Biology subjects

Palmer, A. A.

Publications and source records attributed to Palmer, A. A..

At least 73 records · Page 4Linked to original sources

bioRxiv2020

Multivariate GWAS elucidates the genetic architecture of alcohol consumption and misuse, corrects biases, and reveals novel associations with disease

Genome-wide association studies (GWASs) of the Alcohol Use Disorder Identification Test (AUDIT), a ten-item screener for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders/medical conditions. To explore these unexpected differences in genetic correlations, we conducted the first item-level and largest GWAS of AUDIT items (N=160,824), and applied a multivariate framework to mitigate previous biases. In doing so, we identified novel patterns of similarity (and dissimilarity) among the AUDIT items, and found evidence of a correlated two-factor structure at the genetic level (Consumption and Problems, rg=.80). Moreover, by applying empirically-derived weights to each of the AUDIT items, we constructed an aggregate measure of alcohol consumption that is strongly associated with alcohol dependence (rg=.67) and several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by performing polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, we identified novel genetic associations between alcohol consumption, alcohol misuse, and human health. Our work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD, and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.

genetics↗

bioRxiv2020

Functional validation of a finding from a mouse genome-wide association study demonstrates that a mutant allele of Azi2 alters sensitivity to methamphetamine

Methamphetamine is a widely abused psychostimulant. In a previous genome-wide association study (GWAS), we identified a locus that influenced the stimulant response to methamphetamine. That locus was also an eQTL for the gene Azi2. Based on those findings, we hypothesized that heritable differences in the expression of Azi2 were causally related to the differential response to methamphetamine. In this study, we created a mutant Azi2 allele that caused lower Azi2 expression and enhanced the locomotor response to methamphetamine; however, based on the GWAS findings, we had expected lower Azi2 to decrease rather than increase the stimulant response to methamphetamine. We then sought to explore the mechanism by which Azi2 influenced methamphetamine sensitivity. A recent publication had reported that the 3UTR of Azi2 mRNA downregulates the expression of Slc6a3, which encodes the dopamine transporter (DAT), which is a key target of methamphetamine. We evaluated the relationship between Azi2/Azi2 3UTR and Slc6a3 expression in the VTA in the mutant Azi2 mice and in a new cohort of CFW mice. We did not observe any correlation between Azi2 and Slc6a3 in the VTA in either cohort. However, RNA sequencing confirmed that the Azi2 mutation altered Azi2 expression and also revealed a number of potentially important genes and pathways that were regulated by Azi2, including the metabotropic glutamate receptor group III pathway and nicotinic acetylcholine receptor signaling pathway. Our results support a role for Azi2 in methamphetamine sensitivity; however, the exact mechanism does not appear to involve regulation of Slc6a3 and thus remains unknown.

animal behavior and cognition↗

bioRxiv2020

Sensitivity to food and cocaine cues are independent traits in a large sample of heterogeneous stock rats.

Sensitivity to cocaine and its associated stimuli ("cues") are important factors in the development and maintenance of addiction. Rodent studies suggest that this sensitivity is related, in part, to the propensity to attribute incentive salience to food cues, which, in turn, contributes to the maintenance of cocaine self-administration, and cue-induced relapse of drug-seeking. Whereas each of these traits has established links to drug use, the relatedness between the individual traits themselves has not been well characterized in preclinical models. To this end, the propensity to attribute incentive salience to a food cue was first assessed in a large population of 2716 outbred heterogeneous stock rats. We then determined whether this was associated with performance in two paradigms (cocaine conditioned cue preference and cocaine contextual conditioning). These measure the unconditioned locomotor effects of cocaine, as well as conditioned approach and the locomotor response to a cocaine-paired floor or context. There was large individual variability and sex differences among all traits, but they were largely independent of one another in both males and females. These findings suggest that these traits may contribute to drug-use via independent underlying neuropsychological processes.

animal behavior and cognition↗

bioRxiv2020

Importance of polymorphic SNPs, short tandem repeats and structural variants for differential gene expression among inbred C57BL/6 and C57BL/10 substrains

Mouse substrains are an invaluable model for understanding disease. We compared C57BL/6J, which is the most commonly used inbred mouse strain, with 8 C57BL/6 and 5 C57BL/10 closely related inbred substrains. Whole genome sequencing and RNA-sequencing analysis yielded 352,631 SNPs, 109,096 INDELs, 150,344 short tandem repeats (STRs), 3,425 structural variants (SVs) and 2,826 differentially expressed genes (DEGenes) among these 14 strains. 312,981 SNPs (89%) distinguished the B6 and B10 lineages. These SNPs were clustered into 28 short segments that are likely due to introgressed haplotypes rather than new mutations. Outside of these introgressed regions, we identified 53 SVs, protein-truncating SNPs and frameshifting INDELs that were associated with DEGenes. Our results can be used for both forward and reverse genetic approaches, and illustrate how introgression and mutational processes give rise to differences among these widely used inbred substrains.

