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Contemporary neurobehavioral genetics
PBB-71950; No of Pages 2 Pharmacology, Biochemistry and Behavior xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh
Editorial
Contemporary neurobehavioral genetics
In the history of the study of the biology of behavior there have been two main Western traditions. One, rooted in ethology, of European origin, and the other, comparative psychology, espoused mainly by American scientists. Whereas the ethologists, notably Konrad Lorenz, Nikolaas Tinbergen, Carl von Frisch, and Irenäus Eibl-Eibesfeldt described inherited behaviors and instincts, most comparative psychologists eschewed all things inherited or “built-in.” This included any mention of genetics and indeed, the comparative psychologists asserted that those interested in the genetic basis of behavior were genetic determinists, a particularly pejorative term. Prominent in this movement were John B. Watson, B F Skinner, Howard Moltz, T C Schnerla, and Daniel Lehrman. Perhaps the most outspoken among the critics were Z Y Kuo and Gilbert Gottleib. A smaller movement involving notables such as John Paul Scott, John L. Fuller and Gerald E. McClearn was emerging in the mid-20th century and showing how heredity can influence behavior and how genes can co-operate with the environment in influencing behavioral traits. The effort to bring genetics into the study of behavior and neuroscience received a boost in the 1980s and 90s by direct gene manipulation techniques and new quantitative genetic methods to identify genomic markers that could then be linked to variability in behavioral and neurobiological traits including those related to psychoactive drugs. The old arguments about genetic determinism were gradually fading, but new problems were becoming evident. For the researchers using gene nullification and amplification techniques, effects of these manipulations could vary, depending on the genetic background of the host. This, of course, shows that many of the neurobehavioral traits of interest are influenced by more than one gene. On the quantitative genetics side the ability to associate discrete markers with quantitative traits, i.e. quantitative trait loci or QTL analysis, was met with skepticism about replicability and causal inference. As molecular and quantitative techniques advanced, both approaches became useful and now show investigators how adding genetic definition can increase the power of their research. Nevertheless, many researchers on both sides of the approaches face criticism in publications and grant applications that fail to reflect the numerous improvements in both. We can now apply molecular genetic techniques under the control of the experimenter as to when in the life course, the manipulation is applied. On the quantitative side, extensive genotyping and sequencing of organisms have led to a fuller understanding of genetic background and better success in identifying the genes underlying the QTLs. We have come a long way in studying polygenic traits, gene-environment and gene–gene interactions and how they influence neurobehavioral phenotypes, especially those related to pharmacology. Early studies to identify genetic variants involved in drug responses were primarily conducted in animal models due to the genetic
and genomic tools available and the ability to manipulate the genome under standardized environments. The availability of the human genome sequence, the growing genomic toolbox and accessibility of these tools have made human studies much more tractable. Candidate gene studies to determine the role of specific genetic polymorphisms have given way to genome-wide association studies or GWAS in human populations. Both types of studies are described in this issue by Can et al. as they relate to response to lithium as a therapeutic agent for bipolar and mood disorders. Understanding the genetic factors responsible for a beneficial response to lithium therapy will be invaluable for identifying effective therapeutics and improving treatment outcomes. A paper by Enoch discusses genetic factors that predict individual variability in response to and subsequent use of alcohol by altering metabolism or changing the subjective experience of the drug. The review also details genetic variants of the mu-opioid receptor (OPRM1) and the serotonin transporter 5-HTT gene, SLC6A4, that predict therapeutic response to pharmacotherapies commonly employed to treat alcoholism including naltrexone, selective serotonin reuptake inhibitors and ondansetron. Crist and Berrettini also discuss genetic polymorphisms in OPRM1 that affect the efficacy of opioid analgesics and treatment response to naltrexone. The review focuses on the most studied variant, A118G. The A118G variant has been repeatedly associated with treatment efficacy for pain and alcohol dependence, however, the authors emphasize the need to expand studies to include intronic and synonymous polymorphisms that can affect transcription, splicing or mRNA stability. A review by Vandenbergh and Schlomer addresses the use of noncoding or synonymous polymorphisms to inform genome-wide association studies. Data from the ENCODE project allows for functional analysis of intronic or “non-coding” regions that interact with other regions of the genome or are promoter, enhancer or repressor sites. The use of ENCODE data is described in the context of genome-wide association studies for nicotine pharmacogenetics and the authors present several case studies of how these data can be used to link polymorphisms with functional significance. Logue and Gould look more broadly at naturally occurring genetic polymorphisms that affect executive function. Executive function includes higher order behaviors such as impulse control, working memory and attention that are modulated by dopaminergic, noradrenergic, serotonergic, and cholinergic input. Deficits in executive function are observed in many neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder and addiction. The review describes the circuitry involved in executive function and polymorphisms in genes involved in neurotransmission that alter behavior in both animal models and humans.
