Biology subjects

Palmer, A. A.

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

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Individual differences in oxycodone addiction-like behaviors in a large cohort of heterogeneous stock (HS) rats

Family and twin studies demonstrate that genetic factors determine 20-60% of the vulnerability to opioid use disorder. However, the genes/alleles that mediate the risk of developing addiction-related behaviors, including the sensitivity to the analgesic efficacy of opioids, the development of tolerance, dependence, and escalation of oxycodone taking and seeking, have been ill-defined, thus hindering efforts to design pharmacological interventions to enable precision medicine strategies. Here we characterized oxycodone addiction-like behaviors in heterogeneous stock (HS) rats, that show high genetic diversity that mimics the high genetic variability in humans. HS rats were allowed to self-administer oxycodone for two h/daily for four days (ShA) and then moved to 12h/daily (LgA) for 14 days. Animals were screened for motivation to self-administer oxycodone using a progressive-ratio (PR) schedule of reinforcement and for the development of withdrawal-induced hyperalgesia and tolerance to the analgesic effects of oxycodone using the von-Frey and tail immersion tests, respectively. To reduce cohort-specific effects, we used cohorts of 46-60 rats and normalized the response level within cohorts using a Z-score. To take advantage of the four opioid-related behaviors and further identify subjects that are consistently vulnerable vs. resilient to compulsive oxycodone use, we computed an Addiction Index by averaging normalized responding (Z-scores) for the four behavioral tests. Results showed high individual variability between vulnerable and resilient rats, likely to facilitate the detection of gene variants associated with vulnerable vs. resilient individuals. Such data will have considerable translational value for designing follow-up studies in humans.

neuroscience↗

bioRxiv2022

Identification of individual differences in response to methadone, buprenorphine, and naltrexone in animal models of opioid use disorder

RationaleCurrent medications for opioid use disorder include buprenorphine, methadone, and naltrexone. While these medications show significant efficacy in reducing craving and opioid use, there are substantial individual differences in response to these treatments in humans. The reason for such difference is poorly known. ObjectivesHere, we tested the hypothesis that similar individual differences may be observed in a large population of heterogenous stock rats, that have been bred to maximize genetic diversity, using a behavioral paradigm relevant to opioid use disorder. MethodsOver 500 rats were given intermittent (4d/week) and extended access (12h/day) to oxycodone self-administration for 14 sessions to establish oxycodone dependence and escalation of intake. We then measured the effect of buprenorphine (0.5mg/kg), methadone (3mg/kg) and naltrexone (3mg/kg) on the motivation to self-administer oxycodone by using a progressive ratio schedule of reinforcement. ResultsWe found that naltrexone and buprenorphine significantly decreased motivation to oxycodone rewards. While naltrexone reduced oxycodone intake in both males and females, systemic administration with buprenorphine reduced progressive ratio responses only in males. Methadone reduced motivation to oxycodone self-administration in nearly 25% of the population, without reaching statical significance. Our results showed that the efficacy of these medications depends on the severity of addiction like behaviors, indicated by the addiction index. ConclusionsThese results demonstrate individual differences in response to medications to treat opioid use disorder in a genetically diverse population of rats.

neuroscience↗

bioRxiv2022

Transcriptional Profiling of the Hippocampus in an F2 Cross of a Genetic Rat Model of Internalizing vs. Externalizing Behavior and Addiction Liability

Selectively-bred High Responder (bHR) and Low Responder (bLR) rats model the extreme externalizing and internalizing behavior accompanying many psychiatric disorders. To elucidate gene expression underlying these heritable behavioral differences, bHRs and bLRs (generation 37) were used to produce a F0-F1-F2 cross. We measured exploratory locomotion, anxiety-like behavior, and reward cue sensitivity (Pavlovian Conditioned Approach), and performed hippocampal RNA-Seq in male and female F0s (n=24) and F2s (n=250). Behaviors that diverged during selective breeding remained correlated in F2s, implying a shared genetic basis. F0 bHR/bLR differential expression was robust, surpassing differences associated with sex, and predicted expression patterns associated with F2 behavior. With bHR-like behavior, gene sets related to growth/proliferation were upregulated, whereas with bLR-like behavior, gene sets related to mitochondrial function, oxidative stress, and microglial activation were upregulated. This differential expression could be successfully predicted based on F0 genotype using cis-expression quantitative trait loci (cis-eQTLs) identified in the F2s. Colocalization of these cis-eQTLs with behavioral Quantitative Trait Loci pinpointed 16 differentially expressed genes that were strong candidates for mediating the influence of genetic variation on behavioral temperament. Our findings implicate hippocampal bioenergetic regulation of oxidative stress, microglial activation, and growth-related processes in shaping behavioral temperament, modulating vulnerability to psychiatric disorders.

