New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Εvangelou, Εvangelos; Gao, He; Chu, Congying; Ntritsos, Georgios; Blakeley, Paul; Butts, Andrew R.; Pazoki, Raha; Suzuki, Hideaki; Koskeridis, Fotios; Yiorkas, Andrianos M.; Karaman, Íbrahím; Elliott, Joshua; Luo, Qiang; Aeschbacher, Stefanie; Bartz, Traci M.; Baumeister, Sebastian E.; Braund, Peter S.; Brown, M. R. W.; Brody, Jennifer A.; Clarke, Toni; Dimou, Niki; Faul, Jessica D.; Homuth, Georg; Jackson, Anne; Kentistou, Katherine A.; Joshi, Peter K.; Lemaître, Rozenn N.; Lind, Penelope A.; Lyytikäinen, Leo Pekka; Mangino, Massimo; Milaneschi, Yuri; Nelson, Christopher P.; Nolte, Ilja M.; Perälä, Mia-Maria; Polašek, Ozren; Porteous, David J.; Ratliff, Scott; Smith, Jennifer A.; Stančáková, Alena; Teumer, Alexander; Tuominen, Samuli; Thériault, Sébastien; Vangipurapu, Jagadish; Whitfield, John B.; Wood, Alexis C.; Yao, Jie; Yu, Bing; Zhao, Wei; Arking, Dan E.; Auvinen, Juha; Liu, Chunyu; Männikkö, Minna; Risch, L.; Rotter, Jerome I.; Snieder, Harold; Veijola, Juha; Blakemore, Alexandra I. F.; Boehnke, Michael; Campbell, Harry; Conen, David; Eriksson, Johan G.; Grabe, Hans J.; Guo, Xiuqing; Harst, Pim van der; Hartman, Catharina A.; Hayward, Caroline; Heath, Andrew C.; Järvelin, Marjo Riitta; Kähönen, Mika; Kardia, Sharon L.R.; Kühne, Michael; Kuusisto, Johanna; Laakso, Markku; Lahti, Jari; Lehtimäki, Terho; McIntosh, Andrew M.; Mohlke, Karen L.; Morrison, Alanna C.; Martin, Nicholas G.; Oldehinkel, Albertine J.; Penninx, Brenda W.J.H.; Psaty, Bruce M.; Raitakari, Olli T.; Rudan, Igor; Samani, Nilesh J.; Scott, Laura J.; Spector, Tim D.; Verweij, Niek; Weir, David R.; Wilson, James F.; Levy, Daniel; Tzoulaki, Ioanna; Bell, Jimmy D.; Matthews, Paul M.; Rothenfluh, Adrian; Desrivières, Sylvane; Schumann, Günter; Elliott, Paul

doi:10.1038/s41562-019-0653-z

Cited by 86 publications

(113 citation statements)

References 91 publications

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“…We integrated genomic and bioinformatic analyses which provided a rapid approach for filling the translational space between human and animal genetics research. Similar to other genetic studies of drug use 26-28 , these findings indicated a neuro-epigenetic component to the genetic inheritance of tobacco consumption, while also localizing genomic regions of interest. By using a genetic sample of over 100,000 humans and meta-analyzing across three species from seven gene expression studies, we found that approximately 4.2%-39.5% of the heritability for the frequency of human tobacco use can be attributed to mRNA readout related to nicotine exposure/consumption in the brain.…”

