Alexis C. Edwards

Genome-wide association study of comorbid depressive syndrome and alcohol dependence

Objective Depression and alcohol dependence (AD) are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that AD and depression are genetically correlated. Herein, we report results from a genome-wide association study of a comorbid phenotype, in which cases meet the Diagnostic and Statistical Manual of Mental Disorders-IV symptom threshold for major depressive symptomatology and the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for AD. Methods Samples (N=467 cases and N=407 controls) were of European-American descent and were genotyped using the Illumina Human 1M BeadChip array. Results Although no single-nucleotide polymorphism (SNP) meets genome-wide significance criteria, we identified 10 markers with P values less than 1×10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding P values less than 1×10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, AD, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an AD-only phenotype is modest. Conclusion These results underscore the complex genomic influences on psychiatric phenotypes and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect AD alone.

Genome-wide association study of conduct disorder symptomatology

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD. In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence. Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N=872 with CD and N=3091 without CD). We find four markers that meet the criteria for genome-wide significance (P<5 × 10−8) with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association. These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder.

A population-based twin study of the genetic and environmental relationship of major depression, regular tobacco use and nicotine dependence

BACKGROUND Numerous epidemiological studies have reported a positive association between major depression (MD) and regular tobacco use (RU) or nicotine dependence (ND). However, few have used a genetically informative design to assess whether these traits share a common genetic and/or environmental liability. METHOD We assessed MD, RU and ND in same-sex twins from the population-based Swedish Twin Registry. In males, we examined both cigarette use and snus (smokeless tobacco) use. We used structural equation modeling to examine the relationship between MD, RU, and ND given RU. RESULTS The results suggest modest correlations between MD and RU, and between MD and ND. In males, the liability shared between MD and RU is solely genetic for both cigarettes and snus, while MD and ND share both genetic and unique environmental influences. The continuation to ND given RU differed considerably between cigarette and snus users. In females, both MD-RU and MD-ND relationships are partially attributable to genetic and unique environmental correlations. CONCLUSIONS The relationship among MD, RU and ND is at least partially attributable to shared genetic and environmental risk factors. The genetic and environmental correlations between traits are modest. The nature of the shared liability differs by sex, and in males, by the type of tobacco product used. Differences between previous reports and results presented in the current study are suggestive of population differences in how MD and tobacco use inter-relate.

MAOA-uVNTR and Early Physical Discipline Interact to Influence Delinquent Behavior.

BACKGROUND A functional polymorphism in the promoter region of the monoamine oxidizing gene monoamine oxidase A (MAOA) has been associated with behavioral sensitivity to adverse environmental conditions in multiple studies (e.g., Caspi et al. 2002; Kim-Cohen et al., 2006). The present study investigates the effects of genotype and early physical discipline on externalizing behavior. We expand on the current literature in our assessment of externalizing, incorporating information across multiple reporters and over a broad developmental time period, and in our understanding of environmental risk. METHOD This study uses data from the Child Development Project, an ongoing longitudinal study following a community sample of children beginning at age 5. Physical discipline before age 6 was quantified using a subset of questions from the Conflict Tactics Scale (Straus, 1979). Externalizing behavior was assessed in the male, European-American sub-sample (N = 250) by parent, teacher, and self-report using Achenbachs Child Behavior Checklist, Teacher Report Form, and Youth Self-Report (Achenbach, 1991), at 17 time points from ages 6 to 22. Regression analyses tested the influence of genotype, physical discipline, and their interaction on externalizing behavior, and its subscales, delinquency and aggression. RESULTS We found a significant interaction effect between genotype and physical discipline on levels of delinquent behavior. Similar trends were observed for aggression and overall externalizing behavior, although these did not reach statistical significance. Main effects of physical discipline held for all outcome variables, and no main effects held for genotype. CONCLUSION The adverse consequences of physical discipline on forms of externalizing behavior are exacerbated by an underlying biological risk conferred by MAOA genotype.

