Neurogenetic and multi-omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder.

Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples, and shared neurobiological and genetic influences may in part explain these associations. Links between sensation seeking and alcohol use disorder (AUD) may primarily manifest via increased alcohol consumption rather than through direct effects on increasing problems and consequences. Here the overlap among sensation seeking, alcohol consumption, and AUD was examined using multivariate modelling approaches for genome-wide association study (GWAS) summary statistics in conjunction with neurobiologically informed analyses at multiple levels of investigation. Meta-analytic and genomic structural equation modelling (GenomicSEM) approaches were used to conduct GWAS of sensation seeking, alcohol consumption, and AUD. Resulting summary statistics were used in downstream analyses to examine shared brain tissue enrichment of heritability and genome-wide evidence of overlap (e.g., stratified GenomicSEM, RRHO, genetic correlations with neuroimaging phenotypes), and to identify genomic regions likely contributing to observed genetic overlap across traits (e.g., H-MAGMA and LAVA). Across approaches, results supported shared neurogenetic architecture between sensation seeking and alcohol consumption characterised by overlapping enrichment of genes expressed in midbrain and striatal tissues and variants associated with increased cortical surface area. Alcohol consumption and AUD evidenced overlap in relation to variants associated with decreased frontocortical thickness. Finally, genetic mediation models provided evidence of alcohol consumption mediating associations between sensation seeking and AUD. This study extends previous research by examining critical sources of neurogenetic and multi-omic overlap among sensation seeking, alcohol consumption, and AUD which may underlie observed phenotypic associations.

Dual-systems models of the genetic architecture of impulsive personality traits: neurogenetic evidence of distinct but related factors.

BACKGROUND: Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. METHODS: Using IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared. RESULTS: GenomicSEM dual-systems models underscored important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg = 0.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g. lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). No significant associations were observed with subcortical phenotypes. CONCLUSIONS: Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology.

Specificity in genetic and environmental risk for prescription opioid misuse and heroin use.

BACKGROUND: Many studies aggregate prescription opioid misuse (POM) and heroin use into a single phenotype, but emerging evidence suggests that their genetic and environmental influences may be partially distinct. METHODS: In total, 7164 individual twins (84.12% complete pairs; 59.81% female; mean age = 30.58 years) from the Australian Twin Registry reported their lifetime misuse of prescription opioids, stimulants, and sedatives, and lifetime use of heroin, cannabis, cocaine/crack, illicit stimulants, hallucinogens, inhalants, solvents, and dissociatives via telephone interview. Independent pathway models (IPMs) and common pathway models (CPMs) partitioned the variance of drug use phenotypes into general and drug-specific genetic (a), common environmental (c), and unique environmental factors (e). RESULTS: An IPM with one general a and one general e factor and a one-factor CPM provided comparable fit to the data. General factors accounted for 55% (a = 14%, e = 41%) and 79% (a = 64%, e = 15%) of the respective variation in POM and heroin use in the IPM, and 25% (a = 12%, c = 8%, e = 5%) and 80% (a = 38%, c = 27%, e = 15%) of the respective variation in POM and heroin use in the CPM. Across both models, POM emerged with substantial drug-specific genetic influence (26-39% of total phenotypic variance; 69-74% of genetic variance); heroin use did not (0% of total phenotypic variance; 0% of genetic variance in both models). Prescription sedative misuse also demonstrated significant drug-specific genetic variance. CONCLUSIONS: Genetic variation in POM, but not heroin use, is predominantly drug-specific. Misuse of prescription medications that reduce experiences of subjective distress may be partially influenced by sources of genetic variation separate from illicit drug use.

Educational Attainment Polygenic Scores: Examining Evidence for Gene-Environment Interplay with Adolescent Alcohol, Tobacco and Cannabis Use.

Genes associated with educational attainment may be related to or interact with adolescent alcohol, tobacco and cannabis use. Potential gene-environment interplay between educational attainment polygenic scores (EA-PGS) and adolescent alcohol, tobacco, and cannabis use was evaluated with a series of regression models fitted to data from a sample of 1871 adult Australian twins. All models controlled for age, age2, cohort, sex and genetic ancestry as fixed effects, and a genetic relatedness matrix was included as a random effect. Although there was no evidence that adolescent alcohol, tobacco or cannabis use interacted with EA-PGS to influence educational attainment, there was a significant, positive gene-environment correlation with adolescent alcohol use at all PGS thresholds (ps <.02). Higher EA-PGS were associated with an increased likelihood of using alcohol as an adolescent (ΔR2 ranged from 0.5% to 1.1%). The positive gene-environment correlation suggests a complex relationship between educational attainment and alcohol use that is due to common genetic factors.