neuroscience↗

bioRxiv2022

Genome-Wide Association Study in a Rat Model of Temperament Identifies Multiple Loci for Exploratory Locomotion and Anxiety-Like Traits

Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment (bred High Responders (bHR) vs. Low Responders (bLR)). To identify genes underlying the response to selection, we phenotyped and genotyped 558 rats from an F2 cross between bHR and bLR. Several behavioral traits show high heritability, including the selection trait: exploratory locomotion (EL) in a novel environment. There were significant phenotypic and genetic correlations between tests that capture facets of EL and anxiety. There were also correlations with Pavlovian conditioned approach (PavCA) behavior despite the lower heritability of that trait. Ten significant and conditionally independent loci for six behavioral traits were identified. Five of the six traits reflect different facets of EL that were captured by three behavioral tests. Distance traveled measures from the open field and the elevated plus maze map onto different loci, thus may represent different aspects of novelty-induced locomotor activity. The sixth behavioral trait, number of fecal boli, is the only anxiety-related trait mapping to a significant locus on chromosome 18 within which the Pik3c3 gene is located. There were no significant loci for PavCA. We identified a missense variant in the Plekhf1 gene on the chromosome 1:95 Mb QTL and Fancf and Gas2 as potential candidate genes that may drive the chromosome 1:107 Mb QTL for EL traits. The identification of a locomotor activity-related QTL on chromosome 7 encompassing the Pkhd1l1 and Trhr genes is consistent with our previous finding of these genes being differentially expressed in the hippocampus of bHR vs. bLR rats. The strong heritability coupled with identification of several loci associated with exploratory locomotion and emotionality provide compelling support for this selectively bred rat model in discovering relatively large effect causal variants tied to elements of internalizing and externalizing behaviors inherent to psychiatric and substance use disorders.

genetics↗

bioRxiv2022

Polygenic Transcriptome Risk Scores Can Translate Genetic Results Between Species

Genome-wide association studies (GWAS) have implicated specific alleles and genes as risk factors for numerous complex traits. However, translating GWAS results into biologically and therapeutically meaningful discoveries remains extremely challenging. Most GWAS results identify noncoding regions of the genome, suggesting that differences in gene regulation are the major driver of trait variability. To better integrate GWAS results with gene regulatory polymorphisms, we previously developed PrediXcan (also known as "transcriptome-wide association studies" or TWAS), which maps SNPs to predicted gene expression using GWAS data. In this study, we developed RatXcan, a framework that extends this methodology to outbred heterogeneous stock (HS) rats. RatXcan accounts for the close familial relationships among HS rats by modeling the relatedness with a random effect that encodes the genetic relatedness. RatXcan also corrects for polygenic-driven inflation because of the equivalence between a relatedness random effect and the infinitesimal polygenic model. To develop RatXcan, we trained transcript predictors for 8,934 genes using reference genotype and expression data from five rat brain regions. We found that the cis genetic architecture of gene expression in both rats and humans was sparse and similar across brain tissues. We tested the association between predicted expression in rats and two example traits (body length and BMI) using phenotype and genotype data from 5,401 densely genotyped HS rats and identified a significant enrichment between the genes associated with rat and human body length and BMI. Thus, RatXcan represents a valuable tool for identifying the relationship between gene expression and phenotypes across species and paves the way to explore shared biological mechanisms of complex traits. Author SummaryUnderstanding how genetic variation affects phenotypic variation is critical to leveraging the wealth of genetic studies to make biologically and therapeutically useful discoveries. Since most of the genetic loci associated with complex diseases are regulatory in nature--meaning that they do not alter protein coding but rather subtly affect gene expression--transcriptome-wide association studies have been developed. However, these apply only to human data where large samples of unrelated individuals are available. For animal models, relatedness is much higher, causing higher false-positive rates. We propose a computationally efficient method to address this problem and find shared biology between humans and rats. Taken together, our development paves the way to further explore shared biological mechanisms of complex traits across species.