Polygenic Scores Predict Alcohol Problems in an Independent Sample and Show Moderation by the Environment

Alcohol problems represent a classic example of a complex behavioral outcome that is likely influenced by many genes of small effect. A polygenic approach, which examines aggregate measured genetic effects, can have predictive power in cases where individual genes or genetic variants do not. In the current study, we first tested whether polygenic risk for alcohol problems—derived from genome-wide association estimates of an alcohol problems factor score from the age 18 assessment of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4304 individuals of European descent; 57% female)—predicted alcohol problems earlier in development (age 14) in an independent sample (FinnTwin12; n = 1162; 53% female). We then tested whether environmental factors (parental knowledge and peer deviance) moderated polygenic risk to predict alcohol problems in the FinnTwin12 sample. We found evidence for both polygenic association and for additive polygene-environment interaction. Higher polygenic scores predicted a greater number of alcohol problems (range of Pearson partial correlations 0.07–0.08, all p-values ≤ 0.01). Moreover, genetic influences were significantly more pronounced under conditions of low parental knowledge or high peer deviance (unstandardized regression coefficients (b), p-values (p), and percent of variance (R2) accounted for by interaction terms: b = 1.54, p = 0.02, R2 = 0.33%; b = 0.94, p = 0.04, R2 = 0.30%, respectively). Supplementary set-based analyses indicated that the individual top single nucleotide polymorphisms (SNPs) contributing to the polygenic scores were not individually enriched for gene-environment interaction. Although the magnitude of the observed effects are small, this study illustrates the usefulness of polygenic approaches for understanding the pathways by which measured genetic predispositions come together with environmental factors to predict complex behavioral outcomes.

An extended Swedish national adoption study of alcohol use disorder.

IMPORTANCE Alcohol use disorder (AUD) runs strongly in families. It is unclear to what extent the cross-generational transmission of AUD results from genetic vs environmental factors. OBJECTIVE To determine to what extent genetic and environmental factors contribute to the risk for AUD. DESIGN, SETTING, AND PARTICIPANTS Follow-up in 8 public data registers of adoptees, their biological and adoptive relatives, and offspring and parents from stepfamilies and not-lived-with families in Sweden. In this cohort study, subtypes of AUD were assessed by latent class analysis. A total of 18,115 adoptees (born 1950-1993) and 171,989 and 107,696 offspring of not-lived-with parents and stepparents, respectively (born 1960-1993). MAIN OUTCOMES AND MEASURES Alcohol use disorder recorded in medical, legal, or pharmacy registry records. RESULTS Alcohol use disorder in adoptees was significantly predicted by AUD in biological parents (odds ratio, 1.46; 95% CI, 1.29-1.66) and siblings (odds ratio, 1.94; 95% CI, 1.55-2.44) as well as adoptive parents (odds ratio, 1.40; 95% CI, 1.09-1.80). Genetic and environmental risk indices created from biological and adoptive relatives acted additively on adoptee AUD liability. Results from biological and adoptive relatives were replicated and extended from examinations of, respectively, not-lived-with parents and stepparents. Multivariate models in these families showed that AUD in offspring was significantly predicted by AUD, drug abuse, psychiatric illness, and crime in not-lived-with parents and by AUD, drug abuse, crime, and premature death in stepparents. Latent class analyses of adoptees and offspring of not-lived-with parents with AUDs revealed 3 AUD classes characterized by (1) female preponderance and high rates of psychiatric illness, (2) mild nonrecurrent symptoms, and (3) early-onset recurrence, drug abuse, and crime. These classes had distinct genetic signatures in the patterns of risk for various disorders in their not-lived-with parents and striking differences in the rates of recorded mood disorders. CONCLUSIONS AND RELEVANCE Parent-offspring transmission of AUD results from both genetic and environmental factors. Genetic risk for AUD reflects both a specific liability to AUD and to other externalizing disorders. Environmental risk reflects features of both parental psychopathology and other aspects of the rearing environment. Alcohol use disorder is a heterogeneous syndrome and meaningful subtypes emerged from latent class analysis, which were validated by patterns of disorders in biological parents and specific psychiatric comorbidities. The general population contains informative family constellations that can complement more traditional adoption designs in clarifying the sources of parent-offspring resemblance.

Spit for Science: launching a longitudinal study of genetic and environmental influences on substance use and emotional health at a large US university.