The Association Between Alcohol Consumption and Pain Interference in a Nationally Representative Sample: The Moderating Roles of Gender and Alcohol Use Disorder Symptomatology.

BACKGROUND: Prior research on alcohol consumption and pain has yielded inconsistent results regarding the directionality of effects for both consumption-to-pain and pain-to-consumption relations. The present study sought to examine directionality of these relations by testing bidirectional longitudinal associations between consumption and pain interference, a crucial aspect of pain that captures pain-related disability and has been regarded as a valuable measure of treatment outcome. In addition, this study explored possible moderation of these bidirectional longitudinal associations by gender and alcohol use disorder (AUD) symptomatology. METHODS: Analyses included 29,989 current/former drinkers who were interviewed at both waves (2001 and 2004) of the U.S. National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Analyses used self-report data from both waves on past-year average daily volume of alcohol consumed and past-month pain interference (1 item from the Medical Outcomes Study 12-item Short-Form Health Survey [MOS-SF-12]). AUDADIS-IV data from Wave 1 were used to index baseline AUD symptomatology (i.e., symptom count). Cross-lagged panel modeling and multigroup analyses were employed. RESULTS: Regarding the consumption-to-pain-interference relation, in general, higher baseline alcohol consumption was associated with lower subsequent pain interference at follow-up. However, among men with higher AUD-symptom counts, the opposite pattern emerged, with higher baseline alcohol consumption being significantly related to higher subsequent pain interference at follow-up. Regarding the pain-interference-to-consumption relation, higher baseline pain interference was significantly associated with lower subsequent alcohol consumption at follow-up, and no moderating effects were observed. CONCLUSIONS: The distinctive patterns of the consumption-to-pain-interference relation observed among men with elevated AUD symptomatology suggest that this relation might be driven by different mechanisms across different groups of individuals. Specifically, the detrimental effect of alcohol on pain interference might emerge at relatively advanced stages of AUD among men, consistent with Koob's Dark Side of Alcohol Addiction theory in human research.

Common genetic contributions to high-risk trauma exposure and self-injurious thoughts and behaviors.

BACKGROUND: Prior research has documented shared heritable contributions to non-suicidal self-injury (NSSI) and suicidal ideation (SI) as well as NSSI and suicide attempt (SA). In addition, trauma exposure has been implicated in risk for NSSI and suicide. Genetically informative studies are needed to determine common sources of liability to all three self-injurious thoughts and behaviors, and to clarify the nature of their associations with traumatic experiences. METHODS: Multivariate biometric modeling was conducted using data from 9526 twins [59% female, mean age = 31.7 years (range 24-42)] from two cohorts of the Australian Twin Registry, some of whom also participated in the Childhood Trauma Study and the Nicotine Addiction Genetics Project. RESULTS: The prevalences of high-risk trauma exposure (HRT), NSSI, SI, and SA were 24.4, 5.6, 27.1, and 4.6%, respectively. All phenotypes were moderately to highly correlated. Genetic influences on self-injurious thoughts and behaviors and HRT were significant and highly correlated among men [rG = 0.59, 95% confidence interval (CI) (0.37-0.81)] and women [rG = 0.56 (0.49-0.63)]. Unique environmental influences were modestly correlated in women [rE = 0.23 (0.01-0.45)], suggesting that high-risk trauma may confer some direct risk for self-injurious thoughts and behaviors among females. CONCLUSIONS: Individuals engaging in NSSI are at increased risk for suicide, and common heritable factors contribute to these associations. Preventing trauma exposure may help to mitigate risk for self-harm and suicide, either directly or indirectly via reductions in liability to psychopathology more broadly. In addition, targeting pre-existing vulnerability factors could significantly reduce risk for life-threatening behaviors among those who have experienced trauma.

Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling.

Disordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity.

BACKGROUND: Previous studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported. METHODS: We conducted a meta-analysis of 2 population-based genome-wide association studies of the Self-Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)-based heritability and conducted a series of secondary aggregate genetic analyses. RESULTS: No individual locus reached genome-wide significance. Gene and set based analyses, both overall and using tissue-specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta-analysis of SNP-based heritability resulted in a modest estimate of hSNP2  = 0.19 (SE = 0.10), though this was driven by 1 sample (N = 3,683, hSNP2  = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed. CONCLUSIONS: Findings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings.

