Arpana Agrawal

The genetics of addiction—a translational perspective

Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.

Polygenic Risk for Externalizing Disorders Gene-by-Development and Gene-by-Environment Effects in Adolescents and Young Adults

In this project, we aimed to bring large-scale gene-identification findings into a developmental psychopathology framework. Using a family-based sample, we tested whether polygenic scores for externalizing disorders—based on single nucleotide polymorphism weights derived from genome-wide association study results in adults (n = 1,249)—predicted externalizing disorders, subclinical externalizing behavior, and impulsivity-related traits among adolescents (n = 248) and young adults (n = 207) and whether parenting and peer factors in adolescence moderated polygenic risk to predict externalizing disorders. Polygenic scores predicted externalizing disorders in adolescents and young adults, even after we controlled for parental externalizing-disorder history. Polygenic scores also predicted subclinical externalizing behavior and impulsivity traits in the adolescents and young adults. Adolescent parental monitoring and peer substance use moderated polygenic scores to predict externalizing disorders. This illustrates how state-of-the-science genetics can be integrated with psychological science to identify how genetic risk contributes to the development of psychopathology.

Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence

BACKGROUNDnExcessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE).nnnMETHODSnAll participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory.nnnRESULTSnCNVs in 6q14.1 (p = 1.04 × 10(-6)) and 5q13.2 (p = 3.37 × 10(-4)) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution.nnnCONCLUSIONSnThis is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence.

Rapid video-referenced ratings of reciprocal social behavior in toddlers: a twin study

BACKGROUNDnReciprocal social behavior (RSB) is a developmental prerequisite for social competency, and deficits in RSB constitute a core feature of autism spectrum disorder (ASD). Although clinical screeners categorically ascertain risk of ASD in early childhood, rapid methods for quantitative measurement of RSB in toddlers are not yet established. Such measurements are critical for tracking developmental trajectories and incremental responses to intervention.nnnMETHODSnWe developed and validated a 20-min video-referenced rating scale, the video-referenced rating of reciprocal social behavior (vrRSB), for untrained caregivers to provide standardized ratings of quantitative variation in RSB. Parents of 252 toddler twins [Monozygotic (MZ)xa0=xa031 pairs, Dizygotic (DZ)xa0=xa095 pairs] ascertained through birth records, rated their twins RSB at two time points, on average 6xa0months apart, and completed two developmental measures, the Modified Checklist for Autism in Toddlers (M-CHAT) and the MacArthur Communicative Development Inventory Short Form (MCDI-s).nnnRESULTSnScores on the vrRSB were fully continuously distributed, with excellent 6-month test-retest reliability ([intraclass correlation coefficient] ICCxa0=xa00.704, pxa0<xa0.000). MZ twins displayed markedly greater trait concordance than DZ twins, (MZ ICCxa0=xa00.863, pxa0<xa0.000, DZ ICCxa0=xa00.231, pxa0<xa0.012). VrRSB score distributions were highly distinct for children passing versus failing the M-CHAT (txa0=xa0-8.588, dfxa0=xa031, pxa0<xa0.000), incrementally improved from 18-24xa0months, and were inversely correlated with receptive and expressive vocabulary on the MCDI-s.nnnCONCLUSIONSnLike quantitative autistic trait ratings in school-aged children and adults, toddler scores on the vrRSB are continuously distributed and appear highly heritable. These ratings exhibited minimal measurement error, high inter-individual stability, and developmental progression in RSB as children matured from 18-24xa0months, supporting their potential utility for serially quantifying the severity of early autistic syndromes over time and in response to intervention. In addition, these findings inform the genetic-environmental structure of RSB in early typical development.

An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry

Fast beta (20–28u2009Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10−8. The most significantly associated SNP, rs11720469 (β: −0.124; P<4.5 × 10−9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24u2009h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Evidence of causal effect of major depression on alcohol dependence: Findings from the Psychiatric Genomics Consortium