genomics↗

bioRxiv2020

The Latent Genetic Structure of Impulsivity and its Relation to Internalizing Psychopathology

Factor analyses suggest that impulsivity traits that capture tendencies to act prematurely or take risks tap partially distinct constructs. We applied genomic structure equation modeling to evaluate the genetic factor structure of two well-established impulsivity questionnaires, using published genome-wide association study statistics from up to 22,861 participants. We also tested the hypotheses that delay discounting would be genetically separable from other impulsivity factors, and that emotionally-triggered facets of impulsivity (urgency) would be those most strongly genetically correlated with an internalizing latent factor. A five-factor model best fit the impulsivity data. Delay discounting was genetically distinct from these five factors. As expected, the two urgency subscales were most strongly related to an Internalizing Psychopathology latent factor. These findings provide empirical genetic evidence that impulsivity can be disarticulated into distinct categories of differential relevance for internalizing psychopathology. They also demonstrate how measured genetic markers can be used to inform theories of psychology/personality.

genetics↗

bioRxiv2019

Meta-analysis of problematic alcohol use in 435,563 individuals identifies 29 risk variants and yields insights into biology, pleiotropy and causality

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWASs) have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU combining alcohol use disorder and problematic drinking in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n=67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in genomic conserved and regulatory regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior, and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other outcomes.

genetics↗

bioRxiv2019

Assessing the motivational effects of ethanol in mice using a discrete-trial current-intensity intracranial self-stimulation procedure

BackgroundAlcohol (ethanol) produces both rewarding and aversive effects, and sensitivity to these effects is associated with risk for an alcohol use disorder (AUD). Measurement of these motivational effects in animal models is an important but challenging aspect of preclinical research into the neurobiology of AUD. Here, we evaluated whether a discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure can be used to assess both reward-enhancing and aversive responses to ethanol in mice.\n\nMethodsC57BL/6J mice were surgically implanted with bipolar stimulating electrodes targeting the medial forebrain bundle and trained on a discrete-trial current-intensity ICSS procedure. Mice were tested for changes in response thresholds after various doses of ethanol (0.5 g/kg-1.75 g/kg), using a Latin square design.\n\nResultsA 1 g/kg dose of ethanol produced a significant reward-enhancement (i.e., lowered response thresholds), whereas a 1.75 g/kg dose produced an aversive effect (elevated response thresholds).\n\nConclusionsThe discrete-trial current-intensity ICSS procedure is an effective assay for measuring both reward-enhancing responses to ethanol as well as aversive responses in the same animal. This should prove to be a useful tool for assessing the effects of experimental manipulations on the motivational effects of ethanol in mice.

neuroscience↗

bioRxiv2019

The Effects of Mutations are Modified by Genetic Background in Mice

BackgroundThe majority of quantitative genetic models used to map complex traits assume that alleles have similar effects across all individuals. Significant evidence suggests, however, that epistatic interactions modulate the impact of many alleles. Nevertheless, identifying epistatic interactions remains computationally and statistically challenging. In this work, we address some of these challenges by developing a statistical test for polygenic epistasis that determines whether the effect of an allele is altered by the global genetic ancestry proportion from distinct progenitors. ResultsWe applied our method to data from mice and yeast. For the mice, we observed 49 significant genotype-by-ancestry interaction associations across 14 phenotypes as well as over 1,400 Bonferroni-corrected genotype-by-ancestry interaction associations for mouse gene expression data. For the yeast, we observed 92 significant genotype-by-ancestry interactions across 38 phenotypes. Given this evidence of epistasis, we test for and observe evidence of rapid selection pressure on ancestry specific polymorphisms within one of the cohorts, consistent with epistatic selection. ConclusionsUnlike our prior work in human populations, we observe widespread evidence of ancestry-modified SNP effects, perhaps reflecting the greater divergence present in crosses using mice and yeast. Author SummaryMany statistical tests which link genetic markers in the genome to differences in traits rely on the assumption that the same polymorphism will have identical effects in different individuals. However, there is substantial evidence indicating that this is not the case. Epistasis is the phenomenon in which multiple polymorphisms interact with one another to amplify or negate each others effects on a trait. We hypothesized that individual SNP effects could be changed in a polygenic manner, such that the proportion of as genetic ancestry, rather than specific markers, might be used to capture epistatic interactions. Motivated by this possibility, we develop a new statistical test that allowed us to examine the genome to identify polymorphisms which have different effects depending on the ancestral makeup of each individual. We use our test in two different populations of inbred mice and a yeast panel and demonstrate that these sorts of variable effect polymorphisms exist in 14 different physical traits in mice and 38 phenotypes in yeast as well as in murine gene expression. We use the term "polygenic epistasis" to distinguish these interactions from the more conventional two- or multi-locus interactions.