Whole genome sequence study of cannabis dependence in two independent cohorts.

Recent advances in genome wide sequencing techniques and analytical methods allow for more comprehensive examinations of the genome than microarray-based genome-wide association studies (GWAS). The present report provides the first application of whole genome sequencing (WGS) to identify low frequency variants involved in cannabis dependence across two independent cohorts. The present study used low-coverage whole genome sequence data to conduct set-based association and enrichment analyses of low frequency variation in protein-coding regions as well as regulatory regions in relation to cannabis dependence. Two cohorts were studied: a population-based Native American tribal community consisting of 697 participants nested within large multi-generational pedigrees and a family-based sample of 1832 predominantly European ancestry participants largely nested within nuclear families. Participants in both samples were assessed for Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) lifetime cannabis dependence, with 168 and 241 participants receiving a positive diagnosis in each sample, respectively. Sequence kernel association tests identified one protein-coding region, C1orf110 and one regulatory region in the MEF2B gene that achieved significance in a meta-analysis of both samples. A regulatory region within the PCCB gene, a gene previously associated with schizophrenia, exhibited a suggestive association. Finally, a significant enrichment of regions within or near genes with multiple splice variants or involved in cell adhesion or potassium channel activity were associated with cannabis dependence. This initial study demonstrates the potential utility of low pass whole genome sequencing for identifying genetic variants involved in the etiology of cannabis use disorders.

Comorbidity of Alcohol Use Disorder and Chronic Pain: Genetic Influences on Brain Reward and Stress Systems.

Alcohol use disorder (AUD) is highly comorbid with chronic pain (CP). Evidence has suggested that neuroadaptive processes characterized by reward deficit and stress surfeit are involved in the development of AUD and pain chronification. Neurological data suggest that shared genetic architecture associated with the reward and stress systems may contribute to the comorbidity of AUD and CP. This monograph first delineates the prevailing theories of the development of AUD and pain chronification focusing on the reward and stress systems. It then provides a brief summary of relevant neurological findings followed by an evaluation of evidence documented by molecular genetic studies. Candidate gene association studies have provided some initial support for the genetic overlap between AUD and CP; however, these results must be interpreted with caution until studies with sufficient statistical power are conducted and replications obtained. Genomewide association studies have suggested a number of genes (e.g., TBX19, HTR7, and ADRA1A) that are either directly or indirectly related to the reward and stress systems in the AUD and CP literature. Evidence reviewed in this monograph suggests that shared genetic liability underlying the comorbidity between AUD and CP, if present, is likely to be complex. As the advancement in molecular genetic methods continues, future studies may show broader central nervous system involvement in AUD-CP comorbidity.

Associations Between Genomic Variants in Alcohol Dehydrogenase Genes and Alcohol Symptomatology in American Indians and European Americans: Distinctions and Convergence.

BACKGROUND: Higher rates of alcohol use disorders (AUD) have been observed in some Native American populations than other ethnic groups such as European Americans (EAs) in the United States. Previous studies have shown that variation in the alcohol dehydrogenase (ADH) genes may affect the risk for development of AUD and that the prevalence of these variants differs depending on the ancestral origins of a population. METHODS: In this study, we assessed sequencing variants in the ADH genomic region (ADH1-7) and tested for their associations with AUD phenotypes in 2 independent populations: an American Indian (AI) community sample and an EA cohort from the San Francisco Family Alcohol Study. Association tests were conducted for both common and rare variants using sequencing data for 2 phenotypes: the number of alcohol-related life events and the count of alcohol dependence drinking symptoms. A regularized regression method was used to select the best set of ADH variants associated with phenotypes. Variance component model was incorporated in all analyses to leverage the admixture and relatedness. RESULTS: Two variants near ADH4 and 2 near ADH1C exhibited significant associations with AUD in AIs; no variant was significant in EAs. Common risk variants in AIs were either absent from or much less frequent in EAs. The feature selection method selected mostly distinct yet often colocated subsets of ADH variants to be associated with AUD phenotypes between the 2 cohorts. In the rare-variant analyses, the only association was observed between the whole region and the alcohol-related life events in AIs. CONCLUSIONS: Our results suggest that ADH variants, both common and rare, are more likely to impact risk for alcohol-related symptomatology in this AI population than in this EA sample, and ADH variants that might affect AUD are likely different but convergent on similar regions between the 2 populations.

A cis-eQTL in OPRM1 is Associated with Subjective Response to Alcohol and Alcohol Use.