Background Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. Methods This study was conducted using genome-wide data from the Psychiatric Genomics Consortium (MD: 135,458 cases and 344,901 controls; AD: 10,206 cases and 28,480 controls) and UK Biobank (AC-Frequency: from “daily or almost daily” to “never”, 438,308 individuals; AC-Quantity: total units of alcohol per week, 307,098 individuals). Linkage disequilibrium score regression and Mendelian Randomization (MR) analyses were applied to investigate shared genetic mechanisms (horizontal pleiotropy) and causal relationships (mediated pleiotropy) among these traits. Outcomes Positive genetic correlation was observed between MD and AD (rgMD-AD=+0.47, P=6.6×10-10). AC-Quantity showed positive genetic correlation with both AD (rgAD-AC-Quantity=+0.75, P=1.8×10-14) and MD (rgMD-AC-Quantity=+0.14, P=2.9×10-7), while there was negative correlation of AC-Frequency with MD (rgMD-AC-Frequency=-0.17, P=1.5×10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e., causal relationship) with a causal role of MD on AD (beta=0.28, P=1.29×10-6) that does not appear to be biased by confounding such as horizontal pleiotropy. No evidence of reverse causation was observed as the AD genetic instrument did not show a causal effect on MD. Interpretation Results support a causal role for MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity not only addresses important public health concerns but also has the potential to facilitate prevention and intervention efforts. Funding National Institute of Mental Health and National Institute on Drug Abuse. Putting data into context Evidence before this study We searched PubMed up to August 24, 2018, for research studies that investigated causality among alcohol-and depression related phenotypes using Mendelian randomization approaches. We used the search terms “alcohol” AND “depression” AND “Mendelian Randomization”. No restrictions were applied to language, date, or article type. Ten articles were retrieved, but only two were focused on alcohol consumption and depression-related traits. The studies were based on genetic variants in alcohol dehydrogenase (ADH) genes only, did not find evidence for a causal effect of alcohol consumption on depression phenotypes, with one study finding a causal effect of alcohol consumption on alcoholism. Both studies noted that future studies are needed with increased sample sizes and clinically derived phenotypes. To our knowledge, no previous study has applied two-sample Mendelian randomization to investigate causal relationships between alcohol dependence and major depression. Twin studies show genetic factors influence susceptibility to MD, AD, and alcohol consumption. Differently from observational approaches where several studies have investigated the relationship between alcohol-and depression-related phenotypes, very limited use of molecular genetic data has been applied to investigate this issue. Additionally, the use of genetic information has been shown to be less biased by confounders and reverse causation than observation data. However, genetic approaches, like Mendelian randomization, require large sample sizes to be informative. Added value of this study In this study, we used genome-wide data from the Psychiatric Genomic Consortium and UK Biobank, which include information regarding hundred thousands of individuals, to test the presence of shared genetic mechanisms and causal relationships among major depression, alcohol dependence, and alcohol consumption. The results support a causal influence of MD on AD, while alcohol consumption showed shared genetic mechanisms with respect to both major depression and alcohol dependence. Implications of all the available evidence Given the significant morbidity and mortality associated with MD, AD, and the comorbid condition, understanding mechanisms underlying these associations not only address important public health concerns but also has the potential to facilitate prevention and intervention efforts.

Adolescent cannabis use and repeated voluntary unprotected sex in women

BACKGROUND AND AIMSnSubstance use has been implicated in the onset and maintenance of risky sexual behaviors, which have particularly devastating consequences in young women. This study examined whether (i) adolescent onset of cannabis use is associated with repeated voluntary unprotected sex in women and (ii) whether this association persists after accounting for correlated familial influences.nnnDESIGNnGeneral population sample of female twins.nnnSETTINGnMidwestern United States.nnnPARTICIPANTSnA total of 2784 sexually active twin women (15.5% African American) aged 18-27xa0years (assessed 2002-05), including 119 dizygotic (DZ) and 115 monozygotic (MZ) discordant pairs.nnnMEASUREMENTSnSelf-report interview data on cannabis use that first occurred prior to age 17 (27.1%) and repeated voluntary unprotected sex (27.2%). Key covariates included early onset of regular drinking, regular smoking, sexual debut and menstruation as well as conduct disorder symptoms and childhood sexual abuse.nnnFINDINGSnCompared with never users and those who started using cannabis at a later age, adolescent cannabis users were more likely to report repeated voluntary unprotected sex [odds ratio (OR)xa0=xa02.69; 95% confidence interval (CI)xa0=xa02.24-3.22]. Genetic (rg xa0=xa00.57, 95% CIxa0=xa00.38-0.87) and non-shared environmental (re xa0=xa00.21, 95% CIxa0=xa00.02-0.38) factors contributed to the association. After accounting for correlated familial factors, there was a consistent elevation in the likelihood of repeated voluntary unprotected sex in the exposed twin relative to her genetically identical never/late-onset user co-twin (unadjusted ORxa0=xa02.25, 95% CIxa0=xa01.14-4.44), even after adjustment for covariates (adjusted ORxa0=xa02.27, 95% CIxa0=xa01.08-4.80).nnnCONCLUSIONSnWomen who start using cannabis during adolescence appear to be more likely to report voluntary engagement in repeated unprotected sex than women who never use cannabis or who initiate cannabis use after adolescence. The results appear to be independent of shared genetic influences.