency differences between cases and controls, and the lowest p-value of any SNP was 0.0006. CONCLUSIONS: We provide evidence that several extensively studied candidate loci do not have a strong contribution to risk of developing alcohol dependence in European and African ancestry populations. Owing to the lack of coverage, we were unable to rule out the contribution of other variants, and these genes and particular loci warrant further investigation. Our analysis demonstrates that publicly available GWA results can be used to better understand which if any of previously proposed candidate genes contribute to disease. Furthermore, we illustrate how examining the convergence of candidate gene and GWA studies can help elucidate the genetic architecture of alcoholism and more generally complex diseases.