BACKGROUND: A functional polymorphism within the µ-opioid receptor (OPRM1) gene, rs1799971 (A118G), previously has been associated with measures of alcohol use and sensitivity to its effects, but findings have been inconclusive. A recent study suggested that a second nearby variant within OPRM1, rs3778150, is robustly associated with heroin dependence and fully explained a smaller observed association with rs1799971. Given evidence that the rs3778150-C allele is associated with decreased OPRM1 expression levels in the human brain, the current study sought to test the hypothesis that rs3778150 represents a causal variant within OPRM1 that increases risk for a variety of alcohol use phenotypes. METHODS: Participants with genotype and phenotype data from a larger experimental study (N = 152) were assessed on measures of subjective response to alcohol and alcohol use. Measures included (i) the Self-Rating of the Effects of Alcohol and the Alcohol Sensitivity Questionnaire, (ii) the Biphasic Alcohol Effects Scale (BAES) and ratings of subjective intoxication, and (iii) average number of drinks per week in the past month. RESULTS: Compared to rs3778150-T homozygous individuals, carriers of the rs3778150-C allele exhibited significantly lower retrospective self-report levels of alcohol sensitivity. Carriers of the rs3778150-C allele also exhibited lower levels of BAES alcohol-related stimulation during an alcohol challenge and reported higher levels of drinking in the last 30 days. With the exception of lower levels of BAES alcohol-related sedation, the rs1799971 variant did not show consistent significant association with any of the alcohol phenotypes in the presence of rs3778150. CONCLUSIONS: Results suggest that rs3778150 may be causally related to alcohol use phenotypes, and could potentially account for previously observed associations of rs1799971 with substance use phenotypes. Future studies may investigate potential causal relations among genetic variants in OPRM1, subjective response to alcohol, and drinking phenotypes to further delineate the effects of rs3778150.

A Novel Tobacco Use Phenotype Suggests the 15q25 and 19q13 Loci May be Differentially Associated With Cigarettes per Day and Tobacco-Related Problems.

INTRODUCTION: Tobacco use is associated with variation at the 15q25 gene cluster and the cytochrome P450 (CYP) genes CYP2A6 and CYP2B6. Despite the variety of outcomes associated with these genes, few studies have adopted a data-driven approach to defining tobacco use phenotypes for genetic association analyses. We used factor analysis to generate a tobacco use measure, explored its incremental validity over a simple indicator of tobacco involvement: cigarettes per day (CPD), and tested both phenotypes in a genetic association study. METHODS: Data were from the University of California, San Francisco Family Alcoholism Study (n = 1942) and a Native American sample (n = 255). Factor analyses employed a broad array of tobacco use variables to establish the candidate phenotype. Subsequently, we conducted tests for association with variants in the nicotinic acetylcholine receptor and CYP genes. We explored associations with CPD and our measure. We then examined whether the variants most strongly associated with our measure remained associated after controlling for CPD. RESULTS: Analyses identified one factor that captured tobacco-related problems. Variants at 15q25 were significantly associated with CPD after multiple testing correction (rs938682: p = .00002, rs1051730: p = .0003, rs16969968: p = .0003). No significant associations were obtained with the tobacco use phenotype; however, suggestive associations were observed for variants in CYP2B6 near CYP2A6 (rs45482602: ps = .0082, .0075) and CYP4Z2P (rs10749865: ps = .0098, .0079). CONCLUSIONS: CPD captures variation at 15q25. Although strong conclusions cannot be drawn, these finding suggest measuring additional dimensions of problems may detect genetic variation not accounted for by smoking quantity. Replication in independent samples will help further refine phenotype definition efforts. IMPLICATIONS: Different facets of tobacco-related problems may index unique genetic risk. CPD, a simple measure of tobacco consumption, is associated with variants at the 15q25 gene cluster. Additional dimensions of tobacco problems may help to capture variation at 19q13. Results demonstrate the utility of adopting a data-driven approach to defining phenotypes for genetic association studies of tobacco involvement and provide results that can inform replication efforts.

Genetic Influences on Evening Preference Overlap with Those for Bipolar Disorder in a Sample of Mexican Americans and American Indians.