http://dx.doi.org/10.1016/j.pbb.2014.04.013 0091-3057/© 2014 Published by Elsevier Inc.
Please cite this article as: Tarantino LM, Jones BC, Contemporary neurobehavioral genetics, Pharmacol Biochem Behav (2014), http://dx.doi.org/ 10.1016/j.pbb.2014.04.013
2
Editorial
Finally, a review by O'Leary et al. presents both clinical and preclinical studies that have examined genetic variants that are associated with antidepressant response. A significant number of patients do not respond to first line antidepressant treatment and understanding the genetic mechanisms that determine efficacy will greatly improve treatment outcomes. The review covers genes involved in metabolism, transport and storage of dopamine, noradrenaline and serotonin and also more recent research regarding the role of microRNAs. In this special issue of PB&B, we present these articles to an audience that might not otherwise seek them out if published in other, more genetically oriented journals. It is our overall goal to show the power of genetics and the study of individual differences in response to pharmacological agents and how this approach can be used to elucidate the mechanisms underlying the differences and actions of these agents in general.
Lisa M. Tarantino Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, United States Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States
Byron C. Jones Department of Biobehavioral Health, College of Health and Human Development, The Pennsylvania State University, University Park, PA 16802, United States Available online xxxx
Please cite this article as: Tarantino LM, Jones BC, Contemporary neurobehavioral genetics, Pharmacol Biochem Behav (2014), http://dx.doi.org/ 10.1016/j.pbb.2014.04.013
Contents lists available at ScienceDirect
Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh
Editorial
Contemporary neurobehavioral genetics
In the history of the study of the biology of behavior there have been two main Western traditions. One, rooted in ethology, of European origin, and the other, comparative psychology, espoused mainly by American scientists. Whereas the ethologists, notably Konrad Lorenz, Nikolaas Tinbergen, Carl von Frisch, and Irenäus Eibl-Eibesfeldt described inherited behaviors and instincts, most comparative psychologists eschewed all things inherited or “built-in.” This included any mention of genetics and indeed, the comparative psychologists asserted that those interested in the genetic basis of behavior were genetic determinists, a particularly pejorative term. Prominent in this movement were John B. Watson, B F Skinner, Howard Moltz, T C Schnerla, and Daniel Lehrman. Perhaps the most outspoken among the critics were Z Y Kuo and Gilbert Gottleib. A smaller movement involving notables such as John Paul Scott, John L. Fuller and Gerald E. McClearn was emerging in the mid-20th century and showing how heredity can influence behavior and how genes can co-operate with the environment in influencing behavioral traits. The effort to bring genetics into the study of behavior and neuroscience received a boost in the 1980s and 90s by direct gene manipulation techniques and new quantitative genetic methods to identify genomic markers that could then be linked to variability in behavioral and neurobiological traits including those related to psychoactive drugs. The old arguments about genetic determinism were gradually fading, but new problems were becoming evident. For the researchers using gene nullification and amplification techniques, effects of these manipulations could vary, depending on the genetic background of the host. This, of course, shows that many of the neurobehavioral traits of interest are influenced by more than one gene. On the quantitative genetics side the ability to associate discrete markers with quantitative traits, i.e. quantitative trait loci or QTL analysis, was met with skepticism about replicability and causal inference. As molecular and quantitative techniques advanced, both approaches became useful and now show investigators how adding genetic definition can increase the power of their research. Nevertheless, many researchers on both sides of the approaches face criticism in publications and grant applications that fail to reflect the numerous improvements in both. We can now apply molecular genetic techniques under the control of the experimenter as to when in the life course, the manipulation is applied. On the quantitative side, extensive genotyping and sequencing of organisms have led to a fuller understanding of genetic background and better success in identifying the genes underlying the QTLs. We have come a long way in studying polygenic traits, gene-environment and gene–gene interactions and how they influence neurobehavioral phenotypes, especially those related to pharmacology. Early studies to identify genetic variants involved in drug responses were primarily conducted in animal models due to the genetic
and genomic tools available and the ability to manipulate the genome under standardized environments. The availability of the human genome sequence, the growing genomic toolbox and accessibility of these tools have made human studies much more tractable. Candidate gene studies to determine the role of specific genetic polymorphisms have given way to genome-wide association studies or GWAS in human populations. Both types of studies are described in this issue by Can et al. as they relate to response to lithium as a therapeutic agent for bipolar and mood disorders. Understanding the genetic factors responsible for a beneficial response to lithium therapy will be invaluable for identifying effective therapeutics and improving treatment outcomes. A paper by Enoch discusses genetic factors that predict individual variability in response to and subsequent use of alcohol by altering metabolism or changing the subjective experience of the drug. The review also details genetic variants of the mu-opioid receptor (OPRM1) and the serotonin transporter 5-HTT gene, SLC6A4, that predict therapeutic response to pharmacotherapies commonly employed to treat alcoholism including naltrexone, selective serotonin reuptake inhibitors and ondansetron. Crist and Berrettini also discuss genetic polymorphisms in OPRM1 that affect the efficacy of opioid analgesics and treatment response to naltrexone. The review focuses on the most studied variant, A118G. The A118G variant has been repeatedly associated with treatment efficacy for pain and alcohol dependence, however, the authors emphasize the need to expand studies to include intronic and synonymous polymorphisms that can affect transcription, splicing or mRNA stability. A review by Vandenbergh and Schlomer addresses the use of noncoding or synonymous polymorphisms to inform genome-wide association studies. Data from the ENCODE project allows for functional analysis of intronic or “non-coding” regions that interact with other regions of the genome or are promoter, enhancer or repressor sites. The use of ENCODE data is described in the context of genome-wide association studies for nicotine pharmacogenetics and the authors present several case studies of how these data can be used to link polymorphisms with functional significance. Logue and Gould look more broadly at naturally occurring genetic polymorphisms that affect executive function. Executive function includes higher order behaviors such as impulse control, working memory and attention that are modulated by dopaminergic, noradrenergic, serotonergic, and cholinergic input. Deficits in executive function are observed in many neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder and addiction. The review describes the circuitry involved in executive function and polymorphisms in genes involved in neurotransmission that alter behavior in both animal models and humans.
http://dx.doi.org/10.1016/j.pbb.2014.04.013 0091-3057/© 2014 Published by Elsevier Inc.
Please cite this article as: Tarantino LM, Jones BC, Contemporary neurobehavioral genetics, Pharmacol Biochem Behav (2014), http://dx.doi.org/ 10.1016/j.pbb.2014.04.013
2
Editorial
Finally, a review by O'Leary et al. presents both clinical and preclinical studies that have examined genetic variants that are associated with antidepressant response. A significant number of patients do not respond to first line antidepressant treatment and understanding the genetic mechanisms that determine efficacy will greatly improve treatment outcomes. The review covers genes involved in metabolism, transport and storage of dopamine, noradrenaline and serotonin and also more recent research regarding the role of microRNAs. In this special issue of PB&B, we present these articles to an audience that might not otherwise seek them out if published in other, more genetically oriented journals. It is our overall goal to show the power of genetics and the study of individual differences in response to pharmacological agents and how this approach can be used to elucidate the mechanisms underlying the differences and actions of these agents in general.
Lisa M. Tarantino Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, United States Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States
Byron C. Jones Department of Biobehavioral Health, College of Health and Human Development, The Pennsylvania State University, University Park, PA 16802, United States Available online xxxx
Please cite this article as: Tarantino LM, Jones BC, Contemporary neurobehavioral genetics, Pharmacol Biochem Behav (2014), http://dx.doi.org/ 10.1016/j.pbb.2014.04.013