Genomic and Behavioral Signatures of Selection for Ethanol Preference from the Heterogeneous Stock Collaborative Cross Mice – The Central Nucleus of the Amygdala

Published: April 18, 2025

Abstract Alcohol use disorder (AUD) is a complex disease with heritability of ∼0.5, indicating genetic and non-genetic factors contribute to risk. Identifying gene expression networks contributing risk using post-mortem human brain tissue has the limitation conflating for AUD consequences alcohol use. We leveraged mice selectively bred differential ethanol preference from highly genetically diverse population overcome this limitation. Ethanol intake was correlated preference, high-preferring (HP) consumed more sweet-but not bitter-tasting solutions compared low-preferring (LP) mice, lines did differ in rate elimination. Adult, ethanol-naïve HP LP contributed central nucleus amygdala (CeA), region critical intake. Single-nuclei bulk RNA sequencing data were used identify cell types transcriptome changes related selective breeding preference. Single nuclei analysis identified populations inhibitory (∼48% cells) excitatory (∼23%) neurons, non-neuronal (∼29%) cells, but no differences cell-type composition or between lines. Bulk CeA for: (1) (2996 genes), (2) variability (426 (3) wiring (407 significant gene-gene correlations). Overall, lower variance found line. Reduced correlation, also suggested that selection high induced transcriptional regulation resulting reduced connectivity, specific enriched markers neurons expressing Isl1 Tac1 .

Language: Английский

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Genome‐wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression

Addiction Biology, Journal Year: 2023, Volume and Issue: 28(6)

Published: April 28, 2023

Abstract Opioid use disorder (OUD) and mental disorders are often comorbid, with increased morbidity mortality. The causes underlying this relationship poorly understood. Although these conditions highly heritable, their shared genetic vulnerabilities remain unaccounted for. We applied the conditional/conjunctional false discovery rate (cond/conjFDR) approach to analyse summary statistics from independent genome wide association studies of OUD, schizophrenia (SCZ), bipolar (BD) major depression (MD) European ancestry. Next, we characterized identified loci using biological annotation resources. OUD data were obtained Million Veteran Program, Yale‐Penn Study Addiction: Genetics Environment (SAGE) (15 756 cases, 99 039 controls). SCZ (53 386 77 258 controls), BD (41 917 371 549 controls) MD (170 329 443 provided by Psychiatric Genomics Consortium. discovered enrichment for conditional on associations SCZ, BD, vice versa, indicating polygenic overlap identification 14 novel at condFDR < 0.05 7 unique between ( n = 2), 2) 7) conjFDR concordant effect directions, in line estimated positive correlations. Two one MD. Three risk more than psychiatric disorder, DRD2 chromosome 11 (BD MD), FURIN 15 (SCZ, MD) histocompatibility complex region (SCZ MD). Our findings provide new insights into architecture MD, a relationship, suggesting overlapping neurobiological pathways.

Language: Английский

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Generalized genetic liability to substance use disorders

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(11)

Published: June 2, 2024

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common compared with individual SUDs characterized by greater severity, additional psychiatric comorbidities, worse outcomes. Here, we review evidence for the role generalized genetic liability to various SUDs. Coaggregation has familial contributions, twin studies suggesting a strong contribution additive influences undergirding variety substances (including alcohol, nicotine, cannabis, others). GWAS have documented similarly large correlations between opioid disorders. Extending these findings, recent identified multiple genomic loci that contribute risk problematic tobacco use, implicating dopaminergic regulatory neuronal development mechanisms in pathophysiology SUD liability, certain signals demonstrating cross-species translational validity. Overlap other externalizing behaviors, while substantial, does not explain entirety signal SUD. Polygenic scores (PGS) derived from outperform PGS prediction serious mental health medical comorbidities. Going forward, it will be important further elucidate etiology incorporating SUDs, evaluating clinical presentation across lifespan, increasing granularity investigation (e.g., specific transdiagnostic criteria) ultimately improve nosology, prevention, treatment

Language: Английский

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Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females

The Pharmacogenomics Journal, Journal Year: 2024, Volume and Issue: 24(4)

Published: Aug. 1, 2024

Abstract The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) by sex. From a sample size 1301 adult patients (>18 years age) seen emergency departments three medical centers Ohio, six were found be associated with OUD. Two the variants, rs2740574 ( CYP3A4 ) rs324029 DRD3 ), included having met criteria at least five subjects for each BGAG, variant carrier status, OUD status combinations. Variant carriers African/Afro-Caribbean BGAG had slightly lower predicted probabilities higher Relative sex, all evaluation (five variant, combinations). No statistically significant interactions between given BGAGs Findings suggest testing relative risk can applied across however, studies larger populations are needed.

Language: Английский

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Substance use and common contributors to morbidity: A genetics perspective

EBioMedicine, Journal Year: 2022, Volume and Issue: 83, P. 104212 - 104212

Published: Aug. 12, 2022

Language: Английский

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