Diurnal preference (e.g., being an owl or lark) has been associated with several psychiatric disorders including bipolar disorder (BP), major depressive disorder, and substance use disorders. Previous large-scale genome-wide association studies (GWAS) aimed at identifying genetic influences on diurnal preference have exclusively included subjects of European ancestry. This study examined the genetic architecture of diurnal preference in two minority samples: a young adult sample of Mexican Americans (MAs), and a family-based sample of American Indians (AIs). Typed or imputed variants from exome chip data from the MA sample and low pass whole-genome sequencing from the AI cohort were analyzed using a mixed linear model approach for association with being an owl, as defined by a usual bedtime after 23:00 hrs. Genetic risk score (GRS) profiling detected shared genetic risk between evening preference and related disorders. Four variants in KIAA1549 like (KIAA1549L), a gene previously associated with attempted suicide in bipolar patients, were suggestively associated with being an owl at p < 1.82E-05; post hoc analyses showed the top variant trending in both the MA and AI cohorts at p = 2.50E-05 and p = .030, respectively. Variants associated with BP at p < .03 from the Psychiatric Genomics Consortium nominally predicted being an owl in the MA/AI cohort at p = .012. This study provides some additional evidence that genetic risk factors for BP also confer risk for being an owl in MAs/AIs and that evening preference may be a useful endophenotype for future studies of BP.

Genome-wide meta-analysis identifies a novel susceptibility signal at CACNA2D3 for nicotine dependence.

Nicotine dependence (ND) has a reported heritability of 40-70%. Low-coverage whole-genome sequencing was conducted in 1,889 samples from the UCSF Family study. Linear mixed models were used to conduct genome-wide association (GWA) tests of ND in this and five cohorts obtained from the database of Genotypes and Phenotypes. Fixed-effect meta-analysis was carried out separately for European (n = 14,713) and African (n = 3,369) participants, and then in a combined analysis of both ancestral groups. The meta-analysis of African participants identified a significant and novel susceptibility signal (rs56247223; p = 4.11 × 10-8 ). Data from the Genotype-Tissue Expression (GTEx) study suggested the protective allele is associated with reduced mRNA expression of CACNA2D3 in three human brain tissues (p < 4.94 × 10-2 ). Sequence data from the UCSF Family study suggested that a rare nonsynonymous variant in this gene conferred increased risk for ND (p = 0.01) providing further support for CACNA2D3 involvement in ND. Suggestive associations were observed in six additional regions in both European and merged populations (p < 5.00 × 10-6 ). The top variants were found to regulate mRNA expression levels of genes in human brains using GTEx data (p < 0.05): HAX1 and CHRNB2 (rs1760803), ADAMTSL1 (rs17198023), PEX2 (rs12680810), GLIS3 (rs12348139), non-coding RNA for LINC00476 (rs10759883), and GABBR1 (rs56020557 and rs62392942). A gene-based association test further supported the relation between GABBR1 and ND (p = 6.36 × 10-7 ). These findings will inform the biological mechanisms and development of therapeutic targets for ND.

Molecular genetic approaches to understanding the comorbidity of psychiatric disorders.

Epidemiologic studies demonstrating high rates of co-occurrence among psychiatric disorders at the population level have contributed to large literatures focused on identifying the causal mechanisms underlying the patterns of co-occurrence among these disorders. Such efforts have long represented a core focus of developmental psychopathologists and have more recently been supported by the Research Domain Criteria initiative developed by the NIMH, which provides a further framework for how the hypothesized mechanisms can be studied at different levels of analysis. The present overview focuses on molecular genetic approaches that are being used currently to study the etiology of psychiatric disorders, and how these approaches have been applied in efforts to understand the biological mechanisms that give rise to comorbid conditions. The present report begins with a review of molecular genetic approaches used to identify individual variants that confer risk for multiple disorders and the intervening biological mechanisms that contribute to their comorbidity. This is followed by a review of molecular genetic approaches that use genetic data in aggregate to examine these questions, and concludes with a discussion of how developmental psychopathologists are uniquely positioned to apply these methods in a way that will further our understanding of the causal factors that contribute to the development of comorbid conditions.

Variants Near CCK Receptors are Associated With Electrophysiological Responses to Pre-pulse Startle Stimuli in a Mexican American Cohort.

Neurophysiological measurements of the response to pre-pulse and startle stimuli have been suggested to represent an important endophenotype for both substance dependence and other select psychiatric disorders. We have previously shown, in young adult Mexican Americans (MA), that presentation of a short delay acoustic pre-pulse, prior to the startle stimuli can elicit a late negative component at about 400 msec (N4S), in the event-related potential (ERP), recorded from frontal cortical areas. In the present study, we investigated whether genetic factors associated with this endophenotype could be identified. The study included 420 (age 18-30 years) MA men (n = 170), and women (n = 250). DNA was genotyped using an Affymetrix Axiom Exome1A chip. An association analysis revealed that the CCKAR and CCKBR (cholecystokinin A and B receptor) genes each had a nearby variant that showed suggestive significance with the amplitude of the N4S component to pre-pulse stimuli. The neurotransmitter cholecystokinin (CCK), along with its receptors, CCKAR and CCKBR, have been previously associated with psychiatric disorders, suggesting that variants near these genes may play a role in the pre-pulse/startle response in this cohort.