genomics↗

bioRxiv2022

Private and sub-family specific mutations of founder haplotypes in the BXD family reveal phenotypic consequences relevant to health and disease

The BXD family of recombinant inbred mice were developed by crossing and inbreeding progeny of C57BL/6J and DBA/2J strains. This family is the largest and most extensively phenotyped mammalian experimental genetic resource. Although used in genetics for 52 years, we do not yet have comprehensive data on DNA variants segregating in the BXDs. Using linked-read whole-genome sequencing, we sequenced 152 members of the family at about 40X coverage and quantified most variants. We identified 6.25 million polymorphism segregating at a near-optimal minor allele frequency of 0.42. We also defined two other major variants: strain-specific de novo singleton mutations and epoch-specific de novo polymorphism shared among subfamilies of BXDs. We quantified per-generation mutation rates of de novo variants and demonstrate how founder-derived, strain-specific, and epoch-specific variants can be analyzed jointly to model genome-phenome causality. This integration enables forward and reverse genetics at scale, rapid production of any of more than 10,000 diallel F1 hybrid progeny to test predictions across diverse environments or treatments. Combined with five decades of phenome data, the BXD family and F1 hybrids are a major resource for systems genetics and experimental precision medicine.

genomics↗

bioRxiv2022

The regulatory landscape of multiple brain regions in outbred heterogeneous stock rats

Heterogeneous Stock (HS) rats are a genetically diverse outbred rat population that is widely used for studying genetics of behavioral and physiological traits. Mapping Quantitative Trait Loci (QTL) associated with transcriptional changes would help to identify mechanisms underlying these traits. We generated genotype and transcriptome data for five brain regions from 88 HS rats. We identified 21,392 cis-QTLs associated with expression and splicing changes across all five brain regions and validated their effects using allele specific expression data. We identified 80 cases where eQTLs were colocalized with genome-wide association study (GWAS) results from nine physiological traits. Comparing our dataset to human data from the Genotype-Tissue Expression (GTEx) project, we found that the HS rat data yields twice as many significant eQTLs as a similarly sized human dataset. We also identified a modest but highly significant correlation between genetic regulatory variation among orthologous genes. Surprisingly, we found less genetic variation in gene regulation in HS rats relative to humans, though we still found eQTLs for the orthologs of many human genes for which eQTLs had not been found. These data are available from the RatGTEx data portal (RatGTEx.org) and will enable new discoveries of the genetic influences of complex traits.

genetics↗

bioRxiv2022

A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements characterized by repeated units of 1 or more nucleotides. We leveraged whole genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family derived from C57BL/6J and DBA/2J mice to study the effects of genetic background on genome-wide patterns of new mutations at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and identified a locus on chromosome 13 associated with the propensity of STRs to expand. Several dozen genes lie in the QTL region, including Msh3, a known modifier of STR stability at pathogenic repeat expansions in mice and humans. Detailed analysis of the locus revealed a cluster of variants near the 5 end of Msh3, including multiple protein-coding variants within the DNA mismatch recognition domain of MSH3, and a retrotransposon insertion overlapping an annotated exon. Additionally, gene expression analysis demonstrates co-localization of this QTL with expression QTLs for multiple nearby genes, including Msh3. Our results suggest a novel role for Msh3 in regulating genome-wide patterns of germline STR mutations and demonstrate that inherited genetic variation can contribute to variability in accumulation of new mutations across individuals.

genomics↗

bioRxiv2022

GR-regulated enhancers play a central role in the gene regulatory networks underlying drug addiction

Substance abuse and addiction represent a significant public health problem that impacts multiple dimensions of society, including healthcare, the economy, and the workforce. In 2021, over 100,000 drug overdose deaths were reported in the US, with an alarming increase in fatalities related to opioids and psychostimulants. Understanding the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bonafide enhancers and highlighted the KLF/SP1, RFX, and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, which include glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.

neuroscience↗

bioRxiv2021

Genome-wide association study of open fieldbehavior in outbred heterogeneous stock ratsidentifies multiple loci implicated inpsychiatric disorders