Section: Discussionsupporting

confidence: 82%

Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

Palmer

Benca-Bachman

Bubier

et al. 2019

Preprint

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a These authors contributed equally to this work ABSTRACT 24Computational advances have fostered the development of new methods and tools to integrate 25 gene expression and functional evidence into human-genetic association analyses. Integrative 26 functional genomics analysis for altered response to alcohol in mice provided the first evidence 27 that multi-species analysis tools, such as GeneWeaver, can identify or confirm novel alcohol-28 related loci. The present study describes an integrative framework to investigate how highly-29 connected genes linked by their association to tobacco-related behaviors, contribute to individual 30 differences in tobacco consumption. Data from individuals of European ancestry in the 31 UKBiobank (N=139,043) were used to examine the relative contribution of orthologs of a set of 32 genes that are transcriptionally co-regulated by tobacco or nicotine exposure in model organism 33 experiments to human tobacco consumption. Multi-component mixed linear models using 34 genotyped and imputed single nucleotide variants indicated that: (1) variation within human 35 orthologs of these genes accounted for 2-5% of the observed heritability (meta h 2 SNP-Total =0.08 36 [95% CI: 0.07, 0.09]) of tobacco/nicotine consumption across three independent folds of 37 unrelated individuals (enrichment ranging from 0.85 -2.98), and (2) variation around (5, 10, 15, 38 25, and 50 Kb regions) the set of co-transcriptionally regulated genes accounted for 5-36% of the 39 observed SNP-heritability (enrichment ranging from 1.60 -31.45). Notably, the effects of 40 variants in co-transcriptionally regulated genes were enriched in tobacco GWAS. These findings 41 highlight the advantages of using multiple species evidence to isolate genetic factors to better 42 understand the etiological complexity of tobacco and other nicotine consumption. 43 44 45 However, the GWAS approach is not without limitations. For example, examination of genome-53 wide variation requires a stiff penalty for multiple comparisons leading to the need for 54 increasingly large sample sizes. The requirement of sample sizes in the 100's of thousands to 55 millions (i.e., mega-GWAS) exerts pressure on the depth of phenotyping that may be done (i.e., 56 more intensive and costly phenotypes are untenable for Mega-GWAS studies). Additionally, 57SNPs implicated by GWAS are not always readily associated with gene function. In fact, a 58 majority of GWAS hits fall in non-coding or intergenic regions 1 . Linkage disequilibrium allows 59 for a relatively sparse coverage of the genome to be maximally informative, but simultaneously 60 limits the immediate "translatability" of the signals (i.e., a SNP identified by GWAS may be a 61 proxy for a causative SNP some genomic distance away). In sum, while GWAS findings have 62 become increasingly reproducible as sample sizes increase, it has become increasingly evident 63 that additional sources of data (e.g., gene regulatory and epigenetic data 2 ) are needed to 64 understand how subtle SNP effects in...

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Section: Discussionsupporting

confidence: 82%

Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

Palmer

Benca-Bachman

Bubier

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Previous work has shown that the genetic architecture of AUD (and PAU) differs substantially from that of alcohol consumption [2–4]. There have been larger studies of alcohol quantity-frequency measures [9, 36]; alcohol consumption data are available in many EHRs, thus they were included in many studies of other primary traits, like cardiac disease. AUD diagnoses are collected much less commonly.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

Sanchez‐Roige

et al. 2019

Preprint

Self Cite

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54Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although 55 genome-wide association studies (GWASs) have identified PAU risk genes, the genetic 56 architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis 57 of PAU combining alcohol use disorder and problematic drinking in 435,563 European-ancestry 58 individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically 59 correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide 60 polygenic risk score analysis in an independent biobank sample (BioVU, n=67,589) confirmed 61 the genetic correlations between PAU and substance use and psychiatric disorders. Genetic 62 heritability of PAU was enriched in brain and in genomic conserved and regulatory regions. 63Mendelian randomization suggested causal effects on liability to PAU of substance use, 64 psychiatric status, risk-taking behavior, and cognitive performance. In summary, this large PAU 65 meta-analysis identified novel risk loci and revealed genetic relationships with numerous other 66 outcomes. 67

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“…In humans, genetic variation of the XRCC5 gene is associated with intravenous EtOH self‐administration (Juraeva et al., ). The approach has been extended to a larger set of alcohol‐dependent humans and resulted in the identification of 46 novel loci for alcohol consumption (Evangelou et al., ). Together with functional studies, the results also suggest common genetic mechanisms with other neuropsychiatric disorders.…”

Section: Translation From Flies and Worms To Mammals And Vice Versamentioning

confidence: 99%

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

Scholz

2019

Alcoholism Clin & Exp Res

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Alcohol use disorders (AUDs) are very common worldwide and negatively affect both individuals and societies. To understand how normal behavior turns into uncontrollable use of alcohol, several approaches have been utilized in the last decades. However, we still do not completely understand how AUDs evolve or how they are maintained in the brains of affected individuals. In addition, efficient and effective treatment is still in need of development. This review focuses on alternative approaches developed over the last 20 years using Drosophila melanogaster (Drosophila) and Caenorhabditis elegans (C. elegans) as genetic model systems to determine the mechanisms underlying the action of ethanol (EtOH) and behaviors associated with AUDs. All the results and insights of studies over the last 20 years cannot be comprehensively summarized. Thus, a few prominent examples are provided highlighting the principles of the genes and mechanisms that have been uncovered and are involved in the action of EtOH at the cellular level. In addition, examples are provided of the genes and mechanisms that regulate behaviors relevant to acquiring and maintaining excessive alcohol intake, such as decision making, reward and withdrawal, and/or relapse regulation. How the insight gained from the results of Drosophila and C. elegans models can be translated to higher organisms, such as rodents and/or humans, is discussed, as well as whether these insights have any relevance or impact on our understanding of the mechanisms underlying AUDs in humans. Finally, future directions are presented that might facilitate the identification of drugs to treat AUDs.

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New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders

Cited by 86 publications

References 91 publications

Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

Cross-Species Integration of Transcriptomic Effects of Tobacco and Nicotine Exposure Helps to Prioritize Genetic Effects on Human Tobacco Consumption

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

Unraveling the Mechanisms of Behaviors Associated With AUDs Using Flies and Worms

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