Variant calling in low-coverage whole genome sequencing of a Native American population sample.

BACKGROUND: The reduction in the cost of sequencing a human genome has led to the use of genotype sampling strategies in order to impute and infer the presence of sequence variants that can then be tested for associations with traits of interest. Low-coverage Whole Genome Sequencing (WGS) is a sampling strategy that overcomes some of the deficiencies seen in fixed content SNP array studies. Linkage-disequilibrium (LD) aware variant callers, such as the program Thunder, may provide a calling rate and accuracy that makes a low-coverage sequencing strategy viable. RESULTS: We examined the performance of an LD-aware variant calling strategy in a population of 708 low-coverage whole genome sequences from a community sample of Native Americans. We assessed variant calling through a comparison of the sequencing results to genotypes measured in 641 of the same subjects using a fixed content first generation exome array. The comparison was made using the variant calling routines GATK Unified Genotyper program and the LD-aware variant caller Thunder. Thunder was found to improve concordance in a coverage dependent fashion, while correctly calling nearly all of the common variants as well as a high percentage of the rare variants present in the sample. CONCLUSIONS: Low-coverage WGS is a strategy that appears to collect genetic information intermediate in scope between fixed content genotyping arrays and deep-coverage WGS. Our data suggests that low-coverage WGS is a viable strategy with a greater chance of discovering novel variants and associations than fixed content arrays for large sample association analyses.

Protective variant associated with alcohol dependence in a Mexican American cohort.

BACKGROUND: Mexican Americans, particularly those born in the United States, are at greater risk for alcohol associated morbidity and mortality. The present study sought to investigate whether specific genetic variants may be associated with alcohol use disorder phenotypes in a select population of Mexican American young adults. METHODS: The study evaluated a cohort of 427 (age 18 - 30 years) Mexican American men (n = 171) and women (n = 256). Information on alcohol dependence was obtained through interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). For all subjects, DNA was extracted from blood samples, followed by genotyping using an Affymetrix Axiom Exome1A chip. RESULTS: A protective variant (rs991316) located downstream from the ADH7 (alcohol dehydrogenase 7) gene showed suggestive significance in association with alcohol dependence symptom counts derived from DSM-III-R and DSM-IV criteria, as well as to clustered alcohol dependence symptoms. Additional linkage analysis suggested that nearby variants in linkage disequilibrium with rs991316 were not responsible for the observed association with the alcohol dependence phenotypes in this study. CONCLUSIONS: ADH7 has been shown to have a protective role against alcohol dependence in previous studies involving other ethnicities, but has not been reported for Mexican Americans. These results suggest that variants near ADH7 may play a role in protection from alcohol dependence in this Mexican American cohort.

Correlation analysis of genetic admixture and social identification with body mass index in a Native American community.

OBJECTIVES: Body mass index (BMI) is a well-known measure of obesity with a multitude of genetic and non-genetic determinants. Identifying the underlying factors associated with BMI is difficult because of its multifactorial etiology that varies as a function of geoethnic background and socioeconomic setting. Thus, we pursued a study exploring the influence of the degree of Native American admixture on BMI (as well as weight and height individually) in a community sample of Native Americans (n = 846) while accommodating a variety of socioeconomic and cultural factors. METHODS: Participants' degree of Native American (NA) ancestry was estimated using a genome-wide panel of markers. The participants also completed an extensive survey of cultural and social identity measures: the Indian Culture Scale (ICS) and the Orthogonal Cultural Identification Scale (OCIS). Multiple linear regression was used to examine the relation between these measures and BMI. RESULTS: Our results suggest that BMI is correlated positively with the proportion of NA ancestry. Age was also significantly associated with BMI, while gender and socioeconomic measures (education and income) were not. For the two cultural identity measures, the ICS showed a positive correlation with BMI, while OCIS was not associated with BMI. CONCLUSIONS: Taken together, these results suggest that genetic and cultural environmental factors, rather than socioeconomic factors, account for a substantial proportion of variation in BMI in this population. Further, significant correlations between degree of NA ancestry and BMI suggest that admixture mapping may be appropriate to identify loci associated with BMI in this population.