Many personality traits are influenced by genetic factors. Rodents models provide an efficient system for analyzing genetic contribution to these traits. Using 1,246 adolescent heterogeneous stock (HS) male and female rats, we conducted a genome-wide association study (GWAS) of behaviors measured in an open field, including locomotion, novel object interaction, and social interaction. We identified 30 genome-wide significant quantitative trait loci (QTL). Using multiple criteria, including the presence of high impact genomic variants and co-localization of cis-eQTL, we identified 13 candidate genes (Adarb2, Ankrd26, Cacna1c, Clock, Crhr1, Ctu2, Cyp26b1, Eva1a, Fam114a1, Kcnj9, Mlf2, Rab27b, Sec11a) for these traits. Most of these genes have been implicated by human GWAS of various psychiatric traits. For example, Cacna1c, a gene known to be critical for social behavior in rodents and implicated in human schizophrenia and bipolar disorder, is a candidate gene for distance to the social zone. In addition, the QTL region for total distance to the novel object zone, on Chr1 at 144 Mb, is syntenic to a hotspot on human Chr15 (82.5-90.8 Mb) that contains 14 genes associated with psychiatric or substance abuse traits. Although some of the genes identified by this study appear to replicate findings from prior human GWAS, others likely represent novel findings that can be the catalyst for future molecular and genetic insights into human psychiatric diseases. Together, these findings provide strong support for the use of the HS population to study psychiatric disorders.

genetics↗

bioRxiv2021

Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population

BackgroundA strong predictor for the development of alcohol use disorders (AUDs) is altered sensitivity to the intoxicating effects of alcohol. Individual differences in the initial sensitivity to alcohol are controlled in part by genetic factors. Mice offer a powerful tool for elucidating the genetic basis of behavioral and physiological traits relevant to AUDs; but conventional experimental crosses have only been able to identify large chromosomal regions rather than specific genes. Genetically diverse, highly recombinant mouse populations allow for the opportunity to observe a wider range of phenotypic variation, offer greater mapping precision, and thus increase the potential for efficient gene identification. MethodsWe have taken advantage of the Diversity Outbred (DO) mouse population to identify and precisely map quantitative trait loci (QTL) associated with ethanol sensitivity. We phenotyped 798 male J:DO mice for three measures of ethanol sensitivity: ataxia, hypothermia, and loss of the righting response. We used high density MEGAMuga and GIGAMuga arrays to obtain genotypes ranging from 77,808 - 143,259 SNPs. In addition, we performed RNA sequencing in striatum to map expression QTLs and to identify gene expression-trait correlations. ResultsWe then applied a systems genetic strategy to identify narrow QTLs and construct the network of correlations that exist between DNA sequence, gene expression values and ethanol-related phenotypes to prioritize our list of positional candidate genes. ConclusionsOur results can be used to identify alleles that contribute to AUDs in humans, elucidate causative biological mechanisms, or assist in the development of novel therapeutic interventions.

genetics↗

bioRxiv2021

Characterization of cocaine addiction-like behavior in heterogeneous stock rats

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 h/daily). We analyzed individual differences in escalation of intake, progressive-ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

neuroscience↗

bioRxiv2021

Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats

In addition to its pleasurable effects, weight control is a significant contributor to initiation, maintenance and relapse of cocaine use. This suggests that individual differences in bodyweight control and feeding hormones, such as leptin may contribute to the vulnerability to cocaine use disorder. While pre-clinical studies have shown a mutually inhibitory relationship between leptin and cocaine, they have used small sample sizes and did not investigate individual differences in a large heterogeneous population. Here, we tested if individual differences in bodyweight and blood leptin level is associated with high or low vulnerability to addiction-like behaviors using data from 500 heterogenous stock rats and 160 blood samples from the Cocaine Biobank, using a model of extended access to intravenous self-administration of cocaine. Finally, we tested a separate cohort to evaluate the causal effect of exogenous leptin administration on cocaine seeking. Bodyweight, while changing due to cocaine self-administration in males, was not related to the vulnerability to addiction-like behavior. Blood leptin levels after ~6 weeks of cocaine self-administration did not correlate with addiction-like behaviors, however, baseline blood leptin levels before any access to cocaine negatively predicted addiction-like behavior. Finally, administration of leptin reduced cocaine intake after acute withdrawal and cocaine seeking after 6 weeks of protracted abstinence. These results demonstrate that high blood leptin level before access to cocaine may be a protective factor against the development of cocaine addiction-like behavior, that exogenous leptin reduces the motivation to take and seek cocaine, but that blood leptin level and bodyweight changes in current users are not good biomarkers for addiction-like behaviors.

physiology↗

bioRxiv2021

A wild-derived antimutator drives germline mutation spectrum differences in a genetically diverse murine family