genomics↗

bioRxiv2019

Adapting genotyping-by-sequencing and variant calling for heterogeneous stock rats

The heterogeneous stock (HS) is an outbred rat population derived from eight inbred rat strains. HS rats are ideally suited for genome wide association studies; however, only a few genotyping microarrays have ever been designed for rats and none of them are currently in production. To address the need for an efficient and cost effective method of genotyping HS rats, we have adapted genotype-by-sequencing (GBS) to obtain genotype information at large numbers of single nucleotide polymorphisms (SNPs). In this paper, we have outlined the laboratory and computational steps we took to optimize double digest genotype-by-sequencing (ddGBS) for use in rats. We also evaluate multiple existing computational tools and explain the workflow we have used to call and impute over 3.7 million SNPs. We also compared various rat genetic maps, which are necessary for imputation, including a recently developed map specific to the HS. Using our approach, we obtained concordance rates of 99% with data obtained using data from a genotyping array. The principles and computational pipeline that we describe could easily be adapted for use in other species for which reliable reference genome sets are available.

genetics↗

bioRxiv2019

Genetic risk for major depressive disorder and loneliness in gender-specific associations with coronary artery disease

ImportanceEpidemiological evidence indicates that major depressive disorder (MDD) and loneliness both reduce life expectancies, but mechanisms underlying the excess morbidity are unclear. Electronic health records (EHRs) linked to genetic data offer new opportunities to address this knowledge gap.\n\nObjectiveTo determine the medical morbidity pattern associated with genetic risk factors for MDD and loneliness, two common psychological traits with adverse health outcomes.\n\nDesignPhenome-wide association study using EHRs spanning 1990 to 2017 from the Vanderbilt University Medical Center biobank, BioVU. Top associations with coronary artery disease (CAD) were replicated in the Atherosclerosis Risk in Communities (ARIC) cohort.\n\nSettingHospital-based EHR study, with replication in a population-based cohort study.\n\nParticipants18,385 genotyped adult patients in BioVU. Replication in ARIC included 7,197 genotyped participants. All participants were of European ancestry.\n\nExposuresPolygenic scores for MDD and loneliness were developed for each individual using previously published meta-GWAS summary statistics.\n\nMain Outcomes and MeasuresThe phenome-wide association study included 882 clinical diagnoses ascertained via billing codes in the EHR. ARIC included 1598 incident CAD cases.\n\nResultsBioVU patients had a median EHR length of 9.91 years. In the phenome-wide association study, polygenic scores for MDD and loneliness were significantly associated with psychiatric and cardiac phenotypes. Targeted analyses of CAD in 3,893 cases and 4,197 controls in BioVU found odds ratios of 1.11 (95% CI, 1.04-1.18; P=8.43x10-4) and 1.13 (95% CI, 1.07-1.20; P=4.51x10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Comparable hazard ratios in ARIC were 1.07 (95% CI, 0.99-1.14; P=0.07) and 1.07 (1.01-1.15; P=0.03). Across both studies, the increased risk persisted in women after adjusting for multiple conventional risk factors, a polygenic score for CAD, and psychiatric symptoms (available in BioVU). Controlling for genetic risk factors shared between MDD and loneliness, the polygenic score for loneliness conditioned on MDD remained associated with CAD risk, but the polygenic score for MDD conditioned on loneliness did not.\n\nConclusions and RelevanceGenetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in women. Continued research into the biological and clinical connections between the heart and mind is warranted.

genetics↗

bioRxiv2018

Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness

AO_SCPLOWBSTRACTC_SCPLOWHumans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. While the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. While it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition towards loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we conducted a genome-wide association (GWAS) meta-analysis of loneliness (N=475,661), report 12 associated loci (two novel) and significant genetic correlations with 34 other complex traits. The polygenic basis for loneliness was significantly enriched for evolutionary constrained genes and genes expressed in specific brain tissues: (frontal) cortex, cerebellum, anterior cingulate cortex, and substantia nigra. We built polygenic scores based on this GWAS meta-analysis to explore the genetic association between loneliness and health outcomes in an independent sample of 18,498 individuals for whom electronic health records were available. A genetic predisposition towards loneliness predicted cardiovascular, psychiatric, and metabolic disorders, and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, effect of body fat on loneliness, and a similar weaker causal effect of BMI. Our results provide a framework for ongoing studies of the genetic basis of loneliness and its role in mental and physical health.

genetics↗

bioRxiv2018

Genome wide association study of body weight, body mass index, adiposity, and fasting glucose in 3,173 outbred rats

Objective Obesity is influenced by genetic and environmental factors. Despite success of human genome wide association studies (GWAS), the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify genetic loci underlying obesity and related morphometric and metabolic traits.Methods We measured obesity-relevant traits including body weight, body length, body mass index, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat GWAS to date. Genetic loci were identified using a linear mixed model that accounted for the complex family relationships of the HS and covariate to account for differences among the three phenotyping centers.Results We identified 32 independent loci, several of which contained only a single gene (e.g. Epha5, Nrg1 and Klhl14) or obvious candidate genes (Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and extensive pleiotropy at individual loci.Conclusions These studies demonstrate utility of HS rats for investigating the genetics of obesity related traits across institutions and identify several candidate genes for future functional testing.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2018

Dissociating addiction-related endophenotypes: Incentive salience attribution, sensation-seeking and novelty-seeking are independent traits in male and female heterogeneous stock rats

There are a number of traits that are thought to increase susceptibility to addiction, and some of these are modeled in preclinical studies. For example, \"sensation-seeking\" is predictive of the initial propensity to take drugs; whereas \"novelty-seeking\" predicts compulsive drug-seeking behavior. In addition, the propensity to attribute incentive salience to reward cues can predict the propensity to approach drug cues, and reinstatement or relapse, even after relatively brief periods of drug exposure. The question addressed here is the extent to which these three vulnerability factors are related; that is, predictive of one another. Some relationships have been reported in small samples, but here a large sample of 1,598 outbred male and female heterogeneous stock rats were screened for Pavlovian conditioned approach behavior (to obtain an index of incentive salience attribution; sign-tracking), and subsequently tested for sensation-seeking and novelty-seeking. Despite the large N there were no significant correlations between these traits, in either males or females. There were, however, novel relationships between multiple measures of incentive salience attribution and, based on these findings, we generated a new metric that captures \"incentive value\". Furthermore, there were sex differences on measures of incentive salience attribution and sensation-seeking behavior that were not previously apparent.

animal behavior and cognition↗

bioRxiv2018

Genome-wide association studies of impulsive personality traits (BIS-11 and UPPSP) and drug experimentation in up to 22,861 adult research participants

BackgroundImpulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse.\n\nMethodsIn collaboration with the genetics company 23andMe, Inc., we performed several genome-wide association studies (GWAS) on measures of impulsive personality traits (the short version of the UPPSP Impulsive Behavior Scale, and the Barratt Impulsiveness Scale [BIS-11]) and drug experimentation (the number of drug classes an individual has tried in their lifetime) in up to 22,861 male and female adult research participants of European ancestry.\n\nResultsImpulsive personality traits and drug experimentation showed SNP-heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with the UPPSP Sensation Seeking subscale (P = 8.3 x 10-9, rs139528938) and showed a suggestive association with drug experimentation (P = 3.0 x 10-7, rs2163971; r2 = 0.68 with rs139528938); CADM2 has been previously associated with measures of risky behaviors and self-reported risk tolerance, cannabis initiation, alcohol consumption, as well as information speed processing, body mass index (BMI) variation and obesity. Furthermore, genetic variants in the CACNA1I locus were significantly associated with the UPPSP Negative Urgency subscale (P = 3.8 x 10-8, rs199694726). Multiple subscales from both UPPSP and BIS showed strong genetic correlations (>0.5) with drug experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPSP and BIS subscales were genetically correlated with attention-deficit/hyperactivity disorder (rg = 0.30-0.51, p < 8.69 x 10-3), supporting their validity as endophenotypes.\n\nConclusionsOur findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.

genetics↗

bioRxiv2018

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies. Author SummaryOutbred Sprague Dawley rats are among the most commonly used rats for neuroscience, physiology and pharmacological research; in the year 2020, 4,188 publications contained the keyword "Sprague Dawley". Rats identified as "Sprague Dawley" are sold by several commercial vendors, including Charles River Laboratories and Harlan Sprague Dawley Inc. (now Envigo). Despite their widespread use, little is known about the genetic diversity of SD. We genotyped more than 4,000 SD rats, which we used for a genome-wide association study (GWAS) and to characterize genetic differences between SD rats from Charles River Laboratories and Harlan. Our analysis revealed extensive population structure both between and within vendors. The GWAS for Pavlovian conditioned approach (PavCA) identified a number of genome-wide significant loci for that complex behavioral trait. Our results demonstrate that, despite sharing an identical name, SD rats that are obtained from different vendors are very different. Future studies should carefully define the exact source of SD rats being used and may exploit their genetic diversity for genetic studies of complex traits.