Finding genes involved in complex behavioral outcomes, and understanding the pathways by which they confer risk, is a challenging task, necessitating large samples that are phenotypically well characterized across time. We describe an effort to create a university-wide research project aimed at understanding how genes and environments impact alcohol use and related substance use and mental health outcomes across time in college students. Nearly 70% of the incoming freshman class (N = 2715) completed on-line surveys, with 80% of the students from the fall completing spring follow-ups. 98% of eligible participants also gave DNA. The participants closely approximated the university population in terms of gender and racial/ethnic composition. Here we provide initial results on alcohol use outcomes from the first wave of the sample, as well as associated predictor variables. We discuss the potential for this kind of research to advance our understanding of genetic and environment influences on substance use and mental health outcomes.

Dimensions of Parental Alcohol Use/Problems and Offspring Temperament, Externalizing Behaviors, and Alcohol Use/Problems

BACKGROUND Alcohol consumption (AC) and alcohol problems (AP) are complex traits. How many factors reflecting parental AC and AP are present in the large prospectively followed Avon Longitudinal Study of Parents and Children cohort? Would these factors be uniquely associated with various temperamental and alcohol-related outcomes in the children? METHODS We factor-analyzed multiple items reflecting maternal and paternal AC and AP measured over a 12-year period from before the birth of the child (n = 14,093 families). We examined, by linear regression controlling for socioeconomic status, the relationship between scales derived from these factors and offspring early childhood temperament, externalizing traits, and adolescent AC and AP (ns ranging from 9,732 to 3,454). RESULTS We identified 5 coherent factors: typical maternal AC, maternal AC during pregnancy, maternal AP, paternal AC, and paternal AP. In univariate analyses, maternal and paternal AC and AP were modestly and significantly associated with low shyness, sociability, hyperactivity, and conduct problems in childhood and early adolescence; delinquent behavior at age 15; and AC and AP at ages 15 and 18. AC and AP at age 18 were more strongly predicted by parental factors than at age 15. Maternal AC during pregnancy uniquely predicted externalizing traits at ages 4, 13, and 15. CONCLUSIONS Parental AC and AP are complex multidimensional traits that differ in their association with a range of relevant measures in their children. Controlling for background AC and AP, self-reported levels of maternal AC during pregnancy uniquely predicted externalizing behaviors in childhood and adolescence.

A twin study of depression and nicotine dependence: Shared liability or causal relationship?

BACKGROUND The nature of the relationship between major depression (MD) and phenotypes related to smoking behavior, including nicotine dependence (ND), is complicated. We present results from analyses comparing models wherein MD and ND are influenced by a shared latent factor to one in which causal pathways between phenotypes are examined. METHOD Data were collected for 2906 adult male twins from a population-based sample. Structural equation modeling was used to derive path estimates for shared liability and causal models. MD was assessed according to DSM-III-R diagnostic criteria; ND was assessed using the Fagerstrom Test for Nicotine Dependence (FTND). RESULTS The best fitting shared liability model included genetic, but not environmental, influences shared between MD and FTND; a small proportion of these shared influences were also common to smoking initiation. The best fitting causal model included a unidirectional causal path from FTND to MD, with no direct genetic correlation between MD and smoking initiation. Model fit statistics indicated that these models provided nearly identical fits to the data, with the causal model providing a slightly superior AIC value. CONCLUSIONS The phenotypic association between MD and FTND is likely due to both a causal relationship, wherein increasing levels of nicotine dependence increase ones risk for depression, and to a shared genetic liability between the two. LIMITATIONS This sample consists of Caucasian males born in Virginia, and findings might not be generalizable to others. Statistical power was less than ideal.

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Significance Alcohol abuse is a significant social problem for which the molecular etiology is poorly understood. One recognized component of the progression to abuse disorders is the development of alcohol tolerance, and recently epigenetic modification of gene expression has been implicated in tolerance. Here, we use Caenorhabditis elegans to show that the conserved switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex, which modifies the transcriptional status of target genes, is required in adults and neurons for the development of acute alcohol tolerance. We predicted that allelic variation in genes that modify tolerance phenotypes may modify abuse liability in humans, and we identified a significant association between variation in one member of the SWI/SNF complex and a diagnosis of alcohol dependence in a human genomewide association study. Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.