Summary ParagraphAlthough germline mutation rates and spectra can vary within and between species, genetic modifiers of these traits have long eluded detection. In this study, we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory mouse strains C57BL/6J (B) and DBA/2J (D). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes. We show that mice inheriting D haplotypes at a quantitative trait locus (QTL) on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily due to the activity of a C>A-dominated mutational signature known as SBS18. The B and D QTL haplotypes encode different alleles of the DNA repair gene Mutyh, which underlies the heritable colorectal cancer syndrome in which SBS18 was first identified. The B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.

genetics↗

bioRxiv2021

Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was surprisingly low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winners Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Available methods to control Winners Curse were contingent on the power of the discovery sample, and depending on the method used, both overestimated and underestimated the true effect. Leveraging these observations we integrated information about replication rates, confounding, and Winners Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.

bioinformatics↗

bioRxiv2020

Genetic and pharmacological manipulations of glyoxalase 1 mediate ethanol withdrawal seizure susceptibility in mice

Central nervous system (CNS) hyperexcitability is a clinically significant feature of acute ethanol withdrawal. There is evidence for a genetic contribution to withdrawal severity, but specific genetic risk factors have not be identified. The gene glyoxalase 1 (Glo1) has been previously implicated in ethanol consumption in mice, and GLO1 inhibition can attenuate drinking in mice and rats. Here, we investigated whether genetic and pharmacological manipulations of GLO1 activity can also mediate ethanol withdrawal seizure severity in mice. Mice from two transgenic lines overexpressing Glo1 on different genetic backgrounds (C57BL/6J [B6] and FVB/NJ [FVB]) were tested for handling induced convulsions (HICs) as a measure of acute ethanol withdrawal. Following an injection of 4 g/kg alcohol, both B6 and FVB mice overexpressing Glo1 showed increased HICs compared to wild type littermates, though only the FVB line showed a statistically significant difference. We also administered daily ethanol injections (2 g/kg + 9 mg/kg 4-methylpyrazole) to wild type B6 mice for 10 days and tested them for HICs on the 10th day, following treatment with either vehicle or a GLO1 inhibitor (S-bromobenzylglutathione cyclopentyl diester [pBBG]). Treatment with pBBG reduced HICs, although this effect was only statistically significant following two 10-day cycles of ethanol exposure and withdrawal. These results provide converging genetic and pharmacological evidence that GLO1 can mediate ethanol withdrawal seizure susceptibility. We discuss the possible role of GLO1s substrate, methylglyoxal, acting as an agonist at GABAA receptors.

neuroscience↗

bioRxiv2020

Polygenic transcriptome risk scores improve portability of polygenic risk scores across ancestries

Polygenic risk scores (PRS) are on course to translate the results of genome-wide association studies (GWAS) into clinical practice. To date, most GWAS have been based on individuals of European-ancestry, meaning that the utility of PRS for non-European populations is limited because SNP effects and LD patterns may not be conserved across populations. We hypothesized that cross population prediction at the level of genes rather than SNPs would be more effective, since the effect of genes on traits is likely to be more highly conserved. Therefore, we developed a framework to convert effect sizes at SNPs into effect sizes for genetically predicted transcript abundance, which we used for prediction in non-European populations. We compared this approach, which we call polygenic transcriptome risk scores (PTRS), to PRS, using data from 17 quantitative traits that were measured in multiple ancestries (European, African, East Asian, and South Asian) by UK Biobank. On average, PTRS using whole blood predicted transcriptome had lower absolute prediction accuracy than PRS, as we expected since not all regulatory processes were captured by a single tissue. However, as hypothesized, we found that in the African target set, the portability (prediction accuracy relative to the European reference set) was significantly higher for PTRS than PRS (p=0.03) with additional gain when transcriptomic prediction models ancestry matched the target population (p=0.021). Taken together, our results suggest that using PTRS can improve prediction in underrepresented populations and that increasing the diversity of transcriptomic data may be an effective way to improve portability of GWAS results between populations and help reduce health disparities.

genetics↗

bioRxiv2020

Multivariate genomic analysis of 1.5 million people identifies genes related to addiction, antisocial behavior, and health

Behaviors and disorders related to self-regulation, such as substance use, antisocial conduct, and ADHD, are collectively referred to as externalizing and have a shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The identified loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results captures variation in a broad range of behavioral and medical outcomes that were not part of our genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions, and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental condition.

genetics↗