genetics↗

bioRxiv2018

Genome-wide association study, replication, and mega-analysis using a dense marker panel in a multi-generational mouse advanced intercross line

Replication is considered to be critical for genome-wide association studies (GWAS) in humans, but is not routinely performed in model organisms. We explored replication using an advanced intercross line (AIL) which is the simplest possible multigenerational intercross. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F34; n=428) using a denser marker set and also genotyped a novel cohort of AIL mice (F39-43; n=600) for the first time. We identified 110 significant loci in the F34 cohort, 36 of which were new discoveries attributable to the denser marker set; we also identified 27 novel significant loci in the F39-43 cohort. For traits measured in both cohorts (locomotor activity, body weight, and coat color), the genetic correlations were high, although, the F39-43 cohort showed systematically lower SNP-heritability estimates. We then attempted to replicate loci identified in either F34 or F39-43 in the other cohort. Albino coat color was robustly replicated; we observed only partial replication of associations for locomotor activity and body weight. Finally, we performed a mega-analysis of locomotor activity and body weight by combining F34 and F39-43 cohorts (n=1,028), which identified four novel loci. The incomplete replication was inconsistent with simulations we performed to estimate our power to replicate. This may reflect: 1) false positives errors in the discovery cohort, 2) environmental or genetic heterogeneity between the two samples, or 3) the systematic over estimation of the effect sizes at significant loci (\"Winners Curse\"). Our results demonstrate that it is difficult to replicate GWAS results even when using similarly sized discovery and replication cohorts drawn from the same population.

genetics↗

bioRxiv2018

Genome-wide association study meta-analysis of the Alcohol Use Disorder Identification Test (AUDIT) in two population-based cohorts (N=141,958)

Alcohol use disorders (AUD) are common conditions that have enormous social and economic consequences. We obtained quantitative measures using the Alcohol Use Disorder Identification Test (AUDIT) from two population-based cohorts of European ancestry: UK Biobank (UKB; N=121,604) and 23andMe (N=20,328) and performed a genome-wide association study (GWAS) meta-analysis. We also performed GWAS for AUDIT items 1-3, which focus on consumption (AUDIT-C), and for items 4-10, which focus on the problematic consequences of drinking (AUDIT-P). The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; we also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (rg=0.76-0.92) and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) alcohol dependence (rg=0.33-0.63). AUDIT-P and AUDIT-C showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P was positively genetically correlated with schizophrenia (rg=0.22, p=3.0x10-10), major depressive disorder (rg=0.26, p=5.6x10-3), and attention-deficit/hyperactivity disorder (ADHD; rg=0.23, p=1.1x10-5), whereas AUDIT-C was negatively genetically correlated with major depressive disorder (rg=-0.24, p=3.7x10-3) and ADHD (rg=-0.10, p=1.8x10-2). We also used the AUDIT data in the UKB to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total score of [≤]4 as controls and [≥]12 as cases produced a high genetic correlation with DSM-IV alcohol dependence (rg=0.82, p=3.2x10-6) while retaining most subjects. We conclude that AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and AUD.

genetics↗

bioRxiv2018

Social behavior and anxiety contribute to nicotine self-administration in adolescent outbred rats

Both emotional and social traits interact with genetic factors to influence smoking behavior. We previously established a socially acquired nicotine intravenous self-administration model where social learning of a nicotine-associated odor cue reversed conditioned flavor aversion and promoted nicotine intake. In this study, we first phenotyped ~ 800 adolescent heterogeneous stock rats in open field, novel object interaction, social interaction, elevated plus maze, and marble bury behaviors. These rats were then phenotyped on socially acquired nicotine self-administration. We found 243 significant correlations between different behavioral tests. Principal component regression analysis found that ~ 10-20% of the variance in nicotine-related measures, such as intake during the first or the last three fixed-ratio sessions, the progressive ratio session, and reinstatement behavior, can be explained by variations in behavioral traits. Factors corresponding to social behavior and anxiety were among the strongest predictors of nicotine intake and reinstatement of nicotine-seeking behavior. We also found many sex differences in behavioral measures. These data indicated that the genetic diversity of this population, in combination with social behavior and anxiety, are significant contributors to the divergent nicotine self-administration behavior and indicated a high probability of discovering sex-specific genetic mechanisms for nicotine intake in future genome-wide association studies.

animal behavior and cognition↗