Valerie S. Knopik, Ph.D. - US grants

DESCRIPTION (provided by applicant): Dr. Valerie Knopik, a behavior geneticist with expertise in quantitative genetics, holds a faculty position in the Department of Psychiatry at Washington University School of Medicine. A Mentored Research Scientist Development Award (K01) is solicited, to support 5 years of research on the joint effects of prenatal nicotine exposure and genetic risk factors in the etiology of externalizing behaviors in children. If granted, this award will allow Dr. Knopik a period of intensive training in molecular genetics, behavioral and physiological effects of nicotine, maternal and child psychopathology assessments, and epidemiology, which will include coursework, laboratory work, clinical exposure, and research under the sponsorship of Dr. Andrew Heath, a renowned behavioral geneticist, and Dr. Richard Todd, a renowned child psychiatrist with expertise in molecular genetics. In addition to the evidence for genetic effects on ADHD (Attention-Deficit Hyperactivity Disorder) and conduct problems, there is suggestive evidence for a role of maternal smoking during pregnancy in the risk of offspring externalizing behaviors. To develop a more comprehensive model for the etiology of externalizing behavior, one must consider the joint effects of genotype and prenatal environment. The overall goal of the research plan is to assess genotype and prenatal nicotine effects on childhood externalizing behaviors using a combination of secondary data analyses and new pilot data collection. Most studies that have focused on prenatal exposure to nicotine have implemented statistical control for other potential risk factors, but since the range of potential confounding factors is unknown, such between-mother controls are likely to be imperfect. Using an innovative within-mother comparison that focuses on externalizing disorder outcomes in offspring of mothers discordant for smoking during pregnancy (i.e., full sibling pairs discordant for prenatal nicotine exposure), the new pilot data collection can overcome many of the limitations of previous research. Dr. Knopik's long-term goal is to become an independent investigator with a program of research on prenatal substance exposure and its role in the etiology of externalizing behavior and associated learning and cognitive deficits, and to identify genes (both maternal and offspring) that may affect childhood outcomes of maternal substance use during pregnancy.

genetic susceptibility; smoking; family genetics; mental health epidemiology; embryo /fetus toxicology; attention deficit disorder; maternal behavior; gene environment interaction; psychopathology; health behavior; paternal behavior; driving while intoxicated; alcoholism /alcohol abuse; child psychology; siblings; early experience; nicotine; behavioral /social science research tag; clinical research; interview; human subject;

[unreadable] DESCRIPTION (provided by applicant): This re-revised new investigator R01 seeks funding to investigate the effects of prenatal tobacco exposure on offspring attention problems and associated learning and cognitive deficits. Maternal smoking during pregnancy (MSDP) is a major health concern associated with higher rates of a variety of poor child outcomes, including attention deficit hyperactivity disorder (ADHD); conduct disorder, impaired learning and memory, lowered IQ, and cognitive dysfunction. ADHD and many of these childhood outcomes are clinically significant conditions with clear public health implications and also are, in turn, substantial predictors of adolescent drug use problems. However, the evidence suggesting causal effects of MSDP for these childhood outcomes is muddied in the existing literature due to the frequent inability to separate these prenatal tobacco exposure effects from other confounding environmental and genetic factors. Specifically, the vast majority of prior studies provide only limited control for the fact that prenatal exposures may be correlated with parental behaviors that could also act as important risk factors that are in turn transmitted to their offspring. Failure to control for such (possibly heritable) confounding factors may account for a large part of the suggested associations between MSDP and offspring outcomes, resulting in biased effect sizes. Therefore, this application proposes to collect interview and comprehensive neuropsychological lab-based data from 400 families with at least 2 Missouri-born children (aged 8-15 at the time of testing), where the mother smoked during one pregnancy but not during another pregnancy by the same father (thus, with offspring who are full sibling pairs discordant for prenatal tobacco exposure). This within-mother, between-pregnancy contrast provides the best possible methodologic control for confounding factors, such as heritable and sociodemographic characteristics of the mother that predict increased probability of MSDP, as well as other differences between mothers who do and do not smoke during pregnancy (and their partners). Such confounding factors, if not controlled for, might otherwise artifactually create, or alternatively mask, an association between MSDP and child outcomes (of particular interest for this proposal: memory, executive function, language/reading, and ADHD). Such a design will therefore provide opportunities to accurately determine effect sizes while also allowing us to develop a cohort which, in the future, could be followed longitudinally through periods of increased externalizing symptoms and substance use initiation. PUBLIC HEALTH RELEVANCE: In two or three sentences, describe the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. Maternal smoking during pregnancy (MSDP) is a major public health concern with nearly half of all women who smoke continuing to do so throughout their pregnancies. As a result, more than half a million infants per year are prenatally exposed to maternal smoking. This genetically informed study on effects of prenatal exposure considers the potential confounding effects of differences between women who smoke and don't smoke during pregnancy. Findings could provide yet one more incentive for pregnant women to overcome tobacco dependence and quit, but findings can also guide treatment providers to think more comprehensively about smoking during pregnancy and the potential correlates of said behavior. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The examination of mechanisms by which genetic variability influences cannabis dependence and propensity to use marijuana is a high priority. However, there is a dearth of human studies on the identification of candidate phenotypes that serve as markers of cannabis dependence. The cannabinoid receptor type 1 (CB1), a G-coupled receptor encoded by the CNR1 gene, mediates the psychoactive effects and rewarding actions of marijuana (Ledent et al., 1999;Zhang et al., 2004). In addition, there is evidence that the fatty acid amidohydrolase (FAAH) gene may be an important candidate (Cravatt and Lichtman, 2003). Several polymorphisms in the CNR1 and one in the FAAH genes have been associated with cannabis dependence (Comings et al., 1997;Hopfer et al., 2006;Tyndale et al., 2007), cannabis-related intermediate phenotypes, including withdrawal and craving (Haughey et al, 2008), as well as positive subjective effects and physiological stimulation (Schacht et al., 2008). Despite previous suggestive findings, no studies have been conducted to date that test the association between CNR1 variability and key cannabis-related intermediate phenotypes related to sensitivity to the acute effects of cannabis, such as increased positive affect and reward sensitivity, decreased negative affect, and subjective stimulation and intoxication. Furthermore, it is largely unknown whether CNR1 or FAAH variation is associated with marijuana craving in non-abstinent users. The primary goal of this pilot research is to investigate variability in marijuana's acute and cue-elicited effects associated with empirically-chosen polymorphisms in the CNR1 and FAAH genes. In a 2 (genotype) X 2 (drug administration: marijuana with 2.8% delta-9-tetrahydrocannabinol (THC) vs. marijuana placebo;cue reactivity: neutral vs. marijuana cues) laboratory study, we will examine these effects in 80 Caucasian nontreatment- seeking heavy cannabis users. Genotyping of CNR1 and the FAAH genes will include empirically chosen candidate single nucleotide polymorphisms (SNPs) as well as tagSNPs. The long-term objective of this research is to identify genetic variation underlying individual differences in marijuana effects that may account for individual differences in susceptibility to marijuana dependence. Greater understanding of these mechanisms can inform genetically targeted pharmacotherapeutic approaches for treating cannabis dependence. PUBLIC HEALTH RELEVANCE: This research will help determine the reasons why some people who use marijuana may be at greater risk for abusing or becoming dependent on this drug. Examining individual differences in their genetic makeup will help uncover why some of these individuals may be more sensitive to marijuana's effects. This information could be of significant value to help identify people who would benefit from a particular treatment